トップ›研究者一覧›森野豊之

研究者を探す

研究者にアプローチする
更新情報を通知する

森野豊之

徳島大学

プロフィール
教育活動
研究活動
社会活動
リサーチマップ・
Jグローバル
KAKEN
注目研究

研究者総覧で最新データを確認する

2025年9月16日更新

職名: 教授
電話: 研究者総覧に該当データはありませんでした。
電子メール: morino@tokushima-u.ac.jp
学歴: 研究者総覧に該当データはありませんでした。
学位: 博士 / 博士(医学) (広島大学) (2000年2月)
職歴・経歴: 2021/6: 徳島大学教授, 大学院医歯薬学研究部

専門分野・研究分野: 遺伝学 (Genetics)

研究者総覧で最新データを確認する

2025年9月16日更新

専門分野・研究分野: 遺伝学 (Genetics)
担当経験のある授業科目: 先端医学 (学部)
公衆衛生学 (学部)
助産学特論Ⅱ(生命倫理学) (大学院)
医光インターンシップ (学部)
医学概論 (共通教育)
基礎医学 (学部)
基礎生物化学実験M (共通教育)
技術英語入門 (学部)
生体制御医学実験実習・臨床研究実習 (大学院)
研究室配属 (学部)
遺伝・公衆衛生 (学部)
遺伝学 (学部)
遺伝情報医学 (学部)
遺伝情報医学演習 (大学院)
指導経験: 研究者総覧に該当データはありませんでした。

研究者総覧で最新データを確認する

2025年9月16日更新

専門分野・研究分野: 遺伝学 (Genetics)

研究テーマ: 遺伝性疾患の原因遺伝子検索と病態解明 (遺伝学 (genetics), 神経変性 (neurodegeneration), ゲノム編集 (genome editing), 遺伝子工学 (genetic engineering), 遺伝子治療 (gene therapy))

著書

和泉唯信, 沖良祐, 森野豊之 :
第1部不随意運動第14章運動失調,
株式会社診断と治療社, 2025年6月. Hiroyuki Morino, Yukiko Matsuda and Hideshi Kawakami :
Channelopathies and Cerebellar Disease,
Jan. 2021.

(キーワード): Antisense oligonucleotide (ASO) / CACNA1A / CACNA1G / CACNB4 / CaV2.1 / CaV3.1 / Clustered regularly interspaced short palindromic repeat (CRISPR)/Cas system / EAAT1 / Episodic ataxia type 1 (EA1) / Episodic ataxia type 2 (EA2) / Episodic ataxia type 5 (EA5) / Episodic ataxia type 6 (EA6) / Excitatory amino acid transporter (EAAT) / Familial hemiplegic migraine type 1 (FHM1) / GluD2 / Glutamate receptor / GRID2 / GRM1 / ITPR1 / KCNA1 / KCNC3 / KCND3 / KV1.1 / KV3.3 / KV4.3 / mGluR1 / Oligonucleotide therapeutics / SLC1A3 / Spinocerebellar ataxia type 13 (SCA13) / Spinocerebellar ataxia type 15 (SCA15) / Spinocerebellar ataxia type 19 (SCA19) / Spinocerebellar ataxia type 29 (SCA29) / Spinocerebellar ataxia type 41 (SCA41) / Spinocerebellar ataxia type 42 (SCA42) / Spinocerebellar ataxia type 44 (SCA44) / Spinocerebellar ataxia type 6 (SCA6) / Spinocerebellar ataxia, autosomal recessive type 13 (SCAR13) / Spinocerebellar ataxia, autosomal recessive type 18 (SCAR18) / Transient receptor potential (TRP) channel / TRPC3 / Voltage-gated calcium channel / Voltage-gated potassium channel / Voltage-gated sodium channel
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/978-3-030-23810-0_113
(文献検索サイトへのリンク): ● Summary page in Scopus @ Elsevier: 2-s2.0-85153664271

(DOI: 10.1007/978-3-030-23810-0_113, Elsevier: Scopus) Juliane Eva Vollstedt, Meike Kasten, Christine Klein, Jan Aasly, Charles Adler, Azlina Ahmad-Annuar, Alberto Albanese, N. Roy Alcalay, Bashayer Al-Mubarak, Victoria Alvarez, Brennie Andree-Muñoz, Grazia Annesi, Silke Appel-Cresswell, David Arkadir, Sebastian Armasu, R. Thomas Barber, Soraya Bardien, Melinda Barkhuizen, J. Matthew Barrett, Nazlı A. Başak, Thomas Beach, A. Bruno Benitez, Daniela Berg, Kailash Bhatia, Ferdinand Binkofski, Cornelis Blauwendraat, Vincenzo Bonifati, Vanderci Borges, Maria Bozi, Alexis Brice, Laura Brighina, Kathrin Brockmann, Thomas Brücke, Norbert Brüggemann, Marta Camacho, Francisco Cardoso, Carmine Andrea Belin, Jonathan Carr, Piu Chan, Jorge Chang-Castello, Bruce Chase, Alice Chen-Plotkin, Sun Chung Ju, Roberto Cilia, Jordi Clarimon, Lorraine Clark, Mario Cornejo-Olivas, Christophe Jean Corvol, Carlos Cosentino, Patrick Cras, David Crosiers, Joana Damásio, Parimal Das, Patricia Carvalho Aguiar de, Giuseppe Michele De, Anna Rosa De, Elena Dieguez, Jolanta Dorszewska, Sevda Erer, Sibel Ertan, Matthew Farrer, Ekaterina Fedotova, Rosangela Ferese, Carlo Ferrarese, Henrique Ferraz, Ondrej Fiala, Tatiana Foroud, Andrzej Friedman, Roberta Frigerio, Manabu Funayama, Stefano Gambardella, Gaetan Garraux, M. Emilia Gatto, Gençer Genç, Nir Giladi, Stefano Goldwurm, Carlos Juan Gomez-Esteban, Pilar Gómez-Garre, Ana Gorostidi, Donald Grosset, Hasmet Hanagasi, John Hardy, Anhar Hassan, Nobutaka Hattori, A. Robert Hauser, Peter Hedera, Faycal Hentati, Michael Jens Hertz, L. Janice Holton, Henry Houlden, H. Mara Hutz, Takeshi Ikeuchi, Sergey Illarioshkin, Miguel Inca-Martinez, Jon Infante, Joseph Jankovic, Seok Beom Jeon, Silvia Jesús, Marlene Jimenez-Del-Rio, Valtteri Kaasinen, et al. and Hiroyuki Morino :
Using global team science to identify genetic parkinson's disease worldwide,
Jun. 2019.

(キーワード): Genetic Predisposition to Disease / Global Health / Humans / Interdisciplinary Research / Parkinson Disease
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/ana.25514
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31155756; ● Summary page in Scopus @ Elsevier: 2-s2.0-85068207273

(DOI: 10.1002/ana.25514, PubMed: 31155756, Elsevier: Scopus)

論文

Tomoyuki Iwata, Yoko Mizoguchi, Tetsuya Yoshimoto, Miyuki Tsumura, Fumiaki Sakura, R. Jeffrey Johnson, Shinji Matsuda, Kazuhisa Ouhara, Yukiko Nagatani, Takaki Asano, Hidenori Ohnishi, Zenichiro Kato, Keichiro Mihara, Hirokazu Kanegane, Tomoya Ueda, Shinya Sasaki, Yuri Taniguchi, Yurika Ninomiya, Yoshinori Ohno, Kyoko Suzuki-Takedachi, Yusuke Sotomaru, Tetsushi Sakuma, Takashi Yamamoto, Yukiko Matsuda, Kodai Kume, Terukazu Sanui, Fusanori Nishimura, Mikihito Kajiya, Yasuyoshi Ueki, Hidemi Kurihara, Hiroyuki Morino, Satoshi Okada, Hideshi Kawakami and Noriyoshi Mizuno :
Monoallelic mutations in MMD2 cause autosomal dominant aggressive periodontitis,
The Journal of Experimental Medicine, 222, 9, 2025.

(要約): Aggressive periodontitis causes rapid destruction of periodontal tissue. It occurs at a young age with familial clustering. We report on the first time on molecular and cellular basis of a Mendelian form of autosomal dominant aggressive periodontitis. Monoallelic mutations in the monocyte to macrophage differentiation-associated 2 (MMD2) gene, encoding MMD2, in two Japanese families with autosomal dominant aggressive periodontitis are identified. Mutations, c.347 C>T (p.A116V) and c.377 G>C (p.R126P) in MMD2, disturbed fMLP-induced activation of Ras/ERK signaling. Additionally, abnormalities in the proteins of Golgi apparatus, a crucial contributor to innate immune signaling pathways, were identified in patients' neutrophils. The knock-in and knockout mice exhibited alveolar bone loss by ligature-induced periodontitis, along with impaired fMLP-induced chemotaxis, as found in the patients with MMD2 mutation. Our studies revealed that monoallelic mutations in MMD2 underlie the impairment of neutrophil chemotaxis, which leads to the development of autosomal dominant aggressive periodontitis.
(キーワード): Humans / Animals / Aggressive Periodontitis / Neutrophils / Male / Mice / Mutation / Female / Alleles / Pedigree / Mice, Knockout / Adult / Genes, Dominant / Alveolar Bone Loss / Golgi Apparatus
(出版サイトへのリンク): ● Publication site (DOI): 10.1084/jem.20231911
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 40663042; ● Summary page in Scopus @ Elsevier: 2-s2.0-105011676674

(DOI: 10.1084/jem.20231911, PubMed: 40663042, Elsevier: Scopus) Yuta Eguchi, Yuki Kuwano, Satoshi Okada, Hiroyuki Morino and Kouichi Hashimoto :
Kcnq (Kv7) channels exhibit frequency-dependent responses via partial inductor-like gating dynamics,
Communications Biology, 8, 1, 866, 2025.

(要約): Kcnq channels are low-threshold voltage-dependent K⁺ channels that generate M-currents, which regulate the peri-threshold membrane potential. Kcnq channels reportedly participate in band-pass frequency responses (i.e., resonance), but it remains largely unclear how they contribute to generating resonance. We examined resonance in HEK293 cells expressing mouse Kcnq2 and Kcnq3 (Kcnq2/3) using whole-cell recording. Kcnq2/3-expressing cells generated resonance-like frequency-dependent responses. Kcnh7 channels displayed a rapid opposing conductance change followed by slow activation in response to a depolarizing voltage step, properties thought to be necessary for inductor-like activity. However, Kcnq2/3 channels exhibited only slow activation. The lack of an opposing conductance change was caused by the absence of rapid Kcnq2/3 channel inactivation. These data suggest that core ion channel characteristics that cause resonance-like frequency responses are not uniform among ion channels. The opposing conductance change is not necessary for resonance-like frequency responses but is crucial for fine frequency tuning and oscillation.
(キーワード): HEK293 Cells / Humans / Animals / Mice / Ion Channel Gating / KCNQ2 Potassium Channel / KCNQ3 Potassium Channel / Membrane Potentials / KCNQ Potassium Channels / Nerve Tissue Proteins
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/s42003-025-08302-6
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 40473867; ● Summary page in Scopus @ Elsevier: 2-s2.0-105007475503

(DOI: 10.1038/s42003-025-08302-6, PubMed: 40473867, Elsevier: Scopus) Kazuki Muguruma, Tetsuya Takahashi, Yuichiro Tagane, Keyoumu Nazere, Naoyuki Hara, Masahiro Nakamori, Yu Yamazaki, Hiroyuki Morino and Hirofumi Maruyama :
Intracellular anionic substances cause tau liquid-liquid phase separation.,
Biochemical and Biophysical Research Communications, 757, 2025.

(要約): Tau protein aggregation plays an important role in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease and Niemann-Pick disease type C. Liquid-liquid phase separation has emerged as a key mechanism in the early stages of protein aggregation for these disorders. Tau protein incubated with heparin undergoes liquid-liquid phase separation to form liquid droplets in vitro. However, whether tau liquid droplet formation occurs in vivo remains unresolved. To investigate cellular conditions that promote tau droplet formation, we treated tau-expressing human embryonic kidney 293T cells with reagents that introduced anionic substances or induced intracellular vesicle accumulation. Suppression of Niemann-Pick disease type C1 protein, a lysosomal membrane protein involved in mediating intracellular cholesterol trafficking, or the introduction of negatively charged dextran into cultured cells, increased the formation of tau-positive puncta with liquid droplet characteristics in a concentration-dependent manner. After prolonged observation, these puncta transitioned from a dynamic liquid state to a more solid-like gel phase, indicating progressive aggregation. Our findings suggest that intracellular enrichment of negatively charged substances or vesicles induces tau phase separation, potentially contributing to its pathological aggregation. These results provide insight into the molecular mechanisms underlying tauopathies and highlight potential targets for therapeutic intervention.
(キーワード): Humans / tau Proteins / HEK293 Cells / Anions / Protein Aggregation, Pathological / Heparin / Dextrans / 相転移 (phase transition) / 液-液相分離 (liquid-liquid phase separation)
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.bbrc.2025.151605
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 40107109; ● Search Scopus @ Elsevier (PMID): 40107109; ● Search Scopus @ Elsevier (DOI): 10.1016/j.bbrc.2025.151605

(DOI: 10.1016/j.bbrc.2025.151605, PubMed: 40107109) Tatsuo Itou, Koji Fujita, Yuumi Okuzono, Dnyaneshwar Warude, Shuuichi Miyakawa, Yoshimi Mihara, Naoko Matsui, Hiroyuki Morino, Yusuke Kikukawa and Yuishin Izumi :
Th17 and effector CD8 T cells relate to disease progression in amyotrophic lateral sclerosis: a case control study.,
Journal of Neuroinflammation, 21, 1, 2024.

(要約): naïve natural killer cells in patients with rapidly progressive ALS. Additionally, we employed serum proteomics through a proximity extension assay combined with next-generation sequencing to identify inflammation-related proteins associated with rapid disease progression. Among these proteins, interleukin-17 A correlated with the frequency of Th17, while killer cell lectin-like receptor D1 (CD94) correlated with the frequency of effector CD8 T cells. These findings further support the active roles played by these specific immune cell types in the progression of ALS.
(キーワード): Amyotrophic Lateral Sclerosis / Humans / Disease Progression / 女性 (female) / CD8-Positive T-Lymphocytes / Middle Aged / 男性 (male) / Th17 Cells / Case-Control Studies / Aged / 成人 (adult)
(出版サイトへのリンク): ● Publication site (DOI): 10.1186/s12974-024-03327-w
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 39731185; ● Search Scopus @ Elsevier (PMID): 39731185; ● Search Scopus @ Elsevier (DOI): 10.1186/s12974-024-03327-w

(DOI: 10.1186/s12974-024-03327-w, PubMed: 39731185) Yusuke Osaki, Hiroyuki Nodera, Ryota Sato, Shotaro Haji, Koji Fujita, Ryosuke Miyamoto, Kohei Muto, Hiroki Yamazaki, Hiroyuki Morino, Takashi Kanda, Shigeo Murayama, Ryuji Kaji and Yuishin Izumi :
Peripheral nerve excitability abnormalities in Neuronal Intranuclear Inclusion Disease: Assessment with histopathological analysis,
Clinical Neurophysiology, 170, 156-167, 2024.

(要約): Neuronal Intranuclear Inclusion Disease (NIID) is a neurodegenerative disease affecting the central and peripheral nerves. We aimed to assess the pathophysiological features of peripheral nerve dysfunction in NIID. We observed six unrelated NIID patients through clinical records, nerve conduction studies, and multiple measures of motor nerve excitability. Additionally, we reviewed one NIID patientt who underwent a nerve biopsy. Control measures were obtained from 22 age-matched normal subjects. The NIID patients exhibited mild conduction slowing and distinct nerve excitability abnormalities, including a significant decrease in excitability through hyperpolarizing threshold electrotonus (TE) and increased overshoots in both depolarizing and hyperpolarizing conditions. Histopathology revealed thinly myelinated fibers and axonal degeneration. Mathematical modeling suggested that reduced leak conductance was the key factor contributing to the observed excitability changes. The findings indicate that NIID involves a complex interplay of axonal degeneration and myelin dysfunction, leading to unique peripheral nerve excitability changes. These results provide new insights into the pathophysiology of NIID. Nerve excitability testing offers insight into particular axonal excitability abnormalities especially combined with histopathologic studies.
(キーワード): Axonal excitability / Myelin dysfunction / Neurodegenerative disorders / Neuronal intranuclear inclusion disease / Threshold tracking
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.clinph.2024.12.013
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 39724790; ● Summary page in Scopus @ Elsevier: 2-s2.0-85213072049

(DOI: 10.1016/j.clinph.2024.12.013, PubMed: 39724790, Elsevier: Scopus) Shusuke Yagi, Ryosuke Miyamoto, Masayoshi Tasaki, Hiroyuki Morino, Ryuji Otani, Muneyuki Kadota, Takayuki Ise, Hiroki Yamazaki, Kenya Kusunose, Koji Yamaguchi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Daiju Fukuda, Mitsuharu Ueda and Masataka Sata :
The APOA1 p.Leu202Arg variant potentially causes autosomal recessive cardiac amyloidosis.,
Human Genome Variation, 11, 1, 2024.

(要約): ApoA-I amyloidosis is an extremely rare form of systemic amyloidosis that commonly involves the heart, kidneys, and liver. ApoA-I amyloidosis is caused by amyloidogenic variants of APOA1 that are inherited in an autosomal dominant manner. Here, we report a 69-year-old man with sporadic cardiac amyloidosis who was born to consanguineous parents and carried a homozygous variant of p.Leu202Arg in APOA1.
(徳島大学機関リポジトリ): ● Metadata: 2012255
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/s41439-024-00288-7
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 39152105; ● Summary page in Scopus @ Elsevier: 2-s2.0-85201547622

(徳島大学機関リポジトリ: 2012255, DOI: 10.1038/s41439-024-00288-7, PubMed: 39152105, Elsevier: Scopus) Kenta Hanada, Yusuke Osaki, Ryosuke Miyamoto, Kohei Muto, Shotaro Haji, Keyoumu Nazere, Yuki Kuwano, Hiroyuki Morino, Yoshiteru Azuma, Satoko Miyatake, Naomichi Matsumoto and Yuishin Izumi :
Intermediate phenotype between CMT2Z and DIGFAN associated with a novel MORC2 variant: a case report.,
Human Genome Variation, 11, 1, 29, 2024.

(要約): Charcot-Marie-Tooth disease type 2Z is caused by MORC2 mutations and presents with axonal neuropathy. MORC2 mutations can also manifest as developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (DIGFAN). We report a patient exhibiting an intermediate phenotype between these diseases associated with a novel MORC2 variant. A literature review revealed that the genotype‒phenotype correlation in MORC2-related disorders is complex and that the same mutation can cause a variety of phenotypes.
(徳島大学機関リポジトリ): ● Metadata: 2012806
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/s41439-024-00287-8
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 39143067; ● Search Scopus @ Elsevier (PMID): 39143067; ● Search Scopus @ Elsevier (DOI): 10.1038/s41439-024-00287-8

(徳島大学機関リポジトリ: 2012806, DOI: 10.1038/s41439-024-00287-8, PubMed: 39143067) Shusuke Yagi, Muneyuki Kadota, Ryo Bando, Ryosuke Miyamoto, Hiroyuki Morino, Akiyoshi Kakutani, Yoshiaki Kubo, Takayuki Ise, Rie Ueno, Tomoya Hara, Kenya Kusunose, Koji Yamaguchi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Daiju Fukuda and Masataka Sata :
Pulmonary Arterial Hypertension in Neurofibromatosis Type 1: A Case with a Novel NF1 Gene Mutation,
Internal Medicine, 64, 5, 725-728, 2024.

(要約): Neurofibromatosis type 1 (NF1) is an autosomal dominant multi-organ disease. The clinical manifestations include not only skin lesions and malignant tumors but also lung complications, including pulmonary arterial hypertension (PAH). However, the association between gene mutations in NF1 and the occurrence of PAH has not yet been elucidated. We herein report a case of isolated PAH in a 67-year-old woman with NF1, presumably caused by a novel heterozygous mutation, c.4485_4486delinsAT (p.Lys1496Ter), in the NF1 gene.
(キーワード): neurofibromatosis type 1 / pulmonary arterial hypertension / von Recklinghausen disease
(出版サイトへのリンク): ● Publication site (DOI): 10.2169/internalmedicine.3856-24
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38987187; ● Summary page in Scopus @ Elsevier: 2-s2.0-85219683856

(DOI: 10.2169/internalmedicine.3856-24, PubMed: 38987187, Elsevier: Scopus) Satoko Miyatake, Hiroshi Doi, Hiroaki Yaguchi, Eriko Koshimizu, Naoki Kihara, Tomoyasu Matsubara, Yasuko Mori, Kenjiro Kunieda, Yusaku Shimizu, Tomoko Toyota, Shinichi Shirai, Masaaki Matsushima, Masaki Okubo, Taishi Wada, Misako Kunii, Ken Johkura, Ryosuke Miyamoto, Yusuke Osaki, Takabumi Miyama, Mai Satoh, Atsushi Fujita, Yuri Uchiyama, Naomi Tsuchida, Kazuharu Misawa, Kohei Hamanaka, Haruka Hamanoue, Takeshi Mizuguchi, Hiroyuki Morino, Yuishin Izumi, Takayoshi Shimohata, Kunihiro Yoshida, Hiroaki Adachi, Fumiaki Tanaka, Ichiro Yabe and Naomichi Matsumoto :
Complete nanopore repeat sequencing of SCA27B (GAA-FGF14 ataxia) in Japanese.,
Journal of Neurology, Neurosurgery, and Psychiatry, 95, 12, 1187-1195, 2024.

(出版サイトへのリンク): ● Publication site (DOI): 10.1136/jnnp-2024-333541
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38816190; ● Search Scopus @ Elsevier (PMID): 38816190; ● Search Scopus @ Elsevier (DOI): 10.1136/jnnp-2024-333541

(DOI: 10.1136/jnnp-2024-333541, PubMed: 38816190) Takafumi Tomenaga, Shinobu Minatani, Hiroto Namba, Akitoshi Takeda, Takahito Yoshizaki, Joji Kawabe, Keyoumu Nazere, Hiroyuki Morino, Makoto Higuchi, Tomoyasu Matsubara, Hiroyuki Hatsuta, Masato Hasegawa, Shigeo Murayama and Yoshiaki Itoh :
An autopsy case of type A FTLD-TDP with a GRN mutation presenting with the logopenic variant of primary progressive aphasia at onset and with corticobasal syndrome subsequently.,
Neuropathology, 2024.

(要約): A 68-year-old woman presented with difficulty finding words and writing characters. Neurological examination led to clinical diagnosis at onset of the logopenic variant of primary progressive aphasia accompanied with ideomotor apraxia, visuospatial agnosia on the right, and Gerstmann syndrome. Bradykinesia and rigidity on the right with shuffling gait developed after one year. Treatment with L-dopa had no effect. The patient was diagnosed with corticobasal syndrome (CBS). Brain magnetic resonance imaging revealed diffuse cortical atrophy dominantly on the left, especially in the temporal, parietal, and occipital lobes. Positron emission tomography did not reveal any significant accumulation of amyloid β or tau protein. She died five years later. Neuropathological examination revealed diffuse cortical atrophy with severe neuronal loss and fibrous gliosis in the cortex. Neuronal cytoplasmic inclusions, short dystrophic neurites, and, most notably, neuronal intranuclear inclusions, all immunoreactive for phosphorylated TDP-43, were observed. Western blotting revealed a full length and fragments of phosphorylated TDP-43 at 45 and 23kDa, respectively, confirming the pathological diagnosis of type A FTLD-TDP. Whole exome sequencing revealed a pathogenic mutation in GRN (c.87dupC). FTLD-TDP should be included in the differential diagnosis of CBS.
(出版サイトへのリンク): ● Publication site (DOI): 10.1111/neup.12980
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38715398; ● Search Scopus @ Elsevier (PMID): 38715398; ● Search Scopus @ Elsevier (DOI): 10.1111/neup.12980

(DOI: 10.1111/neup.12980, PubMed: 38715398) Hiroyuki Morino, Takashi Kurashige, Yukiko Matsuda, Maiko Ono, Naruhiko Sahara, Tomohiro Miyasaka, Yoshiyuki Soeda, Hitoshi Shimada, Yu Yamazaki, Tetsuya Takahashi, Yuishin Izumi, Hidefumi Ito, Hirofumi Maruyama, Makoto Higuchi, Koji Arihiro, Tetsuya Suhara, Akihiko Takashima and Hideshi Kawakami :
Clinical and Pathological Features of FTDP-17 with MAPT p.K298_H299insQ Mutation.,
Movement Disorders Clinical Practice, 2024.

(要約): This study confirmed that the insACA mutation caused FTDP-17. The affected patients showed symptoms resembling Parkinson's disease initially and symptoms of progressive supranuclear palsy later. Despite the initial clinical diagnosis of frontotemporal dementia in the autopsy case, the spread of lesions could explain the process of progressive supranuclear palsy. The study of more cases in the future will help clarify the common pathogenesis of MAPT mutations or specific pathogeneses of each mutation.
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/mdc3.14042
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38605589; ● Search Scopus @ Elsevier (PMID): 38605589; ● Search Scopus @ Elsevier (DOI): 10.1002/mdc3.14042

(DOI: 10.1002/mdc3.14042, PubMed: 38605589) Mizuho Kittaka, Noriyoshi Mizuno, Hiroyuki Morino, Tetsuya Yoshimoto, Tianli Zhu, Sheng Liu, Ziyi Wang, Kotoe Mayahara, Kyohei Iio, Kaori Kondo, Toshio Kondo, Tatsuhide Hayashi, Sarah Coghlan, Yayoi Teno, Phung Andrew Anh Doan, Marcus Levitan, B Roy Choi, Shinji Matsuda, Kazuhisa Ouhara, Jun Wan, M Annelise Cassidy, Stephane Pelletier, Sheela Nampoothiri, J Andoni Urtizberea, G Alexander Robling, Mitsuaki Ono, Hideshi Kawakami, J Ernst Reichenberger and Yasuyoshi Ueki :
Loss-of-function OGFRL1 variants identified in autosomal recessive cherubism families.,
JBMR Plus, 8, 6, 2024.

(要約): Cherubism (OMIM 118400) is a rare craniofacial disorder in children characterized by destructive jawbone expansion due to the growth of inflammatory fibrous lesions. Our previous studies have shown that gain-of-function mutations in SH3 domain-binding protein 2 (SH3BP2) are responsible for cherubism and that a knock-in mouse model for cherubism recapitulates the features of cherubism, such as increased osteoclast formation and jawbone destruction. To date, SH3BP2 is the only gene identified to be responsible for cherubism. Since not all patients clinically diagnosed with cherubism had mutations in SH3BP2, we hypothesized that there may be novel cherubism genes and that these genes may play a role in jawbone homeostasis. Here, using whole exome sequencing, we identified homozygous loss-of-function variants in the opioid growth factor receptor like 1 (OGFRL1) gene in 2 independent autosomal recessive cherubism families from Syria and India. The newly identified pathogenic homozygous variants were not reported in any variant databases, suggesting that OGFRL1 is a novel gene responsible for cherubism. Single cell analysis of mouse jawbone tissue revealed that Ogfrl1 is highly expressed in myeloid lineage cells. We generated OGFRL1 knockout mice and mice carrying the Syrian frameshift mutation to understand the in vivo role of OGFRL1. However, neither mouse model recapitulated human cherubism or the phenotypes exhibited by SH3BP2 cherubism mice under physiological and periodontitis conditions. Unlike bone marrow-derived M-CSF-dependent macrophages (BMMs) carrying the SH3BP2 cherubism mutation, BMMs lacking OGFRL1 or carrying the Syrian mutation showed no difference in TNF- mRNA induction by LPS or TNF- compared to WT BMMs. Osteoclast formation induced by RANKL was also comparable. These results suggest that the loss-of-function effects of OGFRL1 in humans differ from those in mice and highlight the fact that mice are not always an ideal model for studying rare craniofacial bone disorders.
(徳島大学機関リポジトリ): ● Metadata: 2000078
(出版サイトへのリンク): ● Publication site (DOI): 10.1093/jbmrpl/ziae050
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38699440; ● Search Scopus @ Elsevier (PMID): 38699440; ● Search Scopus @ Elsevier (DOI): 10.1093/jbmrpl/ziae050

(徳島大学機関リポジトリ: 2000078, DOI: 10.1093/jbmrpl/ziae050, PubMed: 38699440) Hidetada Yamada, Yu Yamazaki, Yoshiko Takebayashi, Kyosuke Yazawa, Miwako Sasanishi, Atsuko Motoda, Masahiro Nakamori, Hiroyuki Morino, Tetsuya Takahashi and Hirofumi Maruyama :
The long-term effects of heated tobacco product exposure on the central nervous system in a mouse model of prodromal Alzheimer's disease.,
Scientific Reports, 14, 1, 2024.

(要約): Heated tobacco products (HTPs) have emerged as novel alternatives to conventional cigarettes (CCs), marketed by the tobacco industry as having a reduced potential for harm. Nevertheless, a significant dearth of information remains regarding the long-term effects of HTPs on the central nervous system (CNS). Here, we sought to shed light on the repercussions of prolonged exposure to HTPs on the CNS, employing a mouse model mimicking prodromal Alzheimer's disease (AD). Our study entailed subjecting App knock-in mice to 16 weeks of HTP exposure, administered 5 days per week, with serum cotinine concentration serving as confirmation of HTP exposure within this model. Histological analysis, aimed at assessing amyloid pathology, unveiled a minimal impact attributable to HTPs. However, exploration of differentially expressed genes in the cerebral cortex, using unadjusted p values, indicated an association between HTP exposure and non-inflammatory pathways, specifically linked to neurohypophyseal and neuropeptide hormone activity within the CNS. Of note, similar results have already been observed after exposure to CCs in vivo. Our study not only contributes insights into the potential non-inflammatory effects of HTPs within the context of AD pathogenesis but also underscores the significance of continued research to comprehend the full scope of their impact on the CNS.
(キーワード): Animals / Mice / Alzheimer Disease / Central Nervous System / Disease Models, Animal / Amyloidogenic Proteins / Tobacco Products / Electronic Nicotine Delivery Systems
(徳島大学機関リポジトリ): ● Metadata: 2012138
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/s41598-023-50941-4
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38167640; ● Search Scopus @ Elsevier (PMID): 38167640; ● Search Scopus @ Elsevier (DOI): 10.1038/s41598-023-50941-4

(徳島大学機関リポジトリ: 2012138, DOI: 10.1038/s41598-023-50941-4, PubMed: 38167640) 和泉唯信, 松原知康, 山﨑博輝, 森野豊之 :
筋萎縮性側索硬化症の核酸医薬,
脳神経内科, 101, 2, 164-169, 2024年.

(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1520020132118024448

(CiNii: 1520020132118024448) 行重佐和香, 井上寛章, 乾友浩, 笹聡一郎, 青山万理子, 後藤正和, 森野豊之, 吉田友紀子, 宮本容子, 滝沢宏光 :
BRCA遺伝学的検査の結果inconclusiveとなった3例,
遺伝性腫瘍, 24, 2, 147-152, 2024年. Mai Kikumoto, Takashi Kurashige, Tomohiko Ohshita, Kodai Kume, Osamu Kikumoto, Tomohisa Nezu, Shiro Aoki, Kazuhide Ochi, Hiroyuki Morino, Eiichi Nomura, Hiroshi Yamashita, Mayumi Kaneko, Hirofumi Maruyama and Hideshi Kawakami :
'Raisin bread sign' feature of pontine autosomal dominant microangiopathy and leukoencephalopathy.,
Brain Communications, 5, 6, fcad281, 2023.

(要約): 3'UTR was observed in two patients with familial small vessel disease and the two selected patients, thereby confirming the pontine autosomal dominant microangiopathy and leukoencephalopathy diagnosis. Furthermore, postmortem examination showed that the distribution of thickened media tunica and hyalinized vessels was different from that in lacunar infarctions. The appearance of characteristic multiple oval small infarctions in the pons, which resemble raisin bread, enable us to make a diagnosis of pontine autosomal dominant microangiopathy and leukoencephalopathy. This feature, for which we coined the name 'raisin bread sign', was also correlated to the pathological changes.
(徳島大学機関リポジトリ): ● Metadata: 2000130
(出版サイトへのリンク): ● Publication site (DOI): 10.1093/braincomms/fcad281
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37953842; ● Search Scopus @ Elsevier (PMID): 37953842; ● Search Scopus @ Elsevier (DOI): 10.1093/braincomms/fcad281

(徳島大学機関リポジトリ: 2000130, DOI: 10.1093/braincomms/fcad281, PubMed: 37953842) Yoshiko Takebayashi, Yu Yamazaki, Hidetada Yamada, Kyosuke Yazawa, Masahiro Nakamori, Takashi Kurashige, Hiroyuki Morino, Tetsuya Takahashi, Yusuke Sotomaru and Hirofumi Maruyama :
Apolipoprotein E genotype-dependent accumulation of amyloid β in APP-knock-in mouse model of Alzheimer's disease.,
Biochemical and Biophysical Research Communications, 683, 2023.

(要約): mice) crossed with human APOE-KI mice. Immunohistochemical and biochemical analyses revealed the APOE genotype-dependent increase in Aβ pathology and glial activation, which was evident within 8 months in the mouse model. These results suggested that this mouse model may be valuable for investigating APOE pathobiology within a reasonable experimental time frame. Thus, this model can be considered in investigating the interaction between APOE and Aβ in vivo, which may not be addressed appropriately by using other transgenic mouse models.
(キーワード): Mice / Humans / Animals / Alzheimer Disease / Amyloid beta-Peptides / Amyloid beta-Protein Precursor / Apolipoproteins E / Mice, Transgenic / Apolipoprotein E3 / Genotype / Disease Models, Animal
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.bbrc.2023.10.038
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37857162; ● Summary page in Scopus @ Elsevier: 2-s2.0-85174140587

(DOI: 10.1016/j.bbrc.2023.10.038, PubMed: 37857162, Elsevier: Scopus) Kodai Kume, Takashi Kurashige, Keiko Muguruma, Hiroyuki Morino, Yui Tada, Mai Kikumoto, Tatsuo Miyamoto, Natsuko Silvia Akutsu, Yukiko Matsuda, Shinya Matsuura, Masahiro Nakamori, Ayumi Nishiyama, Rumiko Izumi, Tetsuya Niihori, Masashi Ogasawara, Nobuyuki Eura, Tamaki Kato, Mamoru Yokomura, Yoshiaki Nakayama, Hidefumi Ito, Masataka Nakamura, Kayoko Saito, Yuichi Riku, Yasushi Iwasaki, Hirofumi Maruyama, Yoko Aoki, Ichizo Nishino, Yuishin Izumi, Masashi Aoki and Hideshi Kawakami :
CGG repeat expansion in LRP12 in amyotrophic lateral sclerosis.,
American Journal of Human Genetics, 110, 7, 1086-1097, 2023.

(要約): Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons. Although repeat expansion in C9orf72 is its most common cause, the pathogenesis of ALS isn't fully clear. In this study, we show that repeat expansion in LRP12, a causative variant of oculopharyngodistal myopathy type 1 (OPDM1), is a cause of ALS. We identify CGG repeat expansion in LRP12 in five families and two simplex individuals. These ALS individuals (LRP12-ALS) have 61-100 repeats, which contrasts with most OPDM individuals with repeat expansion in LRP12 (LRP12-OPDM), who have 100-200 repeats. Phosphorylated TDP-43 is present in the cytoplasm of iPS cell-derived motor neurons (iPSMNs) in LRP12-ALS, a finding that reproduces the pathological hallmark of ALS. RNA foci are more prominent in muscle and iPSMNs in LRP12-ALS than in LRP12-OPDM. Muscleblind-like 1 aggregates are observed only in OPDM muscle. In conclusion, CGG repeat expansions in LRP12 cause ALS and OPDM, depending on the length of the repeat. Our findings provide insight into the repeat length-dependent switching of phenotypes.
(キーワード): 神経変性 (neurodegeneration) / 遺伝学 (genetics) / 神経系 (nervous system) / 遺伝子疾患 (gene disorders) / 神経科学 (neuroscience)
(徳島大学機関リポジトリ): ● Metadata: 2011923
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ajhg.2023.05.014
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37339631; ● Summary page in Scopus @ Elsevier: 2-s2.0-85164273883

(徳島大学機関リポジトリ: 2011923, DOI: 10.1016/j.ajhg.2023.05.014, PubMed: 37339631, Elsevier: Scopus) Shotaro Haji, Ryosuke Miyamoto, Hiroyuki Morino, Yusuke Osaki, Seijiro Tsuji, Ichizo Nishino, Masahiro Abe and Yuishin Izumi :
Autosomal Recessive Spinocerebellar Ataxia Type 9 With a Response to Phosphate Repletion: A Case Report.,
Neurology. Genetics, 9, 3, e200070, 2023.

(要約): This provides Class IV evidence. This is a single observational study without controls.
(出版サイトへのリンク): ● Publication site (DOI): 10.1212/NXG.0000000000200070
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37529414; ● Search Scopus @ Elsevier (PMID): 37529414; ● Search Scopus @ Elsevier (DOI): 10.1212/NXG.0000000000200070

(DOI: 10.1212/NXG.0000000000200070, PubMed: 37529414) Shotaro Haji, Koji Fujita, Ryosuke Oki, Yusuke Osaki, Ryosuke Miyamoto, Hiroyuki Morino, Seiichi Nagano, Naoki Atsuta, Yuki Kanazawa, Yuki Matsumoto, Atsuko Arisawa, Hisashi Kawai, Yasutaka Sato, Satoshi Sakaguchi, Kenta Yagi, Tatsuto Hamatani, Tatsuo Kagimura, Hiroaki Yanagawa, Hideki Mochizuki, Manabu Doyu, Gen Sobue, Masafumi Harada and Yuishin Izumi :
An Exploratory Trial of EPI-589 in Amyotrophic Lateral Sclerosis (EPIC-ALS): Protocol for a Multicenter, Open-Labeled, 24-Week, Single-Group Study,
JMIR Research Protocols, 12, e42032, 2023.

(要約): Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, with its currently approved drugs, including riluzole and edaravone, showing limited therapeutic effects. Therefore, safe and effective drugs are urgently necessary. EPI-589 is an orally available, small-molecule, novel redox-active agent characterized by highly potent protective effects against oxidative stress with high blood-brain barrier permeability. Given the apparent oxidative stress and mitochondrial dysfunction involvement in the pathogenesis of ALS, EPI-589 may hold promise as a therapeutic agent. This protocol aims to describe the design and rationale for the EPI-589 Early Phase 2 Investigator-Initiated Clinical Trial for ALS (EPIC-ALS). EPIC-ALS is an explorative, open-labeled, single-arm trial that evaluates the safety and tolerability of EPI-589 in patients with ALS. This trial consists of 12-week run-in, 24-week treatment, and 4-week follow-up periods. Patients will receive 500 mg of EPI-589 3 times daily over the 24-week treatment period. Clinical assessments include the mean monthly change of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised total score. The biomarkers are selected to analyze the effect on oxidative stress and neuronal damage. The plasma biomarkers are 8-hydroxy-2'-deoxyguanosine (8-OHdG), 3-nitrotyrosine (3-NT), neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), homocysteine, and creatinine. The cerebrospinal fluid biomarkers are 8-OHdG, 3-NT, NfL, pNfH, and ornithine. The magnetic resonance biomarkers are fractional anisotropy in the corticospinal tract and N-acetylaspartate in the primary motor area. This trial began data collection in September 2021 and is expected to be completed in October 2023. This study can provide useful data to understand the characteristics of EPI-589. Japan Primary Registries Network jRCT2061210031; tinyurl.com/2p84emu6. DERR1-10.2196/42032.
(徳島大学機関リポジトリ): ● Metadata: 2011601
(出版サイトへのリンク): ● Publication site (DOI): 10.2196/42032
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 36716091; ● Summary page in Scopus @ Elsevier: 2-s2.0-85149143248

(徳島大学機関リポジトリ: 2011601, DOI: 10.2196/42032, PubMed: 36716091, Elsevier: Scopus) Hidetada Yamada, Shuichiro Neshige, Hiroyuki Morino and Hirofumi Maruyama :
Extubation failure due to atypical parkinsonism with negligible motor and variable non-motor symptoms associated with a variant of DCTN1.,
Internal and Emergency Medicine, 2022.

(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s11739-022-03105-7
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 36504048; ● Search Scopus @ Elsevier (PMID): 36504048; ● Search Scopus @ Elsevier (DOI): 10.1007/s11739-022-03105-7

(DOI: 10.1007/s11739-022-03105-7, PubMed: 36504048) Hidetada Yamada, Masahiro Nakamori, Junichiro Kuga, Akemi Hironaka, Takamichi Sugimoto, Hiroki Ueno, Tomohiko Ohshita, Hiroyuki Morino and Hirofumi Maruyama :
Nerve Ultrasonography for the Diagnosis and Evaluation of Neuralgic Amyotrophy: A Case Report.,
Internal Medicine, 2022.

(要約): Neuralgic amyotrophy (NA) is a peripheral nervous system disorder involving multifocal distribution. Although nerve ultrasonography has shown potential for detecting NA lesions, no established detection method exists for distal forearm NA. A 59-year-old man presented with weakness of the muscles innervated by the left posterior interosseous nerve (PIN), median nerve (MN), anterior interosseous nerve (AIN), and ulnar nerve (UN), following severe left shoulder pain. This case suggests that nerve ultrasonography can help accurately diagnose distal forearm NA.
(出版サイトへのリンク): ● Publication site (DOI): 10.2169/internalmedicine.0005-22
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 36351573; ● Search Scopus @ Elsevier (PMID): 36351573; ● Search Scopus @ Elsevier (DOI): 10.2169/internalmedicine.0005-22

(DOI: 10.2169/internalmedicine.0005-22, PubMed: 36351573) Takashi Kurashige, Hiroyuki Morino, Hiroki Ueno, Tomomi Murao, Tomoaki Watanabe, Takao Hinoi, Ichizo Nishino, Tsuyoshi Torii and Hirofumi Maruyama :
Gastrointestinal cancer occurs as extramuscular manifestation in FSHD1 patients.,
Journal of Human Genetics, 2022.

(要約): Facioscapulohumeral dystrophy type1 (FSHD1) patients with a shortened D4Z4 repeat containing the DUX4 gene have a broad spectrum of clinical manifestations. In addition, high expression of DUX4 protein with an aberrant C terminus is frequently identified in B cell acute lymphoblastic leukemia. We investigated clinical manifestations in 31 FSHD1 patients and 30 non-affected individuals. Gastrointestinal cancers (gastric and colorectal cancers) increased after the age of 40 years and were more frequently observed in FSHD1 patients (n = 10) than in non-affected individuals (n = 2, p = 0.0217), though the incidence of cancers occurring in non-gastrointestinal tissues of FSHD1 patients was the same as that of non-affected individuals (p > 0.999). These comorbidities of FSHD1 patients were not associated with D4Z4 repeat number. Our results suggest that gastrointestinal cancers are among the extramuscular manifestations of adult FSHD1 patients, and do not depend on D4Z4 repeat number.
(徳島大学機関リポジトリ): ● Metadata: 2010846
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/s10038-022-01095-0
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 36336708; ● Search Scopus @ Elsevier (PMID): 36336708; ● Search Scopus @ Elsevier (DOI): 10.1038/s10038-022-01095-0

(徳島大学機関リポジトリ: 2010846, DOI: 10.1038/s10038-022-01095-0, PubMed: 36336708) Takashi Kurashige, Hiroyuki Morino, Tomomi Murao, Yuishin Izumi, Tomohito Sugiura, Kazuya Kuraoka, Hideshi Kawakami, Tsuyoshi Torii and Hirofumi Maruyama :
TDP-43 Accumulation Within Intramuscular Nerve Bundles of Patients With Amyotrophic Lateral Sclerosis.,
JAMA Neurology, 79, 7, 693-701, 2022.

(要約): Results of this dual case-control and retrospective cohort study suggest that axonal pTDP-43 accumulations may be characteristic for patients with ALS. As such findings precede clinical fulfillment of the Gold Coast criteria, TDP-43 in nerve bundles may be a novel diagnostic biomarker for ALS.
(キーワード): Aged / Amyotrophic Lateral Sclerosis / Case-Control Studies / Cohort Studies / DNA-Binding Proteins / Humans / Male / Middle Aged / Retrospective Studies
(出版サイトへのリンク): ● Publication site (DOI): 10.1001/jamaneurol.2022.1113
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 35604654; ● Search Scopus @ Elsevier (PMID): 35604654; ● Search Scopus @ Elsevier (DOI): 10.1001/jamaneurol.2022.1113

(DOI: 10.1001/jamaneurol.2022.1113, PubMed: 35604654) Rieko Kanzaki, Hiroyuki Morino, Keiko Mukaida, Kodai Kume, Ryosuke Ohsawa, Yuko Noda, Sachiko Otsuki, Hirotsugu Miyoshi, Takashi Kondo, Ryuji Nakamura, Masashi Kawamoto, Hideshi Kawakami and Yasuo Tsutsumi :
Genetic screening for malignant hyperthermia and comparison of clinical symptoms in Japan,
Hiroshima Journal of Medical Sciences, 71, 1-2, 31-38, 2022.

(キーワード): CACNA1S / Malignant hyperthermia / Next Generation Sequencing / RYR1
(出版サイトへのリンク): ● Publication site (DOI): 10.24811/hjms.71.1-2_31
(文献検索サイトへのリンク): ● Summary page in Scopus @ Elsevier: 2-s2.0-85146288537

(DOI: 10.24811/hjms.71.1-2_31, Elsevier: Scopus) Keyoumu Nazere, Tetsuya Takahashi, Naoyuki Hara, Kazuki Muguruma, Masahiro Nakamori, Yu Yamazaki, Hiroyuki Morino and Hirofumi Maruyama :
Amyloid Beta Is Internalized via Macropinocytosis, an HSPG- and Lipid Raft-Dependent and Rac1-Mediated Process,
Frontiers in Molecular Neuroscience, 15, 2022.

(徳島大学機関リポジトリ): ● Metadata: 2010532
(出版サイトへのリンク): ● Publication site (DOI): 10.3389/fnmol.2022.804702
(文献検索サイトへのリンク): ● Summary page in Scopus @ Elsevier: 2-s2.0-85125185487

(徳島大学機関リポジトリ: 2010532, DOI: 10.3389/fnmol.2022.804702, Elsevier: Scopus) Kenichi Ishikawa, Mutsuko Araki, Yoshito Nagano, Atsuko Motoda, Takeo Shishido, Takashi Kurashige, Tetsuya Takahashi, Hiroyuki Morino, Hideshi Kawakami, Masayasu Matsumoto and Hirofumi Maruyama :
Knockdown of optineurin controls C2C12 myoblast differentiation via regulating myogenin and MyoD expressions.,
Differentiation; Research in Biological Diversity, 123, 1-8, 2021.

(要約): Mutations in optineurin (OPTN) have been identified in a small proportion of sporadic and familial amyotrophic lateral sclerosis (ALS) cases. Recent evidences suggest that OPTN would be involved in not only the pathophysiological mechanisms of motor neuron death of ALS but also myofiber degeneration of sporadic inclusion body myositis. However, the detailed role of OPTN in muscle remains unclear. Initially, we showed that OPTN expression levels were significantly increased in the denervated muscles of mice, suggesting that OPTN may be involved in muscle homeostasis. To reveal the molecular role of OPTN in muscle atrophy, we used cultured C2C12 myotubes treated with tumor necrosis factor-like inducer of apoptosis (TWEAK) as an in vitro model of muscle atrophy. Our data showed that OPTN had no effect on the process of muscle atrophy in this model. On the other hand, we found that myogenic differentiation was affected by OPTN. Immunoblotting analysis showed that OPTN protein levels gradually decreased during C2C12 differentiation. Furthermore, OPTN knockdown inhibited C2C12 differentiation, accompanied by reduction of mRNA and protein expression levels of myogenin and MyoD. These findings suggested that OPTN may have a novel function in muscle homeostasis and play a role in the pathogenesis of neuromuscular diseases.
(キーワード): Animals / Cell Cycle Proteins / Cell Differentiation / Membrane Transport Proteins / Mice / Muscular Atrophy / MyoD Protein / Myoblasts / Myogenin / Transcription Factor TFIIIA
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.diff.2021.11.004
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34844057; ● Search Scopus @ Elsevier (PMID): 34844057; ● Search Scopus @ Elsevier (DOI): 10.1016/j.diff.2021.11.004

(DOI: 10.1016/j.diff.2021.11.004, PubMed: 34844057) Megumi Toko, Tomohiko Ohshita, Takashi Kurashige, Hiroyuki Morino, Kodai Kume, Hiroshi Yamashita, Gen Sobue, Yasushi Iwasaki, Jun Sone, Hideshi Kawakami and Hirofumi Maruyama :
FXTAS is difficult to differentiate from neuronal intranuclear inclusion disease through skin biopsy: a case report.,
BMC Neurology, 21, 1, 2021.

(要約): The patient underwent neurological assessment and examinations, including laboratory tests, electrophysiologic test, imaging, skin biopsy, and genetic test. A brain MRI showed hyperintensity lesions along the corticomedullary junction on diffusion-weighted imaging (DWI) in addition to middle cerebellar peduncle sign (MCP sign). We suspected NIID from the clinical picture and the radiological findings, and performed a skin biopsy. The skin biopsy specimen showed ubiquitin- and p62-positive intranuclear inclusions, suggesting NIID. However, a genetic analysis for NIID using repeat-primed polymerase chain reaction (RP-PCR) revealed no expansion detected in the Notch 2 N-terminal like C (NOTCH2NLC) gene. We then performed genetic analysis for FXTAS using RP-PCR, which revealed a repeat CGG/GGC expansion in the FMRP translational regulator 1 (FMR1) gene. The number of repeats was 83. We finally diagnosed the patient with FXTAS rather than NIID.
(キーワード): Ataxia / Biopsy / Fragile X Mental Retardation Protein / Fragile X Syndrome / Humans / Intranuclear Inclusion Bodies / Neurodegenerative Diseases / Tremor
(出版サイトへのリンク): ● Publication site (DOI): 10.1186/s12883-021-02425-z
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34641814; ● Summary page in Scopus @ Elsevier: 2-s2.0-85117357424; ● Summary page in Scopus @ Elsevier: 2-s2.0-85117938011

(DOI: 10.1186/s12883-021-02425-z, PubMed: 34641814, Elsevier: Scopus, Elsevier: Scopus) Mai Kikumoto, Tomohisa Nezu, Yuji Shiga, Atsuko Motoda, Megumi Toko, Takashi Kurashige, Hiroki Ueno, Tetsuya Takahashi, Hiroyuki Morino, Jun Sone, Yasushi Iwasaki, Gen Sobue and Hirofumi Maruyama :
Case of Neuronal Intranuclear Inclusion Disease With Dynamic Perfusion Changes Lacking Typical Signs on Diffusion-Weighted Imaging.,
Neurology. Genetics, 7, 4, 2021.

(出版サイトへのリンク): ● Publication site (DOI): 10.1212/NXG.0000000000000601
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34131587; ● Search Scopus @ Elsevier (PMID): 34131587; ● Search Scopus @ Elsevier (DOI): 10.1212/NXG.0000000000000601

(DOI: 10.1212/NXG.0000000000000601, PubMed: 34131587) Hidetada Yamada, Shuichiro Neshige, Takeo Shishido, Hiroki Ueno, Tomohiko Ohshita, Hiroyuki Morino and Hirofumi Maruyama :
Efficacy of Lacosamide in a Patient with Refractory Generalized Epilepsy Based on Video Electroencephalography.,
Internal Medicine, 60, 22, 3621-3624, 2021.

(要約): A 20-year-old man with drug-resistant generalized epilepsy (GE) was admitted for video electroencephalography (vEEG) monitoring under treatment with multiple antiepileptic drugs, including levetiracetam (3,000 mg/day), valproic acid (800 mg/day), and lacosamide (LCM) (100 mg/day). No seizures were noted after the withdrawal of levetiracetam. However, after the withdrawal of LCM, atypical absence seizures with a 2- to 2.5-Hz generalized spike and wave complex frequently appeared, followed by subsequent generalized-onset tonic-clonic seizures. After re-administration of LCM, the seizures and epileptic discharges clearly disappeared. Subsequent LCM titration was successful in achieving a seizure-free status. Our vEEG results suggest that LCM may be a worthwhile antiepileptic drug adjunct in refractory GE patients without a risk of worsening absence seizures.
(キーワード): Adult / Anticonvulsants / Electroencephalography / Epilepsy, Generalized / Humans / Lacosamide / Male / Seizures / Young Adult
(出版サイトへのリンク): ● Publication site (DOI): 10.2169/internalmedicine.7295-21
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34053987; ● Search Scopus @ Elsevier (PMID): 34053987; ● Search Scopus @ Elsevier (DOI): 10.2169/internalmedicine.7295-21

(DOI: 10.2169/internalmedicine.7295-21, PubMed: 34053987) Tomoyasu Matsubara, Yuishin Izumi, Masaya Oda, Masatoshi Takahashi, Hirofumi Maruyama, Ryosuke Miyamoto, Chigusa Watanabe, Yoshiro Tachiyama, Hiroyuki Morino, Hideshi Kawakami, Yuko Saito and Shigeo Murayama :
An autopsy report of a familial amyotrophic lateral sclerosis case carrying VCP Arg487His mutation with a unique TDP-43 proteinopathy,
Neuropathology, 41, 2, 118-126, 2021.

(要約): We here report an autopsy case of familial amyotrophic lateral sclerosis (ALS) with p.Arg487His mutation in the valosin-containing protein (VCP) gene (VCP), in which upper motor neurons (UMNs) were predominantly involved. Moreover, our patient developed symptoms of frontotemporal dementia later in life and pathologically exhibited numerous phosphorylated transactivation response DNA-binding protein of 43 kDa (p-TDP-43)-positive neuronal cytoplasmic inclusions and short dystrophic neurites with a few lentiform neuronal intranuclear inclusions, sharing the features of frontotemporal lobar degeneration with TDP-43 pathology type A pattern. A review of previous reports of ALS with VCP mutations suggests that our case is unique in terms of its UMN-predominant lesion pattern and distribution of p-TDP-43 pathology. Thus, this case report effectively expands the clinical and pathological phenotype of ALS in patients with a VCP mutation.
(キーワード): Amyotrophic Lateral Sclerosis / Autopsy / DNA-Binding Proteins / Frontotemporal Lobar Degeneration / Humans / Intranuclear Inclusion Bodies / 男性 (male) / Middle Aged / Motor Neurons / Mutation / TDP-43 Proteinopathies / Valosin Containing Protein
(出版サイトへのリンク): ● Publication site (DOI): 10.1111/neup.12710
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33415820; ● Search Scopus @ Elsevier (PMID): 33415820; ● Search Scopus @ Elsevier (DOI): 10.1111/neup.12710

(DOI: 10.1111/neup.12710, PubMed: 33415820) Hiroyuki Naito, Tomohisa Nezu, Naohisa Hosomi, Daisuke Kuzume, Shiro Aoki, Yuko Morimoto, Takeshi Yoshida, Teppei Kamimura, Yuji Shiga, Naoto Kinoshita, Hiroki Ueno, Hiroyuki Morino and Hirofumi Maruyama :
Increased Serum Alkaline Phosphatase and Functional Outcome in Patients with Acute Ischemic Stroke Presenting a Low Ankle-Brachial Index.,
Journal of Atherosclerosis and Thrombosis, 29, 5, 719-730, 2021.

(要約): Of the total cohort, 482 patients (22.8%) had a low ABI. ALP levels were higher in patients with a low ABI than in those without (p<0.001). The multivariable logistic analysis revealed that quartiles of ALP levels were significantly associated with a low ABI (odds ratio [OR]: 1.20, 95% confidence interval [CI]: 1.08-1.33). Of the 1322 patients with a premorbid mRS score of 0-2, 434 patients (32.8%) had a poor outcome. The multivariable analysis revealed that elevated serum ALP levels and a low ABI were independently associated with poor stroke outcomes after adjustment for baseline characteristics (OR: 1.21, 95% CI: 1.07-1.38, and OR: 2.00, 95% CI: 1.40-2.84, respectively).
(キーワード): Alkaline Phosphatase / Ankle Brachial Index / Humans / Ischemic Stroke / Predictive Value of Tests / Risk Factors / Stroke
(出版サイトへのリンク): ● Publication site (DOI): 10.5551/jat.62795
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33790143; ● Search Scopus @ Elsevier (PMID): 33790143; ● Search Scopus @ Elsevier (DOI): 10.5551/jat.62795

(DOI: 10.5551/jat.62795, PubMed: 33790143) Y Kanaya, K Kume, Hiroyuki Morino, R Ohsawa, T Kurashige, M Kamada, T Torii, Yuishin Izumi, H Maruyama and H Kawakami :
Analysis of genetic risk factors in Japanese patients with Parkinson's disease,
Journal of Human Genetics, 66, 10, 957-964, 2021.

(要約): Parkinson's disease (PD) is caused by a combination of genetic and environmental factors. Notably, genetic risk factors vary according to ethnicity and geographical regions, and few studies have analyzed the frequency of PD causative genes in Japanese patients. Therefore, we performed genetic analyses of Japanese patients with PD. We recruited 221 participants, including 26 patients with familial PD. Genetic risk factors were evaluated by target sequencing and gene dosage analysis. We detected the genetic risk factors in 58 cases (26.2%) and classified patients into three groups to clarify the differences in genetic risk factors by age at onset (AAO). The early-onset group (AAO < 50 years) included 18 cases (44.7%), who tended to have a larger number of genetic risk factors than the later-onset groups. Regarding the AAO for each causative gene, patients with PRKN variants were significantly younger at onset than those bearing LRRK2 variants. LRRK2 variants showed similar frequency in each AAO group. Of note, we identified two novel variants. Patients with early-onset PD have more genetic risk factors than patients with late-onset PD. In Japanese patients with PD, PRKN, and LRRK2 were the major PD-related genes. Particularly, LRRK2 was a common genetic factor in all age groups because of the presence of the Asian-specific variant such as LRRK2 p.G2385R. Accumulation of genetic and clinical data can contribute to the development of treatments for PD.
(キーワード): Adult / Age of Onset / Asians / Female / Genetic Predisposition to Disease / Genetic Testing / Genotype / Humans / Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Male / Middle Aged / Parkinson Disease / Risk Factors
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/s10038-021-00910-4
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33742109; ● Summary page in Scopus @ Elsevier: 2-s2.0-85102876254

(DOI: 10.1038/s10038-021-00910-4, PubMed: 33742109, Elsevier: Scopus) Shuichiro Neshige, Shiro Aoki, Takeo Shishido, Hiroyuki Morino, Koji Iida and Hirofumi Maruyama :
Socio-economic impact on epilepsy outside of the nation-wide COVID-19 pandemic area.,
Epilepsy & Behavior : E&B, 117, 2021.

(要約): Among the 196 PWE who were evaluated (mean age was 37.8 ± 16.2 years), there were 33 PWE (16.8%) whose seizure frequency had increased after the pandemic began. People with epilepsy with a seizure increase showed a significant association with living alone (p < 0.001), a higher seizure frequency (p < 0.001), negative findings on MRI (p = 0.020), history of dissociative seizure (p < 0.001), mood disorders (p < 0.001), insomnia (p < 0.001), and high psychological stress levels (p = 0.024) at baseline compared with PWE without seizure exacerbation. Multivariate logistic regression analysis revealed that "living alone" (odds ratio (OR) 3.69; 95%CI 1.29-10.52), "high seizure frequency at baseline" (OR 4.53; 95%CI 1.63-12.57), and "comorbidity of insomnia" (OR 9.55; 95%CI 3.71-24.55) were independently associated with seizure exacerbation.
(キーワード): Adult / COVID-19 / Epilepsy / Humans / Middle Aged / Pandemics / SARS-CoV-2 / Socioeconomic Factors / Young Adult
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.yebeh.2021.107886
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33714184; ● Search Scopus @ Elsevier (PMID): 33714184; ● Search Scopus @ Elsevier (DOI): 10.1016/j.yebeh.2021.107886

(DOI: 10.1016/j.yebeh.2021.107886, PubMed: 33714184) Takashi Kurashige, Masahito Kuramochi, Ryosuke Ohsawa, Yui Yamashita, Go Shioi, Hiroyuki Morino, Masaki Kamada, Takashi Ayaki, Hidefumi Ito, Yusuke Sotomaru, Hirofumi Maruyama and Hideshi Kawakami :
Optineurin defects cause TDP43-pathology with autophagic vacuolar formation,
Neurobiology of Disease, 148, 105215, 2020.

(要約): We previously showed that optineurin (OPTN) mutations lead to the development of amyotrophic lateral sclerosis. The association between OPTN mutations and the pathogenesis of amyotrophic lateral sclerosis remains unclear. To investigate the mechanism underlying its pathogenesis, we generated Optn knockout mice. We evaluated histopathological observations of these mice and compared with those of OPTN- amyotrophic lateral sclerosis cases to investigate the mechanism underlying the pathogenesis of amyotrophic lateral sclerosis caused by OPTN mutations. The Optn (-/-) mice presented neuronal autophagic vacuoles immunopositive for charged multivesicular body protein 2b, one of the hallmarks of granulovacuolar degenerations, in the cytoplasm of spinal cord motor neurons at the age of 8 months and the OPTN- amyotrophic lateral sclerosis case with homozygous Q398X mutation. In addition, Optn (-/-) mice showed TAR-DNA binding protein 43/sequestosome1/p62 -positive cytoplasmic inclusions and the clearance of nuclear TAR-DNA binding protein 43. The axonal degeneration of the sciatic nerves was observed in Optn (-/-) mice. However, we could not observe significant differences in survival time, body weight, and motor functions, at 24 months. Our findings suggest that homozygous OPTN deletion or mutations might result in autophagic dysfunction and TAR-DNA binding protein 43 mislocalization, thereby leading to neurodegeneration of motor neurons. These findings indicate that the Optn (-/-) mice recapitulate both common and specific pathogenesis of amyotrophic lateral sclerosis associated with autophagic abnormalities. Optn (-/-) mice could serve as a mouse model for the development of therapeutic strategies.
(キーワード): Charged multivesicular body protein 2b / Granulovacuolar degenerations / Optineurin / TDP-43
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.nbd.2020.105215
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33296728; ● Summary page in Scopus @ Elsevier: 2-s2.0-85098107686

(DOI: 10.1016/j.nbd.2020.105215, PubMed: 33296728, Elsevier: Scopus) Naoyuki Hara, Hiroyuki Morino, Yukiko Matsuda, Kenichi Satoh, Kouichi Hashimoto, Hirofumi Maruyama and Hideshi Kawakami :
Zonisamide can ameliorate the voltage-dependence alteration of the T-type calcium channel CaV3.1 caused by a mutation responsible for spinocerebellar ataxia,
Molecular Brain, 13, 1, 163, 2020.

(要約): Spinocerebellar ataxia (SCA) 42 is caused by a mutation in CACNA1G, which encodes the low voltage-gated calcium channel Ca_V3.1 (T-type). Patients with SCA42 exhibit a pure form of cerebellar ataxia. We encountered a patient with the p.Arg1715His mutation, suffering from intractable resting tremor, particularly head tremor. This symptom improved with the administration of low-dose of zonisamide (ZNS), a T-type calcium channel blocker effective for treating Parkinson's disease and epilepsy. Previous electrophysiological studies showed that the voltage dependence of this mutant Ca_V3.1 was shifted toward the positive potential. This abnormal shift was considered a factor related to disease onset and symptoms. In this study, we performed whole-cell recordings of GFP-expressing HEK293T cells that expressed wild-type or mutant Ca_V3.1 and investigated the changes in the abnormal shift of voltage dependence of the mutant Ca_V3.1. The results showed that ZNS in an amount equivalent to the patient's internal dose significantly ameliorated the abnormal shift in the mutant Ca_V3.1, giving values close to those in the wild-type. On the other hand, ZNS did not affect the voltage dependence of wild-type Ca_V3.1. Because Ca_V3.1 is known to be involved in tremogenesis, modulation of the voltage dependence of mutant Ca_V3.1 by ZNS might have contributed to improvement in the intractable tremor of our patient with SCA42. Moreover, efonidipine, another T-type calcium channel blocker, had no effect on tremors in our patient with SCA42 and did not improve the abnormal shift in the voltage dependence of the mutant Ca_V3.1. This indicates that ZNS is distinct from other T-type calcium channel blockers in terms of modulation of the voltage dependence of the mutant Ca_V3.1.
(キーワード): CaV3.1 / CACNA1G / SCA42 / Spinocerebellar ataxia / T-type calcium channel / Tremor / Zonisamide
(出版サイトへのリンク): ● Publication site (DOI): 10.1186/s13041-020-00700-7
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33243296; ● Summary page in Scopus @ Elsevier: 2-s2.0-85096519318

(DOI: 10.1186/s13041-020-00700-7, PubMed: 33243296, Elsevier: Scopus) Toshinori Matsuoka, Miwako Yamasaki, Manabu Abe, Yukiko Matsuda, Hiroyuki Morino, Hideshi Kawakami, Kenji Sakimura, Masahiko Watanabe and Kouichi Hashimoto :
Kv11 (ether-à-go-go-related gene) voltage-dependent K+ channels promote resonance and oscillation of subthreshold membrane potentials,
The Journal of Physiology, 599, 2, 547-569, 2020.

(要約): Some ion channels are known to behave as inductors and make up the parallel resonant circuit in the plasma membrane of neurons, which enables neurons to respond to current inputs with a specific frequency (so-called 'resonant properties'). Here, we report that heterologous expression of mouse Kv11 voltage-dependent K⁺ channels generate resonance and oscillation at depolarized membrane potentials in HEK293 cells; expressions of individual Kv11 subtypes generate resonance and oscillation with different frequency properties. Kv11.3-expressing HEK293 cells exhibited transient conductance changes that opposed the current changes induced by voltage steps; this probably enables Kv11 channels to behave like an inductor. The resonance and oscillation of inferior olivary neurons were impaired at the resting membrane potential in Kv11.3 knockout mice. This study helps to elucidate basic ion channel properties that are crucial for the frequency responses of neurons. The plasma membranes of some neurons preferentially respond to current inputs with a specific frequency, and output as large voltage changes. This property is called resonance, and is thought to be mediated by ion channels that show inductor-like behaviour. However, details of the candidate ion channels remain unclear. In this study, we mainly focused on the functional roles of Kv11 potassium (K⁺ ) channels, encoded by ether-á-go-go-related genes, in resonance in mouse inferior olivary (IO) neurons. We transfected HEK293 cells with long or short splice variants of Kv11.1 (Merg1a and Merg1b) or Kv11.3, and examined membrane properties using whole-cell recording. Transfection with Kv11 channels reproduced resonance at membrane potentials depolarized from the resting state. Frequency ranges of Kv11.3-, Kv11.1(Merg1b)- and Kv11.1(Merg1a)-expressing cells were 2-6 Hz, 2-4 Hz, and 0.6-0.8 Hz, respectively. Responses of Kv11.3 currents to step voltage changes were essentially similar to those of inductor currents in the resistor-inductor-capacitor circuit. Furthermore, Kv11 transfections generated membrane potential oscillations. We also confirmed the contribution of HCN1 channels as a major mediator of resonance at more hyperpolarized potentials by transfection into HEK293 cells. The Kv11 current kinetics and properties of Kv11-dependent resonance suggested that Kv11.3 mediated resonance in IO neurons. This finding was confirmed by the impairment of resonance and oscillation at -30 to -60 mV in Kcnh7 (Kv11.3) knockout mice. These results suggest that Kv11 channels have important roles in inducing frequency-dependent responses in a subtype-dependent manner from resting to depolarized membrane potentials.
(キーワード): hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) / Kv11 (ether-à-go-go-related gene) / resonance
(出版サイトへのリンク): ● Publication site (DOI): 10.1113/JP280342
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33151574; ● Summary page in Scopus @ Elsevier: 2-s2.0-85096799267

(DOI: 10.1113/JP280342, PubMed: 33151574, Elsevier: Scopus) Kodai Kume, Tadayuki Takata, Hiroyuki Morino, Yukiko Matsuda, Ryosuke Ohsawa, Yui Tada, Takashi Kurashige and Hideshi Kawakami :
The first Japanese case of primary familial brain calcification caused by an MYORG variant,
Journal of Human Genetics, 65, 10, 917-920, 2020.

(要約): Primary familial brain calcification (PFBC) is a hereditary neurological disorder characterized by idiopathic calcification of the bilateral basal ganglia and other areas of the brain. MYORG has been identified as the first causative gene of autosomal recessive PFBC in Chinese families. There have been several reports of PFBC associated with MYORG (MYORG-PFBC) in individuals of Middle Eastern, European, and Latin American ancestry but to date, there have been no reported Japanese cases. We report the first Japanese case of MYORG-PFBC. The patient was a 43-year-old Japanese woman who experienced mild headaches and cerebellar ataxia including dysarthria. Computed tomography showed calcification in the cerebral white matter, basal ganglia, cerebellum, and brainstem. Using exome sequencing, we identified a homozygous variant in the MYORG gene (NM_020702.4: c.794C>T,p.Thr265Met). Our patient presented dysarthria and extensive calcification affecting the pons, which are specific features of MYORG-PFBC. We report clinical symptoms and imaging findings of a case with p.Thr265Met variant.
(キーワード): Adult / Amino Acid Substitution / Asian People / Brain Diseases / Calcinosis / Cerebellar Ataxia / Consanguinity / Dysarthria / Female / Glycoside Hydrolases / Headache / Homozygote / Humans / Japan / Mutation, Missense / Pedigree / Point Mutation / Exome Sequencing
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/s10038-020-0779-x
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32451491; ● Summary page in Scopus @ Elsevier: 2-s2.0-85085386517

(DOI: 10.1038/s10038-020-0779-x, PubMed: 32451491, Elsevier: Scopus) Noriyoshi Mizuno, Kodai Kume, Yukiko Nagatani, Shinji Matsuda, Tomoyuki Iwata, Kazuhisa Ouhara, Mikihito Kajiya, Katsuhiro Takeda, Yukiko Matsuda, Yui Tada, Ryosuke Ohsawa, Hiroyuki Morino, Keichiro Mihara, Tsuyoshi Fujita, Hiroyuki Kawaguchi, Hideki Shiba, Hideshi Kawakami and Hidemi Kurihara :
Aggressive periodontitis and NOD2 variants,
Journal of Human Genetics, 65, 10, 841-846, 2020.

(要約): Aggressive periodontitis (AgP) occurs at an early age and causes rapid periodontal tissue destruction. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) encodes a protein with two caspase recruitment domains and eleven leucine-rich repeats. This protein is expressed mainly in peripheral blood leukocytes and is involved in immune response. NOD2 variants have been associated with increased susceptibility to Crohn's disease, and recently, NOD2 was reported as a causative gene in AgP. The present study aimed to identify potential NOD2 variants in an AgP cohort (a total of 101 patiens: 37 patients with positive family histories and 64 sporadic patients). In the familial group, six patients from two families had a reported heterozygous missense variant (c.C931T, p.R311W). Four patients in the sporadic group had a heterozygous missense variant (c.C1411T, p.R471C), with no reported association to the disease. Overall, two NOD2 variants, were identified in 10% of our AgP cohort. These variants were different from the major variants reported in Crohn's disease. More cases need to be investigated to elucidate the role of NOD2 variants in AgP pathology.
(キーワード): Adult / Aggressive Periodontitis / Female / Genetic Predisposition to Disease / Heterozygote / Humans / Male / Mutation, Missense / Nod2 Signaling Adaptor Protein / Pedigree / Protein Domains
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/s10038-020-0777-z
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32424308; ● Summary page in Scopus @ Elsevier: 2-s2.0-85085014452

(DOI: 10.1038/s10038-020-0777-z, PubMed: 32424308, Elsevier: Scopus) Kodai Kume, Hiroyuki Morino, Ryosuke Miyamoto, Yukiko Matsuda, Ryosuke Ohsawa, Yuhei Kanaya, Yui Tada, Takashi Kurashige and Hideshi Kawakami :
Middle-age-onset cerebellar ataxia caused by a homozygous TWNK variant: A case report,
BMC Medical Genetics, 21, 1, 68, 2020.

(要約): The TWNK gene encodes the twinkle protein, which is a mitochondrial helicase for DNA replication. The dominant TWNK variants cause progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, while the recessive variants cause mitochondrial DNA depletion syndrome 7 and Perrault syndrome 5. Perrault syndrome is characterized by sensorineural hearing loss in both males and females and gonadal dysfunction in females. Patients with Perrault syndrome may present early-onset cerebellar ataxia, whereas middle-age-onset cerebellar ataxia caused by TWNK variants is rare. A Japanese female born to consanguineous parents presented hearing loss at age 48, a staggering gait at age 53, and numbness in her distal extremities at age 57. Neurological examination revealed sensorineural hearing loss, cerebellar ataxia, decreased deep tendon reflexes, and sensory disturbance in the distal extremities. Laboratory tests showed no abnormal findings other than a moderate elevation of pyruvate concentration levels. Brain magnetic resonance imaging revealed mild cerebellar atrophy. Using exome sequencing, we identified a homozygous TWNK variant (NM_021830: c.1358G>A, p.R453Q). TWNK variants could cause middle-age-onset cerebellar ataxia. Screening for TWNK variants should be considered in cases of cerebellar ataxia associated with deafness and/or peripheral neuropathy, even if the onset is not early.
(キーワード): Cerebellar ataxia / Perrault syndrome / TWNK
(出版サイトへのリンク): ● Publication site (DOI): 10.1186/s12881-020-01002-4
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32234020; ● Summary page in Scopus @ Elsevier: 2-s2.0-85082791250

(DOI: 10.1186/s12881-020-01002-4, PubMed: 32234020, Elsevier: Scopus) Noriyoshi Mizuno, Tomoyuki Iwata, Ryosuke Ohsawa, Kazuhisa Ouhara, Shinji Matsuda, Mikihito Kajiya, Yukiko Matsuda, Kodai Kume, Yui Tada, Hiroyuki Morino, Tetsuya Yoshimoto, Yasuyoshi Ueki, Keichiro Mihara, Yusuke Sotomaru, Katsuhiro Takeda, Syuichi Munenaga, Tsuyoshi Fujita, Hiroyuki Kawaguchi, Hideki Shiba, Hideshi Kawakami and Hidemi Kurihara :
Optineurin regulates osteoblastogenesis through STAT1,
Biochemical and Biophysical Research Communications, 525, 4, 889-894, 2020.

(要約): A sophisticated and delicate balance between bone resorption by osteoclasts and bone formation by osteoblasts regulates bone metabolism. Optineurin (OPTN) is a gene involved in primary open-angle glaucoma and amyotrophic lateral sclerosis. Although its function has been widely studied in ophthalmology and neurology, recent reports have shown its possible involvement in bone metabolism through negative regulation of osteoclast differentiation. However, little is known about the role of OPTN in osteoblast function. Here, we demonstrated that OPTN controls not only osteoclast but also osteoblast differentiation. Different parameters involved in osteoblastogenesis and osteoclastogenesis were assessed in Optn^-/- mice. The results showed that osteoblasts from Optn^-/- mice had impaired alkaline phosphatase activity, defective mineralized nodules, and inability to support osteoclast differentiation. Moreover, OPTN could bind to signal transducer and activator of transcription 1 (STAT1) and regulate runt-related transcription factor 2 (RUNX2) nuclear localization by modulating STAT1 levels in osteoblasts. These data suggest that OPTN is involved in bone metabolism not only by regulating osteoclast function but also by regulating osteoblast function by mediating RUNX2 nuclear translocation via STAT1.
(キーワード): OPTN / Osteoblast / Osteoclast / RUNX2 / STAT1
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.bbrc.2020.03.028
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32171527; ● Summary page in Scopus @ Elsevier: 2-s2.0-85081606712

(DOI: 10.1016/j.bbrc.2020.03.028, PubMed: 32171527, Elsevier: Scopus) Yui Tada, Kodai Kume, Yukiko Matsuda, Takashi Kurashige, Yuhei Kanaya, Ryosuke Ohsawa, Hiroyuki Morino, Hayato Tabu, Satoshi Kaneko, Toshihiko Suenaga, Akira Kakizuka and Hideshi Kawakami :
Genetic screening for potassium channel mutations in Japanese autosomal dominant spinocerebellar ataxia,
Journal of Human Genetics, 65, 4, 363-369, 2020.

(要約): Spinocerebellar ataxia (SCA) is a genetically heterogeneous disease characterized by cerebellar ataxia. Many causative genes have been identified to date, the most common etiology being the abnormal expansion of repeat sequences, and the mutation of ion channel genes also play an important role in the development of SCA. Some of them encode calcium and potassium channels. However, due to limited reports about potassium genes in SCA, we screened 192 Japanese individuals with dominantly inherited SCA who had no abnormal repeat expansions of causative genes for potassium channel mutations (KCNC3 for SCA13 and KCND3 for SCA19/SCA22) by target sequencing. As a result, two variants were identified from two patients: c.1973G>A, p.R658Q and c.1018G>A, p.V340M for KCNC3, and no pathogenic variant was identified for KCND3. The newly identified p.V340M exists in the extracellular domain, and p.R658Q exists in the intracellular domain on the C-terminal side, although most of the reported KCNC3 mutations are present at the transmembrane site. Adult-onset and slowly progressive cerebellar ataxia are the main clinical features of SCA13 and SCA19 caused by potassium channel mutations, which was similar in our cases. SCA13 caused by KCNC3 mutations may present with deep sensory loss and cognitive impairment in addition to cerebellar ataxia. In this study, mild deep sensory loss was observed in one case. SCA caused by potassium channel gene mutations is extremely rare, and more cases should be accumulated in the future to elucidate its pathogenesis due to channel dysfunction.
(キーワード): Adult / Asian People / Cognitive Dysfunction / Female / Genetic Testing / Humans / Japan / Magnetic Resonance Imaging / Male / Middle Aged / Mutation / Potassium Channels / Spinocerebellar Ataxias
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/s10038-019-0717-y
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31907387; ● Summary page in Scopus @ Elsevier: 2-s2.0-85077525781

(DOI: 10.1038/s10038-019-0717-y, PubMed: 31907387, Elsevier: Scopus) Yukiko Matsuda, Hiroyuki Morino, Ryosuke Miyamoto, Takashi Kurashige, Kodai Kume, Noriyoshi Mizuno, Yuhei Kanaya, Yui Tada, Ryosuke Ohsawa, Kazunori Yokota, Nobuyuki Shimozawa, Hirofumi Maruyama and Hideshi Kawakami :
Biallelic mutation of HSD17B4 induces middle age-onset spinocerebellar ataxia,
Neurology. Genetics, 6, 1, 2020.

(出版サイトへのリンク): ● Publication site (DOI): 10.1212/NXG.0000000000000396
(文献検索サイトへのリンク): ● Summary page in Scopus @ Elsevier: 2-s2.0-85081931542

(DOI: 10.1212/NXG.0000000000000396, Elsevier: Scopus) Koji Fujita, Tomoyasu Matsubara, Ryosuke Miyamoto, Hiroyuki Sumikura, Toshiaki Takeuchi, Keiko Saladini Maruyama, Toshitaka Kawarai, Hiroyuki Nodera, Fukashi Udaka, Kodai Kume, Hiroyuki Morino, Hideshi Kawakami, Masato Hasegawa, Ryuji Kaji, Shigeo Murayama and Yuishin Izumi :
Co-morbidity of progressive supranuclear palsy and amyotrophic lateral sclerosis: a clinical-pathological case report,
BMC Neurology, 19, 1, 168, 2019.

(要約): The coexistence of distinct neurodegenerative diseases in single cases has recently attracted greater attention. The phenotypic co-occurrence of progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) has been documented in several cases. That said, the clinicopathological comorbidity of these two diseases has not been demonstrated. A 77-year-old man presented with gait disturbance for 2 years, consistent with PSP with progressive gait freezing. At 79 years old, he developed muscle weakness compatible with ALS. The disease duration was 5 years after the onset of PSP and 5 months after the onset of ALS. Neuropathological findings demonstrated the coexistence of PSP and ALS. Immunohistochemical examination confirmed 4-repeat tauopathy, including globose-type neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies as well as TAR DNA-binding protein 43 kDa pathology in association with upper and lower motor neuron degeneration. Immunoblotting showed hyperphosphorylated full-length 4-repeat tau bands (64 and 68 kDa) and C-terminal fragments (33 kDa), supporting the diagnosis of PSP and excluding other parkinsonian disorders, such as corticobasal degeneration. Genetic studies showed no abnormalities in genes currently known to be related to ALS or PSP. Our case demonstrates the clinicopathological comorbidity of PSP and ALS in a sporadic patient. The possibility of multiple proteinopathies should be considered when distinct symptoms develop during the disease course.
(キーワード): Amyotrophic lateral sclerosis / Copathology / Progressive supranuclear palsy / TAR DNA-binding protein 43 kDa (TDP-43) / Tau
(出版サイトへのリンク): ● Publication site (DOI): 10.1186/s12883-019-1402-7
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31319800; ● Summary page in Scopus @ Elsevier: 2-s2.0-85070105063

(DOI: 10.1186/s12883-019-1402-7, PubMed: 31319800, Elsevier: Scopus) A. Ramos, M. Planchat, R. Melo A. Vieira, M. Raposo, U. Shamim, V. Suroliya, K. A. Srivastava, M. Faruq, Hiroyuki Morino, R. Ohsawa, H. Kawakami, L. Jardim Bannach, L. M. Saraiva-Pereira, J. Vasconcelos, C. Santos and M. Lima :
Mitochondrial DNA haplogroups and age at onset of Machado-Joseph disease/spinocerebellar ataxia type 3: a study in patients from multiple populations,
European Journal of Neurology, 26, 3, 506-512, 2018.

(要約): Mitochondrial dysfunction has been implicated in the pathogenesis of several neurodegenerative disorders, including Machado-Joseph disease (MJD), an autosomal dominant late-onset polyglutamine ataxia that results from an unstable expansion of a CAG tract in the ATXN3 gene. The size of the CAG tract only partially explains age at onset (AO), highlighting the existence of disease modifiers. Mitochondrial DNA (mtDNA) haplogroups have been associated with clinical presentation in other polyglutamine disorders, constituting potential modifiers of MJD phenotype. A cross-sectional study, using 235 unrelated patients from Portugal, Brazil, India and Japan, was performed to investigate if mtDNA haplogroups contribute to AO of MJD. mtDNA haplogroups were obtained after sequencing the mtDNA hypervariable region I. Patients were classified in 15 phylogenetically related haplogroup clusters. The AO was significantly different among populations, implying the existence of other non-CAG factors, which seem to be population specific. In the Portuguese population, patients classified as belonging to haplogroup JT presented the earliest onset (estimated onset 34.6 years of age). Haplogroups W and X seem to have a protective effect, causing a delay in onset (estimated onset 47 years of age). No significant association between haplogroup clusters and AO was detected in the other populations or when all patients were pooled. Although haplogroup JT has already been implicated in other neurodegenerative disorders, no previous reports of an association between haplogroups W and X and disease were found. These findings suggest that haplogroups JT, W and X modify AO in MJD. Replication studies should be performed in European populations, where the frequency of the candidate modifiers is similar.
(キーワード): genetic modifier / MJD / mtDNA / polyglutamine disorder / SCA3
(出版サイトへのリンク): ● Publication site (DOI): 10.1111/ene.13860
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30414314; ● Summary page in Scopus @ Elsevier: 2-s2.0-85058072230

(DOI: 10.1111/ene.13860, PubMed: 30414314, Elsevier: Scopus) Tatsuo Miyamoto, Natsuko Silvia Akutsu, Akihiro Fukumitsu, Hiroyuki Morino, Yoshinori Masatsuna, Kosuke Hosoba, Hideshi Kawakami, Takashi Yamamoto, Kenji Shimizu, Hirofumi Ohashi and Shinya Matsuura :
PLK1-mediated phosphorylation of WDR62/MCPH2 ensures proper mitotic spindle orientation,
Human Molecular Genetics, 26, 22, 4429-4440, 2017.

(要約): Primary microcephaly (MCPH) is an autosomal recessive disorder characterized by congenital reduction of head circumference. Here, we identified compound heterozygous mutations c.731 C > T (p.Ser 244 Leu) and c.2413 G > T (p.Glu 805 X) in the WDR62/MCPH2 gene, which encodes the mitotic centrosomal protein WDR62, in two siblings in a Japanese family with microcephaly using whole-exome sequencing. However, the molecular and cellular pathology of microcephaly caused by WDR62/MCPH2 mutation remains unclear. To clarify the physiological role of WDR62, we used the CRISPR/Cas9 system and single-stranded oligonucleotides as a point-mutation-targeting donor to generate human cell lines with knock-in of WDR62/MCPH2 c.731 C > T (p.Ser 244 Leu) missense mutation. In normal metaphase, the mitotic spindle forms parallel to the substratum to ensure symmetric cell division, while WDR62/MCPH2-mutated cells exhibited a randomized spindle orientation caused by the impaired astral microtubule assembly. It was shown that a mitotic kinase, Polo-like kinase 1 (PLK1), is required for the maintenance of spindle orientation through astral microtubule development. In this study, we demonstrated that WDR62 is a PLK1 substrate that is phosphorylated at Ser 897, and that this phosphorylation at the spindle poles promotes astral microtubule assembly to stabilize spindle orientation. Our findings provide insights into the role of the PLK1-WDR62 pathway in the maintenance of proper spindle orientation.
(キーワード): Base Sequence / Cell Cycle Proteins / Cell Division / Cell Line / Centrosome / Female / Gene Knock-In Techniques / HCT116 Cells / Humans / Infant, Newborn / Male / Microcephaly / Microtubules / Mitosis / Mutation, Missense / Nerve Tissue Proteins / Phosphorylation / Pregnancy / Protein Serine-Threonine Kinases / Proto-Oncogene Proteins / Spindle Apparatus / Polo-Like Kinase 1
(出版サイトへのリンク): ● Publication site (DOI): 10.1093/hmg/ddx330
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28973348; ● Summary page in Scopus @ Elsevier: 2-s2.0-85034216371

(DOI: 10.1093/hmg/ddx330, PubMed: 28973348, Elsevier: Scopus) Hiroyuki Naito, Tetsuya Takahashi, Masaki Kamada, Hiroyuki Morino, Hiroyo Yoshino, Nobutaka Hattori, Hirofumi Maruyama, Hideshi Kawakami and Masayasu Matsumoto :
First report of a Japanese family with spinocerebellar ataxia type 10: The second report from Asia after a report from China,
PLoS ONE, 12, 5, e0177955, 2017.

(要約): Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant cerebellar ataxia that is variably accompanied by epilepsy and other neurological disorders. It is caused by an expansion of the ATTCT pentanucleotide repeat in intron 9 of the ATXN10 gene. Until now, SCA10 was almost exclusively found in the American continents, while no cases had been identified in Japan. Here, we report the first case of an SCA10 family from Japan. The clinical manifestations in our cases were cerebellar ataxia accompanied by epilepsy, hyperreflexia and cognitive impairment. Although the primary pathology in SCA10 in humans is reportedly the loss of Purkinje cells, brain MRI revealed frontal lobe atrophy with white matter lesions. This pathology might be associated with cognitive dysfunction, indicating that the pathological process is not limited to the cerebellum. Examination of the SNPs surrounding the SCA10 locus in the proband showed the "C-expansion-G-G-C" haplotype, which is consistent with previously reported SCA10-positive individuals. This result was consistent with the findings that the SCA10 mutation may have occurred before the migration of Amerindians from East Asia to North America and the subsequent spread of their descendants throughout North and South America.
(キーワード): Aged / Ataxin-10 / China / DNA Repeat Expansion / Female / Haplotypes / Humans / Male / Microsatellite Repeats / Middle Aged / Pedigree / Phenotype / Polymorphism, Single Nucleotide / Spinocerebellar Ataxias
(出版サイトへのリンク): ● Publication site (DOI): 10.1371/journal.pone.0177955
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28542277; ● Summary page in Scopus @ Elsevier: 2-s2.0-85019344332

(DOI: 10.1371/journal.pone.0177955, PubMed: 28542277, Elsevier: Scopus) Hiroyuki Morino, Yukiko Matsuda, Keiko Muguruma, Ryosuke Miyamoto, Ryosuke Ohsawa, Toshiyuki Ohtake, Reiko Otobe, Masahiko Watanabe, Hirofumi Maruyama, Kouichi Hashimoto and Hideshi Kawakami :
A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia,
Molecular Brain, 8, 1, 89, 2015.

(要約): Spinocerebellar ataxia (SCA) is a genetically heterogeneous disease. To date, 36 dominantly inherited loci have been reported, and 31 causative genes have been identified. In this study, we analyzed a Japanese family with autosomal dominant SCA using linkage analysis and exome sequencing, and identified CACNA1G, which encodes the calcium channel CaV3.1, as a new causative gene. The same mutation was also found in another family with SCA. Although most patients exhibited the pure form of cerebellar ataxia, two patients showed prominent resting tremor in addition to ataxia. CaV3.1 is classified as a low-threshold voltage-dependent calcium channel (T-type) and is expressed abundantly in the central nervous system, including the cerebellum. The mutation p.Arg1715His, identified in this study, was found to be located at S4 of repeat IV, the voltage sensor of the CaV3.1. Electrophysiological analyses revealed that the membrane potential dependency of the mutant CaV3.1 transfected into HEK293T cells shifted toward a positive potential. We established induced pluripotent stem cells (iPSCs) from fibroblasts of the patient, and to our knowledge, this is the first report of successful differentiation from the patient-derived iPSCs into Purkinje cells. There was no significant difference in the differentiation status between control- and patient-derived iPSCs. To date, several channel genes have been reported as causative genes for SCA. Our findings provide important insights into the pathogenesis of SCA as a channelopathy.
(キーワード): CaV3.1 / CACNA1G / Induced pluripotent stem cell / Spinocerebellar ataxia / T-type calcium channel
(出版サイトへのリンク): ● Publication site (DOI): 10.1186/s13041-015-0180-4
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26715324; ● Summary page in Scopus @ Elsevier: 2-s2.0-84958103770

(DOI: 10.1186/s13041-015-0180-4, PubMed: 26715324, Elsevier: Scopus) Naoki Saji, Toshitaka Kawarai, Ryosuke Miyamoto, Takahiro Sato, Hiroyuki Morino, Antonio Orlacchio, Ryosuke Oki, Kazumi Kimura and Ryuji Kaji :
Exome sequencing identifies a novel intronic mutation in ENG that causes recurrence of pulmonary arteriovenous malformations,
Journal of the Neurological Sciences, 352, 1-2, 29-33, 2015.

(要約): Hereditary hemorrhagic telangiectasia (HHT) occasionally can be discovered in patients with cerebrovascular disease. Pulmonary arteriovenous malformation (PAVM) is one of the complications in HHT and occasionally is causative for life-threatening embolic stroke. Several genetic defects have been reported in patients with HHT. The broad spectrum of phenotype and intrafamilial phenotype variations, including age-at-onset of vascular events, often make an early diagnosis difficult. We present here a Japanese family with a novel intronic heterozygous mutation of ENG, which was identified using whole exome sequencing (WES). The intronic mutation, IVS3+4delAGTG, results in in-frame deletion of exon 3 and would produce a shorter ENG protein lacking the extracellular forty-seven amino acid sequences, which is located within the orphan domain. Our findings highlight the importance of the domain for the downstream signaling pathway of transforming growth factor-beta and bone morphogenesis protein superfamily receptors. Considering the phenotype variations and the available treatment for vascular complications, an early diagnosis using genetic testing, including WES, should be considered for individuals at risk of HHT.
(キーワード): Aberrant transcript / Arteriovenous malformation / Endoglin / Hereditary hemorrhagic telangiectasia / Intronic mutation / Whole exome sequencing
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jns.2015.02.007
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 25868896; ● Summary page in Scopus @ Elsevier: 2-s2.0-84928366268

(DOI: 10.1016/j.jns.2015.02.007, PubMed: 25868896, Elsevier: Scopus) Takashi Ayaki, Hidefumi Ito, Hiroko Fukushima, Takeshi Inoue, Takayuki Kondo, Akito Ikemoto, Takeshi Asano, Akemi Shodai, Takuji Fujita, Satoshi Fukui, Hiroyuki Morino, Satoshi Nakano, Hirofumi Kusaka, Hirofumi Yamashita, Masafumi Ihara, Riki Matsumoto, Jun Kawamata, Makoto Urushitani, Hideshi Kawakami and Ryosuke Takahashi :
Immunoreactivity of valosin-containing protein in sporadic amyotrophic lateral sclerosis and in a case of its novel mutant,
Acta Neuropathologica Communications, 2, 1, 172, 2014.

(要約): Mutations in the valosin-containing protein (VCP) gene were first found to cause inclusion- body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD). Mutations in the VCP gene were later reported to occur in familial amyotrophic lateral sclerosis (ALS). But the role of VCP in the neurodegenerative processes that occur in ALS remains unknown. The purpose of the present study was to elucidate the role of VCP in the neurodegeneration seen in sporadic and VCP mutant ALS. Immunohistochemistry demonstrated that the frequency of distinct VCP-positive nuclei of spinal motor neurons of patients with sporadic ALS (SALS) and the ALS with VCP novel mutation (ALS-VCP, M158V) was increased, compared with that of the control cases. No VCP-positive inclusion bodies were observed in SALS patients, a ALS-VCP patient or in control subjects. Neuropathologic examination of the ALS-VCP case showed loss of motor neurons, the presence of Bunina bodies, and degeneration of the corticospinal tracts. Bunina bodies detected in this case were confirmed to show immunohistochemical and ultrastructural features similar to those previously described. Furthermore, neuronal intracytoplasmic inclusions immunopositive for TAR DNA-binding protein 43 kDa (TDP-43), phosphorylated TDP-43, ubiquitin (Ub), p62, and optineurin were identified in the spinal and medullary motoneurons, but not in the neocortex. Gene analysis of this ALS-VCP patient confirmed the de novo mutation of M158V, which was not found in control cases; and bioinformatics using several in silico analyses showed possible damage to the structure of VCP. Immunocytochemical study of cultured cells showed increased cytoplasmic translocation of TDP-43 in cells transfected with several mutant VCP including our patient's compared with wild-type VCP. These findings support the idea that VCP is associated with the pathomechanism of SALS and familial ALS with a VCP mutation, presumably acting through a dominant-negative mechanism.
(キーワード): Amyotrophic lateral sclerosis / Golgi apparatus fragmentation / Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD) / Paget disease of bone / TAR DNA-binding protein 43 kDa (TDP-43) / Valosin-containing protein (VCP)
(出版サイトへのリンク): ● Publication site (DOI): 10.1186/s40478-014-0172-0
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 25492614; ● Summary page in Scopus @ Elsevier: 2-s2.0-84964697468

(DOI: 10.1186/s40478-014-0172-0, PubMed: 25492614, Elsevier: Scopus) Hiroyuki Morino, B. Sarah Pierce, Yukiko Matsuda, Tom Walsh, Ryosuke Ohsawa, Marta Newby, Keiko Hiraki-Kamon, Masahito Kuramochi, K. Ming Lee, E. Rachel Klevit, Alan Martin, Hirofumi Maruyama, Claire Mary King and Hideshi Kawakami :
Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features,
Neurology, 83, 22, 2054-2061, 2014.

(要約): To identify the genetic cause in 2 families of progressive ataxia, axonal neuropathy, hyporeflexia, and abnormal eye movements, accompanied by progressive hearing loss and ovarian dysgenesis, with a clinical diagnosis of Perrault syndrome. Whole-exome sequencing was performed to identify causative mutations in the 2 affected sisters in each family. Family 1 is of Japanese ancestry, and family 2 is of European ancestry. In family 1, affected individuals were compound heterozygous for chromosome 10 open reading frame 2 (C10orf2) p.Arg391His and p.Asn585Ser. In family 2, affected individuals were compound heterozygous for C10orf2 p.Trp441Gly and p.Val507Ile. C10orf2 encodes Twinkle, a primase-helicase essential for replication of mitochondrial DNA. Conservation and structural modeling support the causality of the mutations. Twinkle is known also to harbor multiple mutations, nearly all missenses, leading to dominant progressive external ophthalmoplegia type 3 and to recessive mitochondrial DNA depletion syndrome 7, also known as infantile-onset spinocerebellar ataxia. Our study identifies Twinkle mutations as a cause of Perrault syndrome accompanied by neurologic features and expands the phenotypic spectrum of recessive disease caused by mutations in Twinkle. The phenotypic heterogeneity of conditions caused by Twinkle mutations and the genetic heterogeneity of Perrault syndrome call for genomic definition of these disorders.
(キーワード): Adult / Amino Acid Sequence / DNA Helicases / Female / Gonadal Dysgenesis, 46,XX / Hearing Loss, Sensorineural / Humans / Mitochondrial Proteins / Molecular Sequence Data / Mutation / Nervous System Diseases / Pedigree / Protein Structure, Secondary / Protein Structure, Tertiary
(出版サイトへのリンク): ● Publication site (DOI): 10.1212/WNL.0000000000001036
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 25355836; ● Summary page in Scopus @ Elsevier: 2-s2.0-84941146214

(DOI: 10.1212/WNL.0000000000001036, PubMed: 25355836, Elsevier: Scopus) Ryoichi Yagi, Ryosuke Miyamoto, Hiroyuki Morino, Yuishin Izumi, Masahito Kuramochi, Takashi Kurashige, Hirofumi Maruyama, Noriyoshi Mizuno, Hidemi Kurihara and Hideshi Kawakami :
Detecting gene mutations in Japanese Alzheimer's patients by semiconductor sequencing,
Neurobiology of Aging, 35, 7, 1780-1780.e5, 2014.

(要約): Alzheimer's disease (AD) is the most common form of dementia. To date, several genes have been identified as the cause of AD, including PSEN1, PSEN2, and APP. The association between APOE and late-onset AD has also been reported. We here used a bench top next-generation sequencer, which uses an integrated semiconductor device, detects hydrogen ions, and operates at a high-speed using nonoptical technology. We examined 45 Japanese AD patients with positive family histories, and 29 sporadic patients with early onset (<60-year-old). Causative mutations were detected in 5 patients in the familial group (11%). Three patients had a known heterozygous missense mutation in the PSEN1 gene (p.H163R). Two patients from 1 family had a novel heterozygous missense mutation in the PSEN1 gene (p.F386L). In the early onset group, 1 patient carrying homozygous APOEϵ4 had a novel heterozygous missense mutation in the PSEN2 gene (p.T421M). Approximately 43% patients were APOEϵ4 positive in our study. This new sequencing technology is useful for detecting genetic variations in familial AD.
(キーワード): Alzheimer's disease / APOE / Ion sequencing technology / Mutations / PSEN1 / PSEN2
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.neurobiolaging.2014.01.023
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24559647; ● Summary page in Scopus @ Elsevier: 2-s2.0-85058205886

(DOI: 10.1016/j.neurobiolaging.2014.01.023, PubMed: 24559647, Elsevier: Scopus) Hiroyuki Morino, Ryosuke Miyamoto, Shizuo Ohnishi, Hirofumi Maruyama and Hideshi Kawakami :
Exome sequencing reveals a novel TTC19 mutation in an autosomal recessive spinocerebellar ataxia patient,
BMC Neurology, 14, 1, 5, 2014.

(要約): Spinocerebellar ataxias (SCAs) are heterogeneous diseases characterized by progressive cerebellar ataxia associated with dysarthria, oculomotor abnormalities, and mental impairment. To identify the causative gene, we performed exome sequencing on a Japanese patient clinically diagnosed with recessive SCA. The patient is a 37-year-old Japanese woman with consanguineous parents. The head magnetic resonance imaging (MRI) showed cerebellar atrophy and T1 low/T2 high intensity at the bilateral inferior olives. Single-nucleotide polymorphism (SNP) genotyping and next-generation sequencing were performed, and the variants obtained were filtered and prioritized. After these manipulations, we identified a homozygous nonsense mutation of the TTC19 gene (p.Q277*). TTC19 has been reported to be a causative gene of a neurodegenerative disease in Italian and Portuguese families and to be involved in the pathogenesis of mitochondrial respiratory chain complex III (cIII) deficiency. This report is the first description of a TTC19 mutation in an Asian population. Clinical symptoms and neuroimaging are consistent with previous reports. The head MRI already showed abnormal features four years before her blood lactate and pyruvate levels were elevated. We should consider the genetic analysis of TTC19 when we observe such characteristic MRI abnormalities. Genes associated with mitochondrial function cause many types of SCAs; the mutation we identified should help to elucidate the pathology of these disorders.
(キーワード): Exome sequencing / Mitochondrial respiratory chain complex III / Nonsense mutation / Spinocerebellar ataxia / TTC19
(出版サイトへのリンク): ● Publication site (DOI): 10.1186/1471-2377-14-5
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24397319; ● Summary page in Scopus @ Elsevier: 2-s2.0-84892175195

(DOI: 10.1186/1471-2377-14-5, PubMed: 24397319, Elsevier: Scopus) Ryosuke Miyamoto, Hiroyuki Morino, Akio Yoshizawa, Yoshimichi Miyazaki, Hirofumi Maruyama, Nagahisa Murakami, Kei Fukada, Yuishin Izumi, Shinya Matsuura, Ryuji Kaji and Hideshi Kawakami :
Exome sequencing reveals a novel MRE11 mutation in a patient with progressive myoclonic ataxia,
Journal of the Neurological Sciences, 337, 1-2, 219-223, 2013.

(要約): Progressive myoclonic ataxia (PMA) is a clinical syndrome defined as progressive ataxia and myoclonus and infrequent seizures in the absence of progressive dementia. Due to the extremely heterogeneous nature of PMA, a large proportion of PMA cases remain molecularly undiagnosed. The aim of this study was to clarify the molecular etiology of PMA. The patient was a 52-year-old female from consanguineous parents. She developed a jerking neck movement at age 9, which gradually expanded to her entire body. On physical examination at age 47, she exhibited generalized, spontaneous myoclonus that occurred continuously. She also presented with mild limb and truncal ataxia. An electroencephalogram revealed no abnormalities. A brain MRI displayed no atrophy of the cerebellum. Electrophysiological studies suggested myoclonus of a subcortical origin. For further evaluation, we performed exome sequencing, and we identified a novel homozygous missense mutation in the MRE11 gene (NM_005590:c.140C>T:p.A47V). Subsequently, we analyzed the expression of MRE11 and related proteins (RAD50 and NBS1) via Western blot, and they were markedly decreased compared to a healthy control. Mutations in the MRE11 gene have been known to cause an ataxia-telangiectasia-like (ATLD) disorder. Accumulating evidence has indicated that its wide phenotypic variations in ATLD correspond to genotypic differences. Interestingly, our case exhibited a relatively mild decrease in NBS1 compared to previously reported cases of a homozygous missense mutation, which may account for the milder phenotype in this patient. Moreover, together with a recently reported case of an MRE11 mutation, it is suggested that MRE11 mutations can present as PMA.
(キーワード): Ataxia-telangiectasia-like disorder / MRE11 / Myoclonus / Neurogenetics / Progressive myoclonic ataxia / Tremor
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jns.2013.11.032
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24332946; ● Summary page in Scopus @ Elsevier: 2-s2.0-84894065668

(DOI: 10.1016/j.jns.2013.11.032, PubMed: 24332946, Elsevier: Scopus) H. Maruyama, Hiroyuki Morino, R. Miyamoto, N. Murakami, T. Hamano and H. Kawakami :
Exome sequencing reveals a novel ANO10 mutation in a Japanese patient with autosomal recessive spinocerebellar ataxia,
Clinical Genetics, 85, 3, 296-297, 2013.

(キーワード): Anoctamins / Atrophy / Cerebellum / Exome / Genes, Recessive / Humans / Japan / Magnetic Resonance Imaging / Male / Membrane Proteins / Middle Aged / Mutation / Positron-Emission Tomography / Spinocerebellar Ataxias
(出版サイトへのリンク): ● Publication site (DOI): 10.1111/cge.12140
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23551081; ● Summary page in Scopus @ Elsevier: 2-s2.0-84893021290

(DOI: 10.1111/cge.12140, PubMed: 23551081, Elsevier: Scopus) Ai Miyashiro, Katsunobu Sugihara, Toshitaka Kawarai, Ryosuke Miyamoto, Yuishin Izumi, Hiroyuki Morino, Hirofumi Maruyama, Antonio Orlacchio, Hideshi Kawakami and Ryuji Kaji :
Oromandibular dystonia associated with SCA36,
Movement Disorders, 28, 4, 558-559, 2013.

(キーワード): Botulinum Toxins, Type A / Dystonia / Dystonic Disorders / Female / Humans / Middle Aged / Nerve Tissue Proteins / Nuclear Proteins / Treatment Outcome
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/mds.25304
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23390045; ● Summary page in Scopus @ Elsevier: 2-s2.0-84876101146

(DOI: 10.1002/mds.25304, PubMed: 23390045, Elsevier: Scopus) Hirofumi Maruyama, Hiroyuki Morino, Yuishin Izumi, Kouichi Noda and Hideshi Kawakami :
Convenient diagnosis of spinal and bulbar muscular atrophy using a microchip electrophoresis system,
American Journal of Neurodegenerative Disease, 2, 1, 35-39, 2013.

(キーワード): Amyotrophic lateral sclerosis / Androgen receptor / CAG repeat / Microchip electrophoresis / Spinal and bulbar muscular atrophy
(文献検索サイトへのリンク): ● Summary page in Scopus @ Elsevier: 2-s2.0-84980052293

(Elsevier: Scopus) Ikuko Takeda, Tetsuya Takahashi, Hiroki Ueno, Hiroyuki Morino, Kazuhide Ochi, Takeshi Nakamura, Naohisa Hosomi, Hideshi Kawakami, Kouichi Hashimoto and Masayasu Matsumoto :
Autosomal recessive Andersen-Tawil syndrome with a novel mutation L94P in Kir2.1,
Neurology and Clinical Neuroscience, 1, 4, 131-137, 2013.

(キーワード): Andersen-Tawil syndrome / Autosomal recessive / KCNJ2 / Kir2.1 / Patch clamp
(出版サイトへのリンク): ● Publication site (DOI): 10.1111/ncn3.38
(文献検索サイトへのリンク): ● Summary page in Scopus @ Elsevier: 2-s2.0-84888005453

(DOI: 10.1111/ncn3.38, Elsevier: Scopus) Katsunobu Sugihara, Hirofumi Maruyama, Hiroyuki Morino, Ryosuke Miyamoto, Hiroki Ueno, Masayasu Matsumoto, Ryuji Kaji, Hiroshi Kitaguchi, Motohiro Yukitake, Yasuto Higashi, Kazuto Nishinaka, Masaya Oda, Yuishin Izumi and Hideshi Kawakami :
The clinical characteristics of spinocerebellar ataxia 36: A study of 2121 Japanese ataxia patients,
Movement Disorders, 27, 9, 1158-1163, 2012.

(要約): Spinocerebellar ataxia 36 is caused by the expansion of the intronic GGCCTG hexanucleotide repeat in NOP56. The original article describing this condition demonstrated that patients with spinocerebellar ataxia 36 present with tongue atrophy, a finding that had not been seen in previous types of spinocerebellar ataxias. A total of 2121 patients with clinically diagnosed spinocerebellar ataxia participated in the study. We screened our patient samples for spinocerebellar ataxia 36 using the repeat-primed polymerase chain reaction method and also determined the clinical features of spinocerebellar ataxia 36. Of the ataxia cases examined, 12 were identified as spinocerebellar ataxia 36. Of these, 7 cases (6 families) were autosomal dominant, 4 cases (three families) had a positive family history but were not autosomal dominant, and 1 case was sporadic. The average age of onset was 51.7 years, and disease progression was slow. The main symptoms and signs of disease included ataxia, dysarthria, and hyperreflexia. Approximately half the affected patients demonstrated nystagmus, bulging eyes, and a positive pathological reflex, although dysphagia, tongue atrophy, and hearing loss were rare. Moreover, the observed atrophy of the cerebellum and brain stem was not severe. The patients identified in this study were concentrated in western Japan. The frequency of spinocerebellar ataxia 36 was approximately 1.2% in the autosomal dominant group, and the age of onset for this condition was later in comparison with other spinocerebellar ataxia subtypes.
(キーワード): Age of onset / Cerebellar atrophy / Hyperreflexia / Regional distribution / SCA36
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/mds.25092
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 22753339; ● Summary page in Scopus @ Elsevier: 2-s2.0-84864741860

(DOI: 10.1002/mds.25092, PubMed: 22753339, Elsevier: Scopus) Hiroki Ueno, Keitaro Kobatake, Masayasu Matsumoto, Hiroyuki Morino, Hirofumi Maruyama and Hideshi Kawakami :
Severe brain atrophy after long-term survival seen in siblings with familial amyotrophic lateral sclerosis and a mutation in the optineurin gene: A case series,
Journal of Medical Case Reports, 5, 2011.

(出版サイトへのリンク): ● Publication site (DOI): 10.1186/1752-1947-5-573
(文献検索サイトへのリンク): ● Summary page in Scopus @ Elsevier: 2-s2.0-83155185448

(DOI: 10.1186/1752-1947-5-573, Elsevier: Scopus) Koichi Hagiwara, Hiroyuki Morino, Jun Shiihara, Tomoaki Tanaka, Hitoshi Miyazawa, Tomoko Suzuki, Masakazu Kohda, Yasushi Okazaki, Kuniaki Seyama and Hideshi Kawakami :
Homozygosity mapping on homozygosity haplotype analysis to detect recessive disease-causing genes from a small number of unrelated, outbred patients,
PLoS ONE, 6, 9, e25059, 2011.

(要約): Genes involved in disease that are not common are often difficult to identify; a method that pinpoints them from a small number of unrelated patients will be of great help. In order to establish such a method that detects recessive genes identical-by-descent, we modified homozygosity mapping (HM) so that it is constructed on the basis of homozygosity haplotype (HM on HH) analysis. An analysis using 6 unrelated patients with Siiyama-type α1-antitrypsin deficiency, a disease caused by a founder gene, the correct gene locus was pinpointed from data of any 2 patients (length: 1.2-21.8 centimorgans, median: 1.6 centimorgans). For a test population in which these 6 patients and 54 healthy subjects were scrambled, the approach accurately identified these 6 patients and pinpointed the locus to a 1.4-centimorgan fragment. Analyses using synthetic data revealed that the analysis works well for IBD fragment derived from a most recent common ancestor (MRCA) who existed less than 60 generations ago. The analysis is unsuitable for the genes with a frequency in general population more than 0.1. Thus, HM on HH analysis is a powerful technique, applicable to a small number of patients not known to be related, and will accelerate the identification of disease-causing genes for recessive conditions.
(キーワード): Adult / Aged / Aged, 80 and over / Case-Control Studies / Chromosome Mapping / Consanguinity / Genes, Recessive / Haplotypes / Homozygote / Humans / Middle Aged / Polymorphism, Single Nucleotide / Young Adult / alpha 1-Antitrypsin Deficiency
(出版サイトへのリンク): ● Publication site (DOI): 10.1371/journal.pone.0025059
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21949849; ● Summary page in Scopus @ Elsevier: 2-s2.0-80052931233

(DOI: 10.1371/journal.pone.0025059, PubMed: 21949849, Elsevier: Scopus) Eiji Tanaka, Hirofumi Maruyama, Hiroyuki Morino and Hideshi Kawakami :
Detection of large expansions in SCA8 using a fluorescent repeat-primed PCR assay,
Hiroshima Journal of Medical Sciences, 60, 3, 63-66, 2011.

(要約): Spinocerebellar ataxia type 8 (SCA8) is a neurodegenerative disorder characterized by slowly progressive cerebellar ataxia. It is caused by bidirectional expression of (CUG)n expansion in the ATXN80S/ATXN8 gene and (CAG)n expansion transcripts in ATXN8. The diagnosis of SCA8 must be confirmed by the presence of a (CTG)n trinucleotide repeat expansion in the ATXN8OS gene. On the other hand, there are many human genetic diseases that are caused by expansion of short tandem repeats. Since Werner et al proposed a repeat-primed fluorescent PCR to detect large CTG-repeats in myotonic dystrophy, Friedreich ataxia, SCA2, SCA7, SCA10 and SCA12 have been reported. In this study, we applied a fluorescent PCR method for detection of expanded repeats in the ATXN8OS/ATXN8 gene. Although this test cannot give a precise estimate of the size of the expansion, it proved useful for confirming the presence of expansions in SCA8.
(キーワード): Repeat-primed PCR / SCA8
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 22053702; ● Summary page in Scopus @ Elsevier: 2-s2.0-82055169539

(PubMed: 22053702, Elsevier: Scopus) W. Katherine Snapinn, B. Eric Larson, Hideshi Kawakami, Hiroshi Ujike, R. Amy Borenstein, Yuishin Izumi, Ryuji Kaji, Hirofumi Maruyama, F. Ignacio Mata, Hiroyuki Morino, Masaya Oda, W. Debby Tsuang, Dora Yearout, L. Karen Edwards and P. Cyrus Zabetian :
The UCHL1 S18Y polymorphism and Parkinson's disease in a Japanese population,
Parkinsonism & Related Disorders, 17, 6, 473-475, 2011.

(要約): UCHL1 plays an important role in the ubiquitin-proteasome system and is a biologically plausible candidate gene for Parkinson's disease (PD). However, results from genetic association studies of the UCHL1 S18Y polymorphism have been equivocal. Meta-analyses indicate that the polymorphism's risk effect might be restricted to Asian populations and early-onset disease. To further explore the role of UCHL1 in PD, we genotyped S18Y in 605 PD patients and 1620 controls of Japanese ancestry. We did not find evidence of an association in the overall sample (SY vs. SS: adjusted OR=1.11, P=0.37; YY vs. SS: adjusted OR=1.01, P=0.94). In the early-onset stratum, however, we observed a trend toward a reduction in risk for those with the Y allele (SY vs. SS, adjusted OR, 0.75; 95% CI, 0.47-1.20; YY vs. SS, OR, 0.64; 95% CI, 0.36-1.14; trend test, P=0.12). These results indicate that, if involved in PD, the S18Y variant is not a major determinant of risk and its effect might be restricted to early-onset disease.
(キーワード): Association study / Parkinson's disease / UCHL1
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.parkreldis.2011.01.019
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21345711; ● Summary page in Scopus @ Elsevier: 2-s2.0-79959368204

(DOI: 10.1016/j.parkreldis.2011.01.019, PubMed: 21345711, Elsevier: Scopus) Katsunobu Sugihara, Hirofumi Maruyama, Masaki Kamada, Hiroyuki Morino and Hideshi Kawakami :
Screening for OPTN mutations in amyotrophic lateral sclerosis in a mainly Caucasian population,
Neurobiology of Aging, 32, 10, 1923-1923.e10, 2011.

(キーワード): ALS / Amyotrophic lateral sclerosis / Optineurin / OPTN / Polymorphism
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.neurobiolaging.2011.03.024
(文献検索サイトへのリンク): ● Summary page in Scopus @ Elsevier: 2-s2.0-80051570216

(DOI: 10.1016/j.neurobiolaging.2011.03.024, Elsevier: Scopus) (名) Huqun, Ichiro Shun Fukuyama, Hiroyuki Morino, Hiroshi Miyazawa, Tomoaki Tanaka, Tomoko Suzuki, Masakazu Kohda, Hideshi Kawakami, Yasushi Okazaki, Kuniaki Seyama and Koichi Hagiwara :
A quantitatively-modeled homozygosity mapping algorithm, qHomozygosityMapping, utilizing whole genome single nucleotide polymorphism genotyping data,
BMC Bioinformatics, 11, SUPPL. 7, S5, 2010.

(要約): Homozygosity mapping is a powerful procedure that is capable of detecting recessive disease-causing genes in a few patients from families with a history of inbreeding. We report here a homozygosity mapping algorithm for high-density single nucleotide polymorphism arrays that is able to (i) correct genotyping errors, (ii) search for autozygous segments genome-wide through regions with runs of homozygous SNPs, (iii) check the validity of the inbreeding history, and (iv) calculate the probability of the disease-causing gene being located in the regions identified. The genotyping error correction restored an average of 94.2% of the total length of all regions with run of homozygous SNPs, and 99.9% of the total length of them that were longer than 2 cM. At the end of the analysis, we would know the probability that regions identified contain a disease-causing gene, and we would be able to determine how much effort should be devoted to scrutinizing the regions. We confirmed the power of this algorithm using 6 patients with Siiyama-type α1-antitrypsin deficiency, a rare autosomal recessive disease in Japan. Our procedure will accelerate the identification of disease-causing genes using high-density SNP array data.
(キーワード): Algorithms / Consanguinity / Genes, Recessive / Genome / Genomics / Genotype / Homozygote / Humans / Japan / Models, Genetic / Polymorphism, Single Nucleotide / Reproducibility of Results / alpha 1-Antitrypsin Deficiency
(出版サイトへのリンク): ● Publication site (DOI): 10.1186/1471-2105-11-S7-S5
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21106127; ● Summary page in Scopus @ Elsevier: 2-s2.0-77957924025

(DOI: 10.1186/1471-2105-11-S7-S5, PubMed: 21106127, Elsevier: Scopus) Hirofumi Maruyama, Hiroyuki Morino, Hidefumi Ito, Yuishin Izumi, Hidemasa Kato, Yasuhito Watanabe, Yoshimi Kinoshita, Masaki Kamada, Hiroyuki Nodera, Hidenori Suzuki, Osamu Komure, Shinya Matsuura, Keitaro Kobatake, Nobutoshi Morimoto, Koji Abe, Naoki Suzuki, Masashi Aoki, Akihiro Kawata, Takeshi Hirai, Takeo Kato, Kazumasa Ogasawara, Asao Hirano, Toru Takumi, Hirofumi Kusaka, Koichi Hagiwara, Ryuji Kaji and Hideshi Kawakami :
Mutations of optineurin in amyotrophic lateral sclerosis,
Nature, 465, 7295, 223-226, 2010.

(要約): Amyotrophic lateral sclerosis (ALS) has its onset in middle age and is a progressive disorder characterized by degeneration of motor neurons of the primary motor cortex, brainstem and spinal cord. Most cases of ALS are sporadic, but about 10% are familial. Genes known to cause classic familial ALS (FALS) are superoxide dismutase 1 (SOD1), ANG encoding angiogenin, TARDP encoding transactive response (TAR) DNA-binding protein TDP-43 (ref. 4) and fused in sarcoma/translated in liposarcoma (FUS, also known as TLS). However, these genetic defects occur in only about 20-30% of cases of FALS, and most genes causing FALS are unknown. Here we show that there are mutations in the gene encoding optineurin (OPTN), earlier reported to be a causative gene of primary open-angle glaucoma (POAG), in patients with ALS. We found three types of mutation of OPTN: a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation within its ubiquitin-binding domain. Analysis of cell transfection showed that the nonsense and missense mutations of OPTN abolished the inhibition of activation of nuclear factor kappa B (NF-kappaB), and the E478G mutation revealed a cytoplasmic distribution different from that of the wild type or a POAG mutation. A case with the E478G mutation showed OPTN-immunoreactive cytoplasmic inclusions. Furthermore, TDP-43- or SOD1-positive inclusions of sporadic and SOD1 cases of ALS were also noticeably immunolabelled by anti-OPTN antibodies. Our findings strongly suggest that OPTN is involved in the pathogenesis of ALS. They also indicate that NF-kappaB inhibitors could be used to treat ALS and that transgenic mice bearing various mutations of OPTN will be relevant in developing new drugs for this disorder.
(キーワード): Adolescent / Adult / Aged / Aged, 80 and over / Amino Acid Sequence / Amyotrophic Lateral Sclerosis / Asian People / Base Sequence / Cell Cycle Proteins / Child / Codon, Nonsense / Consanguinity / Cytoplasm / DNA-Binding Proteins / Exons / Female / Humans / Japan / Male / Membrane Transport Proteins / Middle Aged / Mutant Proteins / Mutation / Mutation, Missense / NF-kappa B / Pedigree / Polymorphism, Single Nucleotide / Protein Transport / Sequence Deletion / Superoxide Dismutase / Superoxide Dismutase-1 / Transcription Factor TFIIIA / Young Adult
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/nature08971
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20428114; ● Summary page in Scopus @ Elsevier: 2-s2.0-77952419246

(DOI: 10.1038/nature08971, PubMed: 20428114, Elsevier: Scopus) P. Cyrus Zabetian, Mitsutoshi Yamamoto, N. Alexis Lopez, Hiroshi Ujike, F. Ignacio Mata, Yuishin Izumi, Ryuji Kaji, Hirofumi Maruyama, Hiroyuki Morino, Masaya Oda, M. Carolyn Hutter, L. Karen Edwards, D. Gerard Schellenberg, W. Debby Tsuang, Dora Yearout, B. Eric Larson and Hideshi Kawakami :
LRRK2 mutations and risk variants in Japanese patients with Parkinson's disease,
Movement Disorders, 24, 7, 1034-1041, 2009.

(要約): Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic determinant of Parkinson's disease (PD) in European-derived populations, but far less is known about LRRK2 mutations and susceptibility alleles in Asians. To address this issue, we sequenced the LRRK2 coding region in 36 patients with familial PD, then genotyped variants of interest in an additional 595 PD cases and 1,641 controls who were all of Japanese ancestry. We also performed a meta-analysis of studies on G2385R, a polymorphism previously reported to associate with PD. One pathogenic (G2019S) and one putative pathogenic (R1067Q) mutation were each observed in two patients with sporadic PD. The overall mutation frequency among patients was 0.6%. G2385R was highly associated with PD under a dominant model in our dataset (adjusted OR, 1.83; 95% CI, 1.31-2.54; P = 3.3 x 10(-4)) and similar results were seen in the meta-analysis (summary OR assuming fixed effects, 2.55; 95% CI, 2.10-3.10). G2385R represents the first consistently replicated common PD susceptibility variant in a non-European population and its effect size is substantially greater than that reported for other well-validated genetic risk factors for the disease. However, LRRK2 mutations appear to be rare among Japanese patients with PD.
(キーワード): Mutation / Parkinson / Polymorphism
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/mds.22514
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19343804; ● Summary page in Scopus @ Elsevier: 2-s2.0-67651173105

(DOI: 10.1002/mds.22514, PubMed: 19343804, Elsevier: Scopus) Masaki Kamada, Hirofumi Maruyama, Eiji Tanaka, Hiroyuki Morino, Reika Wate, Hidefumi Ito, Hirofumi Kusaka, Yuji Kawano, Tetsuro Miki, Hiroyuki Nodera, Yuishin Izumi, Ryuji Kaji and Hideshi Kawakami :
Screening for TARDBP mutations in Japanese familial amyotrophic lateral sclerosis,
Journal of the Neurological Sciences, 284, 1-2, 69-71, 2009.

(要約): TAR-DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene on chromosome 1p36.22, has been identified as the major pathological protein in abnormal inclusions in neurons and glial cells in sporadic amyotrophic lateral sclerosis (SALS), SOD1-negative familial ALS (FALS) and frontotemporal lobar dementia (FTLD). Twenty mutations of TARDBP in SOD1-negative FALS and SALS cases have been reported so far. To investigate the presence and frequency of TARDBP mutations in Japanese SOD1-negative FALS patients, we performed mutational screening of TARDBP in 30 SOD1-negative FALS patients. An N352S mutation was found in one case of FALS, but no TARDBP mutations were found in cases of SALS. It was thought that this mutation increases TDP-43 phosphorylation. This might lead to impaired nuclear cytoplasmic transport or protein-protein interaction, thereby leading to TDP-43 accumulation.
(キーワード): ALS / Amyotrophic lateral sclerosis / Familial / TARDBP mutation / TDP-43
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jns.2009.04.017
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19411082; ● Summary page in Scopus @ Elsevier: 2-s2.0-67849106393

(DOI: 10.1016/j.jns.2009.04.017, PubMed: 19411082, Elsevier: Scopus) Isha Shrestha, Tomohiko Ohshita, Hiromitsu Naka, Hiroyuki Morino and Masayasu Matsumoto :
Cytotoxic edema in neuro-Behcet's disease?,
Internal Medicine, 47, 23, 2073-2076, 2008.

(要約): We report a case of a 52-year-old woman with Behcet's disease who presented with dysarthria and right-sided hemiparesis. T2-weighted and diffusion-weighted images (DWI) showed a hyperintense lesion in the left pons with a relatively decreased apparent diffusion coefficient (ADC). Imaging showed almost complete resolution of the lesion after treatment with prednisolone. The atypical DWI and ADC findings in this case may reflect cytotoxic edema due to excitotoxic brain injury. This case thus illustrates the radiological diversity of neuro-Behcet's lesions.
(キーワード): Apparent diffusion coefficient / Cytotoxic edema / Diffusion-weighted imaging / Magnetic resonance imaging / Neuro-Behcet's disease
(出版サイトへのリンク): ● Publication site (DOI): 10.2169/internalmedicine.47.1134
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19043264; ● Summary page in Scopus @ Elsevier: 2-s2.0-61749099999

(DOI: 10.2169/internalmedicine.47.1134, PubMed: 19043264, Elsevier: Scopus) Kate Craig, Yoshihisa Takiyama, Wen Bing Soong, B. Laura Jardim, Luiza Maria Saraiva-Pereira, Kieren Lythgow, Hiroyuki Morino, Hirofumi Maruyama, Hideshi Kawakami and F. Patrick Chinnery :
Pathogenic expansions of the SCA6 locus are associated with a common CACNA1A haplotype across the globe: Founder effect or predisposing chromosome?,
European Journal of Human Genetics : EJHG, 16, 7, 841-847, 2008.

(要約): Spinocerebellar ataxia type 6 (SCA6) is a common cause of dominantly inherited ataxia due to an expansion of the CAG repeat in the CACNA1A gene. Affected individuals from the same population share a common haplotype, raising the possibility that most SCA6 cases have descended from a small number of common founders across the globe. To test this hypothesis, we carried out haplotype analysis on SCA6 families from Europe, South America and the Far East, including an established de novo SCA6 expansion. A core CACNA1A disease haplotype was found in affected individuals across the globe. This was also present in the unaffected father of the de novo case, suggesting that the shared chromosome predisposes to the CAG repeat expansion at the SCA6 locus. The SCA6 expansion lies within a CpG island, which could act as a cis-acting element predisposing to repeat expansion as for other CAG/CTG repeat diseases. Polymorphic variation in this region may explain the high-risk haplotype found in SCA6 families.
(キーワード): Alleles / Case-Control Studies / Chromosomes, Human / Chromosomes, Human, Pair 19 / Computational Biology / Family / Female / Founder Effect / Haplotypes / Humans / Male / Microsatellite Repeats / Pedigree / Spinocerebellar Ataxias
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/ejhg.2008.20
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18285829; ● Summary page in Scopus @ Elsevier: 2-s2.0-45749103722

(DOI: 10.1038/ejhg.2008.20, PubMed: 18285829, Elsevier: Scopus) Eiji Tanaka, Hirofumi Maruyama, Hiroyuki Morino, Eiko Nakajima and Hideshi Kawakami :
The CNTN4 c.4256C>T mutation is rare in Japanese with inherited spinocerebellar ataxia,
Journal of the Neurological Sciences, 266, 1-2, 180-181, 2007.

(要約): To confirm the incidence of SCA16 in Japan, we screened DNA samples from a number of patients of ataxia of unknown etiology for the substitution. We examined a total of 323 DNA samples from Japanese patients with inherited spinocerebellar ataxia. We found no 317-base pair band in the patients with ataxia of unknown etiology. It seemed that this mutation (c.4256C>T) is rare in Japanese patients with inherited spinocerebellar ataxia. Mutations in other populations should be analyzed. Pathological examinations and molecular biological examinations are needed to confirm that this mutation is a true cause of SCA16.
(キーワード): Contactin 4 / Mutation / SCA16
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jns.2007.09.004
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 17915252; ● Summary page in Scopus @ Elsevier: 2-s2.0-38749132487

(DOI: 10.1016/j.jns.2007.09.004, PubMed: 17915252, Elsevier: Scopus) Keiko Hiramoto, Hideshi Kawakami, Kimiko Inoue, Takahiro Seki, Hirofumi Maruyama, Hiroyuki Morino, Masayasu Matsumoto, Kaoru Kurisu and Norio Sakai :
Identification of a new family of spinocerebellar ataxia type 14 in the Japanese spinocerebellar ataxia population by the screening of PRKCG exon 4,
Movement Disorders, 21, 9, 1355-1360, 2006.

(要約): Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant neurodegenerative disorder characterized by cerebellar ataxia and intermittent axial myoclonus. Various mutations have been found in the PRKCG gene encoding protein kinase C gamma in SCA14 families. Most of those mutations have been found in exon 4 of the PRKCG gene. We performed polymerase chain reaction (PCR)-based screening to clarify the approximate morbidity rate of the disease in the Japanese SCA population. We screened exon 4 of the PRKCG gene in 882 SCA patients with undefined etiologies using denaturing high-performance liquid chromatography and subsequent direct sequencing. We found a novel C/T missense mutation with a Ser119-to-Phe substitution (S119F) in 2 patients and subsequently found that they belonged to the same family. This S119F mutation was not found in 259 control individuals. Further PCR-based analysis revealed an additional 5 members with the same mutation in this family. Cerebellar ataxia was manifested in 5 of those 7 members. The main symptom in 4 of the 5 affected members was pure cerebellar ataxia with late onset. They had no myoclonus, extrapyramidal signs, ophthalmoplegia, or intellectual disturbance, some of which were found in previously reported SCA families. One patient showed intractable epilepsy, severe walking disturbance, and trunk ataxia with early onset. The results of this study suggest that the frequency of SCA14 in the Japanese SCA population is very low.
(キーワード): Point mutation / Protein kinase C / Spinocerebellar ataxia
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/mds.20970
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16763984; ● Summary page in Scopus @ Elsevier: 2-s2.0-33750348973

(DOI: 10.1002/mds.20970, PubMed: 16763984, Elsevier: Scopus) P. C. Zabetian, Hiroyuki Morino, H. Ujike, M. Yamamoto, M. Oda, H. Maruyama, Y. Izumi, R. Kaji, A. Griffith, C. B. Leis, W. J. Roberts, D. Yearout, A. Samii and H. Kawakami :
Identification and haplotype analysis of LRRK2 G2019S in Japanese patients with Parkinson disease,
Neurology, 67, 4, 697-699, 2006.

(要約): LRRK2 G2019S is the most common known cause of Parkinson disease (PD) in patients of European origin, but little is known about its distribution in other populations. The authors identified two of 586 Japanese patients with PD heterozygous for the mutation who shared a haplotype distinct from that observed in Europeans. This suggests that G2019S originated from separate founders in Europe and Japan and is more widely dispersed than previously recognized.
(キーワード): Adolescent / Adult / Aged / Aged, 80 and over / DNA Mutational Analysis / Female / Genetic Markers / Genetic Predisposition to Disease / Haplotypes / Humans / Japan / Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Male / Middle Aged / Mutation / Parkinson Disease / Prevalence / Protein Serine-Threonine Kinases / Risk Assessment / Risk Factors / Washington
(出版サイトへのリンク): ● Publication site (DOI): 10.1212/01.wnl.0000227732.37801.d4
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16728648; ● Summary page in Scopus @ Elsevier: 2-s2.0-33747701497

(DOI: 10.1212/01.wnl.0000227732.37801.d4, PubMed: 16728648, Elsevier: Scopus) Michie Nishitani, 森野豊之, Naoki Matsuoka, Takafumi Miyachi, Hirofumi Maruyama, Tatsuo Kohriyama, Yasuyo Mimori, Masayasu Matsumoto, Hiromitsu Naka, Eiichi Nomura, Hiroshi Kajikawa :
Ultrasonographic evaluation of bow hunter's syndrome,
日本内科学会雑誌, 93, 11, 2424-2426, 2004年.

(キーワード): Adult / Female / Head Movements / Humans / Magnetic Resonance Angiography / Neck / Syndrome / Ultrasonography / Vertebrobasilar Insufficiency
(出版サイトへのリンク): ● Publication site (DOI): 10.2169/naika.93.2424
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15624482; ● Summary page in Scopus @ Elsevier: 2-s2.0-16644366523

(DOI: 10.2169/naika.93.2424, PubMed: 15624482, Elsevier: Scopus) Hideo Terasawa, Masaya Oda, Hiroyuki Morino, Takafumi Miyachi, Yuishin Izumi, Hirofumi Maruyama, Masayasu Matsumoto and Hideshi Kawakami :
A novel haplotype of spinocerebellar ataxia type 6 contributes to the highest prevalence in Western Japan,
Neuroscience Letters, 358, 2, 107-110, 2004.

(要約): The highest prevalence rate of spinocerebellar ataxia type 6 (SCA6) in the worldwide population is in the Chugoku and Kansai areas of Western Japan, but the reason of this geographic characteristics is unclear. We investigated the predisposing haplotypes and their geographic distribution. Genotyping of five microsatellite markers and three single nucleotide polymorphisms linked to the CACNA1A gene in 150 Japanese SCA6 patients from unrelated 118 families revealed three major haplotypes, carrying a pool of one common haplotype core. A founder chromosome was thought to have historically diverged into at least three types. One of the major haplotypes newly identified showed a strong geographical cluster around the Seto Inland Sea in the Chugoku and Kansai areas of Western Japan, whereas the others were widely distributed throughout Japan. The distribution of predisposing haplotypes contributes to the geographical differences in prevalence of SCA6.
(キーワード): CACNA1A / CAG-repeat / Founder effect / Haplotype / Microsatellite / Single nucleotide polymorphisms / Spinocerebellar ataxia type 6
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.neulet.2004.01.007
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15026160; ● Summary page in Scopus @ Elsevier: 2-s2.0-1542509359

(DOI: 10.1016/j.neulet.2004.01.007, PubMed: 15026160, Elsevier: Scopus) Masaya Oda, Hirofumi Maruyama, Osamu Komure, Hiroyuki Morino, Hideo Terasawa, Yuishin Izumi, Tohru Imamura, Minoru Yasuda, Keiji Ichikawa, Masafumi Ogawa, Masayasu Matsumoto and Hideshi Kawakami :
Possible Reduced Penetrance of Expansion of 44 to 47 CAG/CAA Repeats in the TATA-Binding Protein Gene in Spinocerebellar Ataxia Type 17,
Archives of Neurology, 61, 2, 209-212, 2004.

(要約): Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant cerebellar ataxia caused by expansion of CAG/CAA trinucleotide repeats in the TATA-binding protein (TBP) gene. Because the number of triplets in patients with SCA17 in previous studies ranged from 43 to 63, the normal number of trinucleotide units has been considered to be 42 or less. However, some healthy subjects in SCA17 pedigrees carry alleles with the same number of expanded repeats as patients with SCA17. To investigate the minimum number of CAG/CAA repeats in the TBP gene that causes SCA17. We amplified the region of the TBP gene containing the CAG/CAA repeat by means of polymerase chain reaction and performed fragment and sequence analyses. The subjects included 734 patients with SCA (480 patients with sporadic SCA and 254 patients with familial SCA) without CAG repeat expansions at the SCA1, SCA2, Machado-Joseph disease, SCA6, SCA7, or dentatorubral-pallidolluysian atrophy loci, with 162 healthy subjects, 216 patients with Parkinson disease, and 195 with Alzheimer disease as control subjects. Eight patients with SCA possessed an allele with more than 43 CAG/CAA repeats. Among the non-SCA groups, alleles with 43 to 45 repeats were seen in 3 healthy subjects and 2 with Parkinson disease. In 1 SCA pedigree, a patient with possible SCA17 and her healthy sister had alleles with 45 repeats. A 34-year-old man carrying alleles with 47 and 44 repeats (47/44) had developed progressive cerebellar ataxia and myoclonus at 25 years of age, and he exhibited dementia and pyramidal signs. He was the only affected person in his pedigree, although his father and mother carried alleles with mildly expanded repeats (44/36 and 47/36, respectively). In another pedigree, 1 patient carried a 43-repeat allele, whereas another patient had 2 normal alleles, indicating that the 43-repeat allele may not be pathologic in this family. We estimate that 44 CAG/CAA repeats is the minimum number required to cause SCA17. However, the existence of unaffected subjects with mildly expanded triplets suggests that the TBP gene mutation may not penetrate fully. Homozygosity of alleles with mildly expanded triplet repeats in the TBP gene might contribute to the pathologic phenotype.
(キーワード): Adult / Alleles / Alzheimer Disease / DNA / DNA Primers / Dementia / Female / Gait Ataxia / Humans / Male / Memory Disorders / Middle Aged / Myoclonus / Pedigree / Penetrance / Reverse Transcriptase Polymerase Chain Reaction / Speech Disorders / Spinocerebellar Ataxias / TATA-Box Binding Protein / Trinucleotide Repeats
(出版サイトへのリンク): ● Publication site (DOI): 10.1001/archneur.61.2.209
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 14967767; ● Summary page in Scopus @ Elsevier: 2-s2.0-10744232450

(DOI: 10.1001/archneur.61.2.209, PubMed: 14967767, Elsevier: Scopus) Masaya Oda, Hirofumi Maruyama, Yuishin Izumi, Hiroyuki Morino, Tsuyoshi Torii, Shigenobu Nakamura and Hideshi Kawakami :
Dinucleotide Repeat Polymorphism in Interferon-γ Gene Is Not Associated with Sporadic Alzheimer's Disease,
American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 124 B, 1, 48-49, 2004.

(要約): Various factors have been suggested to participate in Alzheimer's disease (AD) pathology, and some inflammatory cytokines may play an important role in the development of AD. Interferon-gamma (IFNG), an important pro-inflammatory cytokine, is encoded by a single gene mapped to chromosome 12, one of the candidate locus of AD. The first intron in the IFNG gene represents a CA repeat polymorphism that is possible to affect the IFNG secretion dose. We speculate that the polymorphism may have some roles on the inflammatory process and the pathologic change in AD, so we analyzed the IFNG gene polymorphism in 199 Japanese AD patients and 225 Japanese controls. There were no significant differences in allele frequency between the AD and control groups. We conclude that IFNG gene polymorphism is not associated with development of AD.
(キーワード): Alzheimer's disease / Interferon-γ gene / Polymorphism
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/ajmg.b.20097
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 14681912; ● Summary page in Scopus @ Elsevier: 2-s2.0-0346102516

(DOI: 10.1002/ajmg.b.20097, PubMed: 14681912, Elsevier: Scopus) Yuishin Izumi, Hirofumi Maruyama, Masaya Oda, Hiroyuki Morino, Takayuki Okada, Hidefumi Ito, Iwao Sasaki, Hiroyasu Tanaka, Osamu Komure, Fukashi Udaka, Shigenobu Nakamura and Hideshi Kawakami :
SCA8 repeat expansion: Large CTA/CTG repeat alleles are more common in ataxic patients, including those with SCA6,
American Journal of Human Genetics, 72, 3, 704-709, 2003.

(要約): We analyzed the SCA8 CTA/CTG repeat in a large group of Japanese subjects. The frequency of large alleles (85-399 CTA/CTG repeats) was 1.9% in spinocerebellar ataxia (SCA), 0.4% in Parkinson disease, 0.3% in Alzheimer disease, and 0% in a healthy control group; the frequency was significantly higher in the group with SCA than in the control group. Homozygotes for large alleles were observed only in the group with SCA. In five patients with SCA from two families, a large SCA8 CTA/CTG repeat and a large SCA6 CAG repeat coexisted. Age at onset was correlated with SCA8 repeats rather than SCA6 repeats in these five patients. In one of these families, at least one patient showed only a large SCA8 CTA/CTG repeat allele, with no large SCA6 CAG repeat allele. We speculate that the presence of a large SCA8 CTA/CTG repeat allele influences the function of channels such as alpha(1A)-voltage-dependent calcium channel through changing or aberrant splicing, resulting in the development of cerebellar ataxia, especially in homozygous patients.
(キーワード): Asian People / Base Sequence / Calcium Channels / DNA / DNA Primers / Female / Humans / Japan / Male / Nerve Tissue Proteins / Parkinson Disease / Pedigree / RNA, Long Noncoding / RNA, Untranslated / Reference Values / Spinocerebellar Ataxias / Trinucleotide Repeats
(出版サイトへのリンク): ● Publication site (DOI): 10.1086/367775
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 12545428; ● Summary page in Scopus @ Elsevier: 2-s2.0-0037372986

(DOI: 10.1086/367775, PubMed: 12545428, Elsevier: Scopus) Hirofumi Maruyama, Yuishin Izumi, Hiroyuki Morino, Masaya Oda, Nakamura Toji Shigenobu Hiromasa and Hideshi Kawakami :
Difference in disease-free survival curve and regional distribution according to subtype of spinocerebellar ataxia: A study of 1,286 Japanese patients,
American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 114, 5, 578-583, 2002.

(要約): Expansions of trinucleotide repeats have been discovered in spinocerebellar ataxia (SCA) types 1, 2, 6, 7, 12, and 17, Machado-Joseph disease (MJD/SCA3), and dentatorubropallidoluysian atrophy (DRPLA). However, the frequency of familial SCA in Japan remains unclear. The number of trinucleotide repeats was determined for 1,286 patients. Three hundred and thirty families (523 cases) were autosomal dominant group (A), and 165 families were positive for family history but not autosomal dominant group (B), while the remaining 598 cases were the sporadic group (C). The frequency of SCA subtypes in autosomal dominant group was: 1) 5.5% for SCA1; 2) 2.4% for SCA2; 3) 27.6% for MJD/SCA3; 4) 25.5% for SCA6; 5) 0.3% for SCA17; and 6) 7.3% for DRPLA. Abnormal expansion of SCA12 was not detected. Another 31.5% of the patients in the autosomal dominant group had unknown genetic abnormalities. Within group B, SCA6 was the most prominent and within the sporadic group MJD/SCA3 and SCA6 were the most common subtypes observed. The disease-free survival curve of SCA6 was different from that of other SCAs and the mean age at onset for SCA6 was found to be later than that of the other types. Regional differences were observed in the relative rate of SCA subtypes. MJD/SCA3 appears more common in the Kanto and Kyushu districts of Japan, whereas SCA6 is most common in the Chugoku district. In order to establish an effective social welfare system for SCA patients, clinical course and regional differences in the prevalence of SCA subtypes must be taken into consideration.
(キーワード): CAG repeat / Regional difference / Spinocerebellar ataxia / Survival curve
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/ajmg.10514
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 12116198; ● Summary page in Scopus @ Elsevier: 2-s2.0-0037043031

(DOI: 10.1002/ajmg.10514, PubMed: 12116198, Elsevier: Scopus) Masataka Nishimura, Hideshi Kawakami, Osamu Komure, Hirofumi Maruyama, Hiroyuki Morino, Yuishin Izumi, Shigenobu Nakamura, Ryuji Kaji and Sadako Kuno :
Contribution of the interleukin-1β gene polymorphism in multiple system atrophy,
Movement Disorders, 17, 4, 808-811, 2002.

(要約): We studied genetic polymorphisms in the promoter region at position -511 of the interleukin (IL) -1beta gene (IL-1B-511) and at position -889 of the IL-1alpha gene (IL-1A-889), in 111 Japanese patients with multiple system atrophy (MSA) and 160 controls. The distribution of IL-1B-511 was significantly different between MSA patients and controls, because of the under-representation of patients with homozygotes for allele 2 (IL-1B-511*2), a high producer of IL-1beta. The frequency of IL-1A-889*2, a high secretor of IL-1alpha, was also decreased in MSA patients. Our findings suggest that abnormal cytokine expression may be implicated in the pathogenesis of MSA.
(キーワード): IL-1α / IL-1β / Multiple system atrophy / Polymorphism
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/mds.10124
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 12210881; ● Summary page in Scopus @ Elsevier: 2-s2.0-0036654040

(DOI: 10.1002/mds.10124, PubMed: 12210881, Elsevier: Scopus) Kie Honjo, Yasuyo Mimori, 森野豊之, Sadao Katayama, Shigenobu Nakamura :
A case of late onset mitochondrial neuromyopathy,
日本老年医学会雑誌, 39, 3, 318-321, 2002年.

(要約): A 68-year-old woman was admitted with dysesthesia on both soles, hands and buttocks. She first noticed the dysesthesia in the left first toe two years before admission. One year before admission, serum creatine kinase and lactate dehydrogenase levels were elevated but she had no clinical symptoms suggesting myopathy. Nerve conduction study showed no apparent abnormalities, and an electromyogram showed mild myogenic change. Computed tomography of the muscle showed fatty degeneration of the trunk, major gluteus muscle, and biceps femoris muscle and atrophic change of the biceps femoris muscle. Muscle biopsy revealed a slight variation in fiber size, the presence of cytochrome c oxidase (CCO)-negative fibers by CCO staining, ragged-red fibers by Gomori trichrome staining, and mild denervation fiber by neuron specific enolase (NSE) staining. Analysis of her mitochondrial DNA (mtDNA) revealed a large deletion of mtDNA (approximately 8.5 Kb), and mitochondrial neuromyophy was diagnosed. The frequency of mtDNA deletion increases with aging. Although her mtDNA abnormality was compatible with chronic progressive external ophthalmoplegia (CPEO), we speculate that the aging process may be contributed to the mtDNA abnormality, which would be related to the late onset of her symptoms. As the phenotype of this mitochondrial disorder shows a wide variation and mtDNA abnormality is more frequent among elderly people, we should consider the possibility of mitochondrial disorders even in elderly people.
(キーワード): Age of Onset / Aged / DNA, Mitochondrial / Female / Humans / Mitochondrial Encephalomyopathies / Muscle, Skeletal / Ophthalmoplegia, Chronic Progressive External / Tomography, X-Ray Computed
(出版サイトへのリンク): ● Publication site (DOI): 10.3143/geriatrics.39.318
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 12073596; ● Summary page in Scopus @ Elsevier: 2-s2.0-0036562143

(DOI: 10.3143/geriatrics.39.318, PubMed: 12073596, Elsevier: Scopus) Masaya Oda, Hiroyuki Morino, Hirofumi Maruyama, Hideo Terasawa, Yuishin Izumi, Tsuyoshi Torii, Ken Sasaki, Shigenobu Nakamura and Hideshi Kawakami :
Dinucleotide repeat polymorphisms in the Neprilysin gene are not associated with sporadic Alzheimer's disease,
Neuroscience Letters, 320, 1-2, 105-107, 2002.

(要約): In the pathological process of Alzheimer's disease (AD), deposition of amyloid beta-peptide (A beta) in the brain parenchyma plays an important role. Neprilysin (NEP), a neutral endopeptidase, degrades A beta, and it is postulated that decreased NEP activity may contribute to the development of AD by promoting the accumulation of A beta. The human NEP gene possesses four dinucleotide repeat polymorphisms, and it is possible that these polymorphisms regulate the NEP expression levels and influence the pathological cascade of AD. Therefore, we investigated the association of these polymorphisms with AD. We performed genotyping of each polymorphism in 201 Japanese sporadic AD patients and 208 Japanese controls. There were no significant differences between the AD and control groups in allele frequencies of each polymorphism. We conclude that these polymorphisms in the NEP gene do not contribute to genetic risk factors for sporadic AD.
(キーワード): Alzheimer's disease / Amyloid β-peptide degrading enzyme / Genetic / Japanese / Neprilysin / Polymorphism / Sporadic
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/S0304-3940(02)00057-5
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11849775; ● Summary page in Scopus @ Elsevier: 2-s2.0-0036498998

(DOI: 10.1016/S0304-3940(02)00057-5, PubMed: 11849775, Elsevier: Scopus) H. Maruyama, Y. Izumi, M. Oda, T. Torii, Hiroyuki Morino, H. Toji, K. Sasaki, H. Terasawa, S. Nakamura and Hideshi Kawakami :
Lack of an association between cystatin C gene polymorphisms in Japanese patients with Alzheimer's disease,
Neurology, 57, 2, 337-339, 2001.

(要約): Associations between polymorphisms of the cystatin C gene (CST3) at 5' flanking region and exon 1 in Caucasian patients with late onset AD and exon 1 in a US study of late onset AD have been reported. Clinically diagnosed Japanese patients with AD and Japanese normal control subjects were assessed for the presence of polymorphisms of CST3. The authors could not confirm the previously reported association between CST3 polymorphisms and AD in Japan. Age had no effect on the CST3 genotype.
(キーワード): Aged / Aged, 80 and over / Alzheimer Disease / Apolipoproteins E / Cystatin C / Cystatins / Genotype / Humans / Japan / Linkage Disequilibrium / Polymorphism, Genetic
(出版サイトへのリンク): ● Publication site (DOI): 10.1212/WNL.57.2.337
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11468325; ● Summary page in Scopus @ Elsevier: 2-s2.0-0035943066

(DOI: 10.1212/WNL.57.2.337, PubMed: 11468325, Elsevier: Scopus) Yuishin Izumi, Hiroyuki Morino, Masaya Oda, Hirofumi Maruyama, Fukashi Udaka, Masakuni Kameyama, Sigenobu Nakamura and Hideshi Kawakami :
Genetic studies in Parkinson's disease with an α-synuclein/NACP gene polymorphism in Japan,
Neuroscience Letters, 300, 2, 125-127, 2001.

(要約): Dinucleotide repeat polymorphism has been observed in the promoter of the alpha-synuclein (alpha-SYN)/NAC precursor protein (NACP) gene. Alpha-SYN/NACP allele 3 (described by Xia et al. (Ann. Neurol., 40 (1996) 207), equivalent to allele 1 described by Krüger et al. (Ann. Neurol. 45 (1999) 611) is reported to be significantly more frequent among patients with sporadic Parkinson's disease (sPD) than controls. In this study, we genotyped the same alpha-SYN/NACP polymorphism in Japanese sPD patients and healthy controls, but found that any aliele showed no significant difference between the two groups.
(キーワード): Alpha synuclein/NACP promoter polymorphism / Japanese population / Parkinson's disease / Risk factor
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/S0304-3940(01)01557-9
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11207390; ● Summary page in Scopus @ Elsevier: 2-s2.0-0035831303

(DOI: 10.1016/S0304-3940(01)01557-9, PubMed: 11207390, Elsevier: Scopus)

MISC

Yuishin Izumi, Ryosuke Miyamoto, Hiroyuki Morino, Akio Yoshizawa, Kazuto Nishinaka, Fukashi Udaka, Masakuni Kameyama, Hirofumi Maruyama and Hideshi Kawakami :
Cerebellar ataxia with SYNE1 mutation accompanying motor neuron disease,
Neurology, 80, 6, 600-601, 2013.

(キーワード): Adolescent / Adult / Age of Onset / Cerebellar Ataxia / Child / Cytoskeletal Proteins / Female / Humans / Motor Neuron Disease / Mutation / Nerve Tissue Proteins / Nuclear Proteins / Young Adult
(出版サイトへのリンク): ● Publication site (DOI): 10.1212/WNL.0b013e3182815529
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23325900; ● Summary page in Scopus @ Elsevier: 2-s2.0-84873697535

(DOI: 10.1212/WNL.0b013e3182815529, PubMed: 23325900, Elsevier: Scopus) Takashi Kurashige, Hiroyuki Morino, Yukiko Matsuda, Tomoya Mukai, Tomomi Murao, Megumi Toko, Kodai Kume, Ryosuke Ohsawa, Tsuyoshi Torii, Hiroshi Tokinobu, Hirofumi Maruyama and Hideshi Kawakami :
Retinitis pigmentosa prior to familial ALS caused by a homozygous cilia and flagella-associated protein 410 mutation,
Journal of Neurology, Neurosurgery, and Psychiatry, 91, 2, 220-222, 2019.

(キーワード): motor neuron disease / neurogenetics / neuroophthalmology
(出版サイトへのリンク): ● Publication site (DOI): 10.1136/jnnp-2019-321279
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31431468; ● Summary page in Scopus @ Elsevier: 2-s2.0-85071104559

(DOI: 10.1136/jnnp-2019-321279, PubMed: 31431468, Elsevier: Scopus) Kodai Kume, Hiroyuki Morino, Osamu Komure, Yukiko Matsuda, Ryosuke Ohsawa, Takashi Kurashige, Yuhei Kanaya, Yui Tada and Hideshi Kawakami :
C-terminal mutations in SYNE1 are associated with motor neuron disease in patients with SCAR8,
Journal of the Neurological Sciences, 402, 118-120, 2019.

(キーワード): Chilaiditi syndrome / Motor neuron disease / Spinocerebellar ataxia, autosomal recessive 8 / SYNE1
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jns.2019.05.001
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31129264; ● Summary page in Scopus @ Elsevier: 2-s2.0-85065905617

(DOI: 10.1016/j.jns.2019.05.001, PubMed: 31129264, Elsevier: Scopus) Naoyuki Hara, Tomohisa Nezu, Keitaro Kobatake, Hiroyuki Morino, Hideshi Kawakami and Hirofumi Maruyama :
Treatment of intractable resting tremor of spinocerebellar ataxia 42 with zonisamide,
Journal of the Neurological Sciences, 396, 119-120, 2018.

(キーワード): CACNA1G / Spinocerebellar ataxia / T-type calcium channel / Tremor / Zonisamide
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jns.2018.11.013
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30448718; ● Summary page in Scopus @ Elsevier: 2-s2.0-85056618849

(DOI: 10.1016/j.jns.2018.11.013, PubMed: 30448718, Elsevier: Scopus) Yuishin Izumi, Hiroyuki Morino, Ryosuke Miyamoto, Yukiko Matsuda, Ryosuke Ohsawa, Takashi Kurashige, Yoshimitsu Shimatani, Ryuji Kaji and Hideshi Kawakami :
Compound heterozygote mutations in the SIGMAR1 gene in an oldest-old patient with amyotrophic lateral sclerosis,
Geriatrics & Gerontology International, 18, 10, 1519-1520, 2018.

(キーワード): Aged, 80 and over / Amyotrophic Lateral Sclerosis / DNA / DNA Mutational Analysis / Heterozygote / Humans / Male / Mutation / Receptors, sigma / Sigma-1 Receptor
(出版サイトへのリンク): ● Publication site (DOI): 10.1111/ggi.13506
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30311446; ● Summary page in Scopus @ Elsevier: 2-s2.0-85054604126

(DOI: 10.1111/ggi.13506, PubMed: 30311446, Elsevier: Scopus) Ryosuke Miyamoto, Hidetaka Koizumi, Hiroyuki Morino, Toshitaka Kawarai, Hirofumi Maruyama, Yohei Mukai, Ai Miyashiro, Wataru Sako, Yuishin Izumi, Hideshi Kawakami and Ryuji Kaji :
DYT6 in Japan-genetic screening and clinical characteristics of the patients,
Movement Disorders, 29, 2, 278-280, 2013.

(キーワード): Adolescent / Adult / Aged / Aged, 80 and over / Anti-Dyskinesia Agents / Apoptosis Regulatory Proteins / Botulinum Toxins / Child / Child, Preschool / DNA-Binding Proteins / Deep Brain Stimulation / Dystonia / Female / Genetic Testing / Humans / Japan / Male / Middle Aged / Nuclear Proteins / Young Adult
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/mds.25745
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24227593; ● Summary page in Scopus @ Elsevier: 2-s2.0-84894236517

(DOI: 10.1002/mds.25745, PubMed: 24227593, Elsevier: Scopus)

総説・解説

森野豊之, 丸山博文 :
遺伝性ALSオーバービュー,
Clinical Neuroscience, 41, 3, 330-333, 2023年3月.

(キーワード): 筋萎縮性側索硬化症 / 原因遺伝子

Tomoyasu Matsubara, Masaya Oda, Tetsuya Takahashi, Chigusa Watanabe, Yoshiro Tachiyama, Hiroyuki Morino, Hideshi Kawakami, Ryuji Kaji, Hirofumi Maruyama, Shigeo Murayama and Yuishin Izumi :
Amyotrophic lateral sclerosis of long clinical course clinically presenting with progressive muscular atrophy,
Neuropathology, 39, 1, 47-53, Dec. 2018.

(要約): Amyotrophic lateral sclerosis (ALS) primarily affects upper and lower motor neurons. Phosphorylated trans-activation response DNA-binding protein of 43 kDa (TDP-43) inclusion bodies are reportedly a pathological hallmark of sporadic ALS. Here, we present an atypical case of sporadic ALS that progressed very slowly, persisted for 19 years, and clinically appeared to only affect the lower motor neurons; however, upper motor neuron degeneration was detected at autopsy. Furthermore, no inclusion bodies positive for phosphorylated TDP-43, ubiquitin, fused in sarcoma, or superoxide dismutase-1 were detected in the central nervous system. We performed exome-sequencing data analysis but found no genetic disorders. This was therefore an unusual case of lower motor neuron-predominant ALS without TDP-43 pathology or known gene-disease associations. We also reviewed autopsied ALS cases that progressed slowly and had no phosphorylated TDP-43 or ubiquitin-positive inclusions and present the clinicopathological features of such cases. Based on these results, there may be a sporadic ALS subgroup that progresses slowly and shows no accumulation of phosphorylated TDP-43.
(キーワード): amyotrophic lateral sclerosis / autopsy / motor neuron disease / progressive muscular atrophy / TDP-43
(出版サイトへのリンク): ● Publication site (DOI): 10.1111/neup.12523
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30511354; ● Summary page in Scopus @ Elsevier: 2-s2.0-85057985562

(DOI: 10.1111/neup.12523, PubMed: 30511354, Elsevier: Scopus) Hirofumi Maruyama, 森野豊之, Hideshi Kawakami :
Causative genes for amyotrophic lateral sclerosis,
脳と神経 - 神経研究の進歩, 68, 9, 1081-1086, 2016年9月.

(要約): About 20 causative genes were reported for amyotrophic lateral sclerosis. Using next generation sequencer, new genes have been sequentially reported. These genes' products are thought to be involved in the pathologic mechanism of ALS. The pathophysiology is investigated and disease characteristics are discussed according to the causative genes. In addition, genetic counseling is recommended when genetic diagnosis is attempted.
(キーワード): Amyotrophic lateral sclerosis / Causative gene / Genetic counseling / Next generation sequencer / OMIM (online mendelian inheritance in man)
(出版サイトへのリンク): ● Publication site (DOI): 10.11477/mf.1416200555
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 27667492; ● Summary page in Scopus @ Elsevier: 2-s2.0-84991800887

(DOI: 10.11477/mf.1416200555, PubMed: 27667492, Elsevier: Scopus)

講演・発表

Koji Fujita, Shotaro Haji, N Atsuta, S Nagano, Y Kanazawa, Y Matsumoto, R Oki, Yusuke Osaki, Ryosuke Miyamoto, Hiroyuki Morino, A Arisawa, H Kawai, Y Sato, S Sakaguchi, K Yagi, T Kagimura, H Yanagawa, K Ishizawa, T Hamatani, H Mochizuki, M Doyu, G Sobue, M Harada and Yuishin Izumi :
EPIC-ALS: A phase 2 trial of EPI-589 in ALS,
35th International Symposium on ALS/MNS, Montreal, Dec. 2024. Yuki Kuwano, Keyoumu Nazere and Hiroyuki Morino :
The biological role of m6A RNA methylation in cytoplasmic localization of TDP-43,
第65回日本神経学会学術大会/AOCN2024, May 2024. Yusuke Osaki, Hiroyuki Nodera, Ryosuke Miyamoto, Hiroyuki Morino, M Chan, Ryuji Kaji and Yuishin Izumi :
Peripheral nerve excitability abnormality in spinocerebellar ataxia type 6,
Neuroscience 2023, Nov. 2023. Shotaro Haji, Koji Fujita, Ryosuke Oki, Yusuke Osaki, Hiroyuki Morino, S Nagano, N Atsuta, Y Kanazawa, Y Matsumoto, A Arisawa, H Kawai, S Sakaguchi, K Yagi, T Hamatani, M Harada, G Sobue and Yuishin Izumi :
An Exploratoruy Trial of EPI-589 in Amyotrophic Lateral Sclerosis (EPIC-ALS),
Pan-Asian Consortium for Treatment and Research in ALS (PACTALS), Kuala Lumpur, Sep. 2023. 中森正博, 田金裕一郎, 森野豊之, 丸山博文 :
SCA42の原因である変異型Cav3.1によるシナプス関連タンパク質輸送障害,
第19回パーキンソン病・運動障害疾患コングレス, 2025年7月. Yuichiro Tagane, Masahiro Nakamori, Hiroyuki Morino and Hirofumi Maruyama :
Mutant Cav3.1 impairs synapse-associated protein transport in neurons,
第48回日本神経科学大会, Jul. 2025. 井上寛章, 行重佐和香, 乾友浩, 笹聡一郎, 三崎万理子, 森野豊之, 吉田友紀子, 宮本容子, 今井芳枝, 滝沢宏光 :
当院におけるHBOC血縁者に対するBRCA遺伝学的検査実施状況,
第31回日本遺伝性腫瘍学会学術集会, 2025年6月. 井上寛章, 行重佐和香, 乾友浩, 笹聡一郎, 青山万理子, 森野豊之, 吉田友紀子, 宮本容子, 今井芳枝, 滝沢宏光 :
当院におけるHBOC血縁者に対するBRCA遺伝学的検査実施状況,
第31回日本遺伝性腫瘍学会学術集会, 2025年6月. 桑野由紀, 森野豊之 :
大腸がん悪性化におけるマイクロRNAの新規調節機構の可能性,
第66回日本生化学会中国四国支部例会, 2025年5月. Koji Fujita, T Itou, Y Okuzono, D Warude, S Miyakawa, Y Mihara, Naoko Matsui, Hiroyuki Morino, Y Kikukawa and Yuishin Izumi :
Th17 and effector CD8 T cells relate to disease progression in amyotrophic lateral sclerosis,
第66回日本神経学会学術大会, May 2025. Satoko Miyatake, Hiroshi Doi, Hiroaki Yaguchi, Hiroyuki Morino, Yuishin Izumi, Takayoshi Shimohata, Kunihiro Yoshida, Hiroaki Adachi, Fumiaki Tanaka, Ichiro Yabe and Naomichi Matsumoto :
Unraveling the Genetic Landscape of SCA27B: Nanopore Sequencing of GAA-FGF14 Ataxia in Japanese,
第66回日本神経学会学術大会, May 2025. 鎌田正紀, Nazere Keyoumu, 桑野由紀, 森野豊之 :
パーキンソン病患者の死因について,
第66回日本神経学会学術大会, 2025年5月. Yuki Kuwano, Keyoumu Nazere, Masaki Kamada and Hiroyuki Morino :
m6A RNA methylation mediates cytoplasmic localization and pathogenicity of TDP-43,
第66回日本神経学会学術大会, May 2025. 武藤浩平, 宮本亮介, 桑野由紀, Nazere Keyoumu, 福本竜也, 橘このか, 山内翔葵, 鎌田正紀, 和泉唯信, 森野豊之 :
筋萎縮性側索硬化症(ALS)患者における新規リピート異常伸長の探索,
第66回日本神経学会学術大会, 2025年5月. 桑野由紀, Nazere Keyoumu, 大濱菜々子, 谷口颯月, 西田憲生, 鎌田正紀, 森野豊之 :
RNA結合タンパク質TRA2BのmicroRNA新規生合成経路を介した大腸がん悪性化機構の解明,
第46回日本分子生物学会年会, 2024年11月. Hiroshi Miyamoto, Ayuka Mineda, Sawaka Yukishige, Soichiroh Sasa, Kei Daizumoto, Tomoya Fukawa, Yasuyuki Okada, Yasuhiro Mitsui, Koichi Okamoto, Yasushi Sato, Hiroyuki Morino and Tetsuji Takayama :
Management of patients with presumed germline pathogenic variant from comprehensive genomic profiling tests.,
日本人類遺伝学会第69回大会, Oct. 2024. 橘このか, 宮本亮介, 森野豊之, 福本竜也, 松本真一, 目崎高広, 小泉英貴, 村瀬永子, 向井洋平, 星野恭子, 浅沼光太郎, 坂本崇, 梶龍兒, 和泉唯信 :
Genetic and clinical features inn a cohort of Japanese patients with dystonia,
日本人類遺伝学会第69回大会, 2024年10月. 行重佐和香, 井上寛章, 乾友浩, 笹聡一郎, 青山万理子, 後藤正和, 森野豊之, 吉田友紀子, 宮本容子, 今井芳枝, 滝沢宏光 :
Two cases of surveillance using DWIBS in Li-Fraumeni syndrome,
日本人類遺伝学会第69回大会, 2024年10月. 今井芳枝, 井上寛章, 宮本容子, 吉田友紀子, 森野豊之, 湊沙希, 笹聡一郎, 行重佐和香, 宮本弘志 :
BRCA2 variant of uncertain significanceと診断された乳癌症例の血縁者に対するサーベイランスの一考,
第31回日本がん予防学会総会, 2024年9月. 森野豊之 :
いかに神経変性疾患の原因遺伝子を同定するか,
What's New in Neuroscience & Medicine 17th, 2024年7月. 木原直輝, 宮本亮介, 橘このか, 松原知康, 藤田浩司, 森野豊之, 和泉唯信 :
異常行動，失文法を呈しCSF1R 遺伝子の新規バリアントを認めたALSP/HDLSの1例,
第115回日本神経学会中国・四国地方会, 2024年6月. 橘このか, 宮本亮介, 武藤浩平, 福本竜也, 松原知康, 山内翔葵, 中森正博, 目崎高広, 向井洋平, 山城正喬, 鈴木啓生, 梶龍兒, 森野豊之, 和泉唯信 :
本邦におけるANO3ジストニア (DYT-ANO3) の臨床的特徴,
第65回日本神経学会学術大会/AOCN2024, 2024年6月. 山内翔葵, 橘このか, 宮本亮介, 村瀬永子, 武藤浩平, 福本竜也, 桑野由紀, Nazere Keyoumu, 梶龍兒, 森野豊之, 和泉唯信 :
本邦におけるVPS16ジストニア (DYT-VPS16) の臨床的特徴,
第65回日本神経学会学術大会/AOCN2024, 2024年6月. Keyoumu Nazere, Konoka Tachibana, Yuki Kuwano, Ryosuke Miyamoto, Ryuji Kaji, Yuishin Izumi and Hiroyuki Morino :
The identification and functional analysis of novel variants in ADCY5- related movement disorders,
第65回日本神経学会学術大会/AOCN2024, May 2024. 井上寛章, 行重佐和香, 乾友浩, 笹聡一郎, 青山万理子, 森野豊之, 吉田友紀子, 宮本容子, 今井芳枝, 後藤正和, 滝沢宏光 :
当院乳癌患者におけるBRCA遺伝学的検査の現状,
第30回日本遺伝性腫瘍学会学術集会, 2024年5月. 武藤浩平, 宮本亮介, 桑野由紀, Nazere Keyoumu, 松原知康, 福本竜也, 橘このか, 山内翔葵, 和泉唯信, 森野豊之 :
筋萎縮性側索硬化症(ALS)患者における原因リピート伸長変異の探索,
第65回日本神経学会学術大会, 2024年5月. 森野豊之 :
ゲノム情報から診断/治療技術の開発へ,
第11回大学発ベンチャー創出研究会, 2024年2月. 橘このか, 宮本亮介, 武藤浩平, 福本竜也, 山内翔葵, 中森正博, 梶龍兒, 森野豊之, 和泉唯信 :
家族間で異なる表現型を呈したANO3ジストニアの1家系,
第114回日本神経学会中国・四国地方会, 2023年12月. 桑野由紀, Nazere Keyoumu, 西田憲生, 森野豊之 :
抗老化RNA uc.138 のm6Aメチル化修飾を介した大腸がん悪性化メカニズム,
第46回日本分子生物学会年会, 2023年12月. 森野豊之 :
ゲノム情報から診断/治療技術の開発へ,
ものづくり未来共創機構シンポジウム2023, 2023年12月. 森野豊之 :
ゲノム医療の進歩と徳島大学病院の取り組み,
2023年度第9回徳島市医師会学術講演会, 2023年12月. 山田英忠, 山崎雄, 竹林佳子, 矢澤恭介, 笹西美和子, 元田敦子, 中森正博, 森野豊之, 高橋哲也, 丸山博文 :
加熱式タバコのエアロゾル吸入がアルツハイマー病マウスモデル中枢神経系に及ぼす影響,
第42回日本認知症学会学術集会, 2023年11月. 森野豊之 :
ゲノム技術の進歩と小児診療におけるゲノム医療,
第159回日本小児科学会徳島地方会学術集会, 2023年6月. 行重佐和香, 井上寛章, 乾友浩, 笹聡一郎, 青山万理子, 奥村和正, 森野豊之, 吉田友紀子, 宮本容子, 滝沢宏光 :
BRCA遺伝学的検査の結果inconclusiveとなった3例,
第29回日本遺伝性腫瘍学会学術集会, 2023年6月. 山内翔葵, 宮本亮介, 武藤浩平, 桑野由紀, Nazere Keyoumu, 西田憲生, 橘このか, 和泉唯信, 森野豊之 :
表現型に基づく優先順位付けを用いたALSの病的バリアント検索,
第64回日本神経学会学術大会, 2023年6月. K Tachibana, Ryosuke Miyamoto, Hiroyuki Morino, T Fukumoto, S Matsumoto, T Mezaki, K Hoshino, Koutaro Asanuma, T Sakamoto, Ryuji Kaji and Yuishin Izumi :
Japan Dystonia Consortium, Genetical and clinical features in a cohort of Japanese patients with dystonia,
第64回日本神経学会学術大会, May 2023. Konoka Tachibana, Ryosuke Miyamoto, Hiroyuki Morino, Tatsuya Fukumoto, Shinichi Matsumoto, Takahiro Mezaki, Kyoko Hoshino, Koutaro Asanuma, Takashi Sakamoto, Ryuji Kaji, Yuishin Izumi and Japan Dystonia Consortium :
Genetical and clinical features in a cohort of Japanese patients with dystonia,
第64回日本神経学会学術大会, May 2023. 森野豊之 :
徳島大学病院のゲノム医療センターについて,
難病医療講演会プログラムIRUD, 2023年1月. Aya Gohji, Hiroyuki Morino, Asami Okada, Tatsuo Mori, Ken-ichi Suga, Yumiko Kotani, Rie Seyama, Yuri Uchiyama and Naomichi Matsumoto :
Coffin-siris syndrome with persistent open anterior fontanelle in a boy arising from a novel de novo ARID2 variant,
日本人類遺伝学会第67回大会, Dec. 2022. 花田健太, 大崎裕亮, 宮本亮介, 土師正太郎, 森野豊之, 和泉唯信 :
新規のMORC2変異を認めたCharcot-Marie-Tooth病2Z型の1例,
第112回日本神経学会中国・四国地方会, 2022年12月. 花田健太, 大崎裕亮, 宮本亮介, 土師正太郎, 森野豊之, 和泉唯信 :
MORC2新規変異を認めたCharcot-Marie-Tooth病2Z型の1例,
第33回日本末梢神経学会学術集会, 2022年9月. 倉重毅志, 森野豊之, 村尾智美, 和泉唯信, 杉浦智仁, 倉岡和矢, 川上秀史, 鳥居剛, 丸山博文 :
ALS患者の筋内神経束でのTDP-43凝集,
第8回日本筋学会学術集会, 2022年8月. 武藤浩平, 宮本亮介, 沖良祐, 宮﨑由道, 藤井大樹, 二宮伸介, 秋山倫之, 梶龍兒, 森野豊之, 和泉唯信 :
Geniospasm4,
第63回日本神経学会学術大会, 2022年5月. 武藤浩平, 宮本亮介, 沖良祐, 宮﨑由道, 藤井大樹, 二宮伸介, 秋山倫之, 梶龍兒, 森野豊之, 和泉唯信 :
本邦におけるGeniospasmの4家系,
第63回日本神経学会学術大会, 2022年5月. 大崎裕亮, 宮本亮介, 森野豊之, 和泉唯信 :
Distal hereditary motor neuropathyを呈したMARS新規変異を有する1家系,
第63回日本神経学会学術大会, 2022年5月. 桑野由紀, 西田憲生, 森野豊之 :
RNA修飾を介した大腸がん細胞の抗老化スイッチの解明,
第44回日本分子生物学会年会, 2021年12月. 森野豊之 :
脊髄小脳変性症42型の原因と新規治療戦略,
徳島県市民公開講座難病医療講演会, 2021年10月. Takashi Kurashige, Hiroyuki Morino, Hiroki Ueno, Tomomi Murao, Tomoaki Watanabe, Takao Hinoi, Ichizo Nishino, Tsuyoshi Torii and Hirofumi Maruyama :
Gastrointestinal cancer occurs as extramuscular manifestation in FSHD1 patients,
日本人類遺伝学会第66回大会, Oct. 2021. Naoyuki Hara, Hiroyuki Morino, Yukiko Matsuda, Kenichi Satoh, Kouichi Hashimoto, Hirofumi Maruyama and Hideshi Kawakami :
Zonisamide can ameliorate the conduction of the mutant CaV3.1 that causes spinocerebellar ataxia,
第62回日本神経学会学術大会, May 2021. Yukiko Matsuda, Hiroyuki Morino, Yusuke Sotomaru, Takashi Kurashige, Hirofumi Maruyama and Hideshi Kawakami :
Transcriptomic analysis using model mice of spinocerebellar ataxia 42,
第62回日本神経学会学術大会, May 2021.

研究会・報告書: 松井尚子, 山﨑博輝, 森野豊之, 山下賢, 西野一三, 梶龍兒, 和泉唯信 :
当施設における封入体筋炎の現状と今後の目標,
稀少難治性筋疾患に関する調査研究班「IBM分科会」(令和6年度), 2025年1月. 桑野由紀, Nazere Keyoumu, 森野豊之 :
m6A RNAメチル化がトリガーするALS原因因子TDP-43の細胞質封入体形成の調節機構,
先端酵素学研究所交流シンポジウム, 2024年8月. 森野豊之 :
神経筋疾患とゲノム情報,
第15回脳科学クラスターミニリトリート, 2024年2月. 坂原英皓, 内藤裕之, 頼近恭典, 田妻卓, 中森正博, 青木志郎, 山崎雄, 森野豊之, 高橋哲也, 丸山博文 :
濃厚な家族歴を有し，パーキンソニズムを呈した50歳女性例,
第53回症例から学ぶ脳神経内科in広島, 2024年2月. 松井尚子, 山﨑博輝, 高松直子, 宮本亮介, 森野豊之, 西野一三, 梶龍兒, 和泉唯信 :
当院で経験したIBM兄弟例,
稀少難治性筋疾患に関する調査研究班「IBM分科会」(令和5年度), 2024年2月. 森野豊之 :
遺伝性神経疾患に対する遺伝カウンセリング,
遺伝性ATTRアミロイドーシスセミナー in 徳島, 2024年2月. 森野豊之 :
神経変性疾患の遺伝学的解析,
Fukuoka Neurology Research Forum, 2023年9月. 森野豊之 :
ゲノム技術の進歩と今後の医学,
2022遺伝・発生・再生クラスターミニリトリート, 2022年12月. 森野豊之 :
遺伝的要因から考えるパーキンソン病の発症機序と治療戦略,
第42回症例から学ぶ神経内科 in 広島, 2022年2月. 植野美彦, 中村豊, 森野豊之, 酒井徹, 安井敏之, 川人伸次, 尾崎和美, 藤野裕道, 一宮昌司, 浅田元子, 齊藤隆仁, 上岡麻衣子 :
令和6年度徳島大学高等教育研究センターアドミッション部門報告書,
令和6年度徳島大学高等教育研究センターアドミッション部門報告書, 2025年3月.

特許: 研究者総覧に該当データはありませんでした。
作品: 研究者総覧に該当データはありませんでした。
補助金・競争的資金: Necroptosisを介したALSの運動神経変性の病態機序と新規治療の探索 (研究課題/領域番号: 23K27518 )
パーキンソン病におけるα-シヌクレイン凝集機序の解明と新規治療への応用 (研究課題/領域番号: 23K06828 )
新規ミトコンドリア蛋白質の構造異常によるALS病態の解析と評価モデル系の開発 (研究課題/領域番号: 23K24211 )
脊髄小脳変性症モデルマウスを用いたCRISPR/Cas13による新しい核酸医療 (研究課題/領域番号: 19K07994 )
ヒト一倍体細胞を用いた遺伝子トラップ法によるTDP-43関連遺伝子の同定 (研究課題/領域番号: 16K15481 )
iPS細胞を用いたミトコンドリアDNA維持機構の破綻と神経変性への関与 (研究課題/領域番号: 15K15083 )
遺伝学的アプローチによる小脳機能障害の解明 (研究課題/領域番号: 26242085 )
ＡＬＳにおけるＯｐｔｉｎｅｕｒｉｎの神経細胞毒性に関する分子メカニズムの解明 (研究課題/領域番号: 23591246 )
常染色体劣性脊髄小脳変性症の新規遺伝子 (研究課題/領域番号: 19390241 )
研究者番号（10397953）による検索

その他: 研究者総覧に該当データはありませんでした。

研究者総覧で最新データを確認する

2025年9月16日更新

専門分野・研究分野: 遺伝学 (Genetics)
所属学会・所属協会: 日本神経学会
日本老年医学会
日本人類遺伝学会
委員歴・役員歴: 日本神経学会 (代議員 [2021年5月〜2025年5月])
日本老年医学会 (代議員 [2018年7月〜2025年7月])
日本人類遺伝学会 (評議員 [2023年10月〜2027年10月])
受賞: 2024年10月, 最優秀ポスター賞 (日本人類遺伝学会第69回大会)
活動: 研究者総覧に該当データはありませんでした。

リサーチマップで最新データを確認するＪグローバルで最新データを確認する

2025年9月14日更新

2025年9月13日更新

Ｊグローバル

Jグローバル最終確認日: 2025/9/13 01:48
氏名（漢字）: 森野豊之
氏名（フリガナ）: JグローバルAPIで取得できませんでした。
氏名（英字）: Morino Hiroyuki
所属機関: 徳島大学大学院教授

リサーチマップ

researchmap最終確認日: 2025/9/14 04:16
氏名（漢字）: 森野豊之
氏名（フリガナ）: リサーチマップAPIで取得できませんでした。
氏名（英字）: Morino Hiroyuki
プロフィール: リサーチマップAPIで取得できませんでした。
登録日時: 2018/11/19 16:56
更新日時: 2025/4/15 10:22
アバター画像URI: リサーチマップAPIで取得できませんでした。
ハンドル: リサーチマップAPIで取得できませんでした。
eメール: リサーチマップAPIで取得できませんでした。
eメール（その他）: リサーチマップAPIで取得できませんでした。
携帯メール: リサーチマップAPIで取得できませんでした。
性別: リサーチマップAPIで取得できませんでした。
没年月日: リサーチマップAPIで取得できませんでした。
所属ID: 0344000000
所属: 徳島大学大学院
部署: 医歯薬学研究部遺伝情報医学分野
職名: 教授
学位: 博士（医学）
学位授与機関: 広島大学
URL: リサーチマップAPIで取得できませんでした。
科研費研究者番号: リサーチマップAPIで取得できませんでした。
Google Analytics ID: リサーチマップAPIで取得できませんでした。
ORCID ID: リサーチマップAPIで取得できませんでした。
その他の所属ID: リサーチマップAPIで取得できませんでした。
その他の所属名: リサーチマップAPIで取得できませんでした。
その他の所属部署: リサーチマップAPIで取得できませんでした。
その他の所属職名: リサーチマップAPIで取得できませんでした。
最近のエントリー: リサーチマップAPIで取得できませんでした。
Read会員ID: リサーチマップAPIで取得できませんでした。
経歴: リサーチマップAPIで取得できませんでした。
受賞
Misc
論文
講演・口頭発表等: リサーチマップAPIで取得できませんでした。
書籍等出版物: リサーチマップAPIで取得できませんでした。
研究キーワード
研究分野
所属学協会: リサーチマップAPIで取得できませんでした。
担当経験のある科目: リサーチマップAPIで取得できませんでした。
その他: リサーチマップAPIで取得できませんでした。
Works: リサーチマップAPIで取得できませんでした。
特許: リサーチマップAPIで取得できませんでした。
学歴: リサーチマップAPIで取得できませんでした。
委員歴
社会貢献活動: リサーチマップAPIで取得できませんでした。

ＫＡＫＥＮで最新データを確認する

2025年9月13日更新

研究者番号: 10397953

所属（現在）: 2025/4/1 : 徳島大学, 大学院医歯薬学研究部(医学域), 教授

所属（過去の研究課題 情報に基づく）*注記: 2021/4/1 – 2024/4/1 : 徳島大学, 大学院医歯薬学研究部(医学域), 教授
2015/4/1 – 2017/4/1 : 広島大学, 原爆放射線医科学研究所, 准教授
2011/4/1 – 2013/4/1 : 広島大学, 原爆放射線医科学研究所, 助教
2007/4/1 – 2009/4/1 : 広島大学, 原爆放射線医科学研究所, 助教

審査区分/研究分野

研究代表者

生物系 / 医歯薬学 / 内科系臨床医学 / 神経内科学
生物系 / 医歯薬学 / 基礎医学 / 病態医化学
小区分51030:病態神経科学関連

研究代表者以外

生物系 / 医歯薬学 / 内科系臨床医学 / 神経内科学
総合系 / 複合領域 / 脳科学 / 基盤・社会脳科学
小区分52020:神経内科学関連
小区分51030:病態神経科学関連

キーワード

研究代表者

神経分子病態 / 筋萎縮性側索硬化症 / 神経分子病態学 / 遺伝子 / 脳神経疾患 / ミトコンドリア / パーキンソン病 / エンドソーム-ライソソーム系 / 品質管理 / α-シヌクレイン / オートファジー / 凝集体形成 / ライソソーム

研究代表者以外

臨床神経分子遺伝学 / 脊髄小脳変性症 / 劣性遺伝 / SNP / 脳神経疾患 / ゲノム解析 / 遺伝学 / Ca チャンネル / 遺伝子 / 神経科学 / 遺伝性脊髄小脳変性症 / TDP-43 / 筋萎縮性側索硬化症 / プルキンエ細胞 / CACNA1G / FUS / DHX30 / RNA / 低分子スクリーニング / Fused in sarcoma (FUS) / 変異遺伝子スクリーニング / ノックインマウス / necroptosis / 逆行性進展 / OPTN / TMEM106B / ALS

研究課題研究成果共同研究者

「研究課題をさがす」で表示
テキスト（CSV）で出力

テキスト（CSV）で出力

2024年4月30日

エピトランスクリプトームを応用した新規創薬技術の開発

Nazere Keyoumu 桑野由紀森野豊之

研究者を探す

森野 豊之

Ｊグローバル

リサーチマップ

研究代表者

研究代表者以外

研究代表者

研究代表者以外

森野豊之