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Molecular genetic research with a view to treating Charcot-Marie-Tooth disease

Research Project

Project/Area Number 21H02842
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 52020:Neurology-related
Research InstitutionKagoshima University

Principal Investigator

Takashima Hiroshi  鹿児島大学, 医歯学域医学系, 教授 (80372803)

Co-Investigator(Kenkyū-buntansha) 樋口 雄二郎  鹿児島大学, 医歯学域鹿児島大学病院, 助教 (10867724)
安藤 匡宏  鹿児島大学, 鹿児島大学病院, 特任助教 (60896976)
橋口 昭大  鹿児島大学, 医歯学域鹿児島大学病院, 講師 (70760560)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2023: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2021: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
KeywordsCharcot-Marie-Tooth / リピート伸長 / RFC1 / NOTCH2NLC / Charcot-Marie-Tooth病 / 遺伝性ニューロパチー / ゲノム解析 / 遺伝子診断 / 末梢神経 / RFC1遺伝子
Outline of Research at the Start

Charcot-Marie-Tooth病患者の包括的遺伝子診断を継続して行う事により、個別のCMT病患者の診断をすることはもちろん、本邦の分子疫学を正確に把握する。
また、遺伝子別にCMTの特徴を明らかにし、疾患の特徴や予後などを検討する。
加えてCMT病の新規原因遺伝子の同定を行い、治療法開発をめざした病態解明のブレイクスルーを行い、個別に治療法についてヒントを得る。発見された遺伝子は、共同研究で動物モデルを作製し、病態解析をして、将来の治療につなげる。

Outline of Final Research Achievements

We investigated the expansion of GGC repeats in the RFC1 gene, which is the cause of CANVAS, and the expansion of pentanucleotide repeats in the NOTCH2NLC gene, which is the cause of neuronal intranuclear inclusion disease (NIID), in patients with hereditary peripheral neuropathy. We found repeat expansions in NOTCH2NLC in 23 cases and RFC1 in 18 cases out of 2,780 patients with hereditary neuropathy, and also found that many cases of both diseases showed only peripheral neuropathy. We summarized these results in four papers, including JNNP and Front Neurol. Furthermore, we discovered and reported four genes that cause new mitochondrial-related hereditary neuropathy in patients with neuropathy (J Neurol 2022).

Academic Significance and Societal Importance of the Research Achievements

我々は、2003年以来、本邦のCMTの包括的遺伝子診断システムを開発し、遺伝子検査を提供してきた。年間250例を引き受け、3000例を超えるまでになった。次世代シークエンサーと大規模エクソームにより、900例以上のCMTの原因を同定した。2800例の症例解析はでは、NEFH変異のCMT2型、RFC1関連疾患のまとめや新規のミトコンドリア関連ニューロパチーの原因の報告、NOTCH2NLCの位置づけの報告を行った。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (28 results)

All 2024 2023 2022 2021

All Journal Article (28 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 28 results,  Open Access: 14 results)

  • [Journal Article] Spatial Fluctuation of Central Nervous System Lesions in X-linked Charcot-Marie-Tooth Disease with a Novel <i>GJB1</i> Mutation2024

    • Author(s)
      Yoshimoto Yukiyo、Yoshimoto Shoko、Kakiuchi Kensuke、Miyagawa Rumina、Ota Shin、Hosokawa Takafumi、Ishida Shimon、Higuchi Yujiro、Hashiguchi Akihiro、Takashima Hiroshi、Arawaka Shigeki
    • Journal Title

      Internal Medicine

      Volume: 63 Issue: 4 Pages: 571-576

    • DOI

      10.2169/internalmedicine.1713-23

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2024-02-15
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Charcot-Marie-Tooth Disease with a Novel Variant in <i>Gap Junction Protein Beta 1</i> Presenting with Visual Field Defects2023

    • Author(s)
      Nozaki Ichiro、Hashiguchi Akihiro、Takashima Hiroshi、Yamashita Yoko、Higashide Tomomi、Iwasa Kazuo、Ono Kenjiro
    • Journal Title

      Internal Medicine

      Volume: 62 Issue: 20 Pages: 3033-3036

    • DOI

      10.2169/internalmedicine.1403-22

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2023-10-15
    • Related Report
      2023 Annual Research Report 2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The Current State of Charcot-Marie-Tooth Disease Treatment2023

    • Author(s)
      Okamoto Yuji、Takashima Hiroshi
    • Journal Title

      Genes

      Volume: 14 Issue: 7 Pages: 1391-1391

    • DOI

      10.3390/genes14071391

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A case of myofibrillary myopathy due to <i>Bcl2-Associated Athanogene 3</i> (<i>BAG3</i>) mutation complicated by peripheral neuropathy2023

    • Author(s)
      Nagatomo Risa、Higuchi Yujiro、Takei Jun、Nakamura Tomonori、Hashiguchi Hiroaki、Takashima Hiroshi
    • Journal Title

      Rinsho Shinkeigaku

      Volume: 63 Issue: 12 Pages: 836-842

    • DOI

      10.5692/clinicalneurol.cn-001915

    • ISSN
      0009-918X, 1882-0654
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A case of Charcot–Marie–Tooth disease type 2 caused by homozygous <i>MME</i> gene mutation2023

    • Author(s)
      Yamashiro Masataka、Ohnari Keiko、Higuchi Yujiro、Hashiguchi Hiroaki、Takashima Hiroshi、Okada Kazumasa
    • Journal Title

      Rinsho Shinkeigaku

      Volume: 63 Issue: 11 Pages: 743-747

    • DOI

      10.5692/clinicalneurol.cn-001870

    • ISSN
      0009-918X, 1882-0654
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CANVAS-related RFC1 mutations in patients with immune-mediated neuropathy2023

    • Author(s)
      Hirano Makito、Kuwahara Motoi、Yamagishi Yuko、Samukawa Makoto、Fujii Kanako、Yamashita Shoko、Ando Masahiro、Oka Nobuyuki、Nagano Mamoru、Matsui Taro、Takeuchi Toshihide、Saigoh Kazumasa、Kusunoki Susumu、Takashima Hiroshi、Nagai Yoshitaka
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1 Pages: 17801-17801

    • DOI

      10.1038/s41598-023-45011-8

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum2023

    • Author(s)
      Higuchi Yujiro、Ando Masahiro、Kojima Fumikazu、Yuan Junhui、Hashiguchi Akihiro、Yoshimura Akiko、Hiramatsu Yu、Nozuma Satoshi、Fukumura Shinobu、Yahikozawa Hiroyuki、Abe Erika、Toyoshima Itaru、Sugawara Masashiro、Okamoto Yuji、Matsuura Eiji、Takashima Hiroshi
    • Journal Title

      Journal of Neurology

      Volume: 271 Issue: 1 Pages: 419-430

    • DOI

      10.1007/s00415-023-11998-3

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Involvement of autonomic nervous system since middle age in elderly patient with giant axonal neuropathy caused by novel genetic mutation2023

    • Author(s)
      Imoto Makiko、Nakamura Kota、Inoue Kimiko、Ando Masahiro、Higuchi Yujiro、Takashima Hiroshi、Okuda Shiho
    • Journal Title

      Rinsho Shinkeigaku

      Volume: 63 Issue: 9 Pages: 566-571

    • DOI

      10.5692/clinicalneurol.cn-001822

    • ISSN
      0009-918X, 1882-0654
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Genetic, electrophysiological, and pathological studies on patients with <scp><i>SCN9A</i></scp>‐related pain disorders2023

    • Author(s)
      Yuan Jun‐Hui、Cheng Xiaoyang、Matsuura Eiji、Higuchi Yujiro、Ando Masahiro、Hashiguchi Akihiro、Yoshimura Akiko、Nakachi Ryo、Mine Jun、Taketani Takeshi、Maeda Kenichi、Kawakami Saori、Kira Ryutaro、Tanaka Shoko、Kanai Kazuaki、Dib‐Hajj Fadia、Dib‐Hajj Sulayman D.、Waxman Stephen G.、Takashima Hiroshi
    • Journal Title

      Journal of the Peripheral Nervous System

      Volume: 28 Issue: 4 Pages: 597-607

    • DOI

      10.1111/jns.12590

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Case report: Mitochondrial trifunctional protein deficiency caused by HADHB gene mutation (c.1175C>T) characterized by higher brain dysfunction followed by neuropathy, presented gadolinium enhancement on brain imaging in an adult patient2023

    • Author(s)
      Ishikawa Ruoyi、Nakamori Masahiro、Takenaka Megumi、Aoki Shiro、Yamazaki Yu、Hashiguchi Akihiro、Takashima Hiroshi、Maruyama Hirofumi
    • Journal Title

      Frontiers in Neurology

      Volume: 14

    • DOI

      10.3389/fneur.2023.1187822

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical phenotypic diversity of NOTCH2NLC-related disease in the largest case series of inherited peripheral neuropathy in Japan2023

    • Author(s)
      Ando Masahiro、Higuchi Yujiro、Yuan Jun-Hui、Yoshimura Akiko、Dozono Mika、Hobara Takahiro、Kojima Fumikazu、Noguchi Yutaka、Takeuchi Mika、Takei Jun、Hiramatsu Yu、Nozuma Satoshi、Nakamura Tomonori、Sakiyama Yusuke、Hashiguchi Akihiro、Matsuura Eiji、Okamoto Yuji、Sone Jun、Takashima Hiroshi
    • Journal Title

      Journal of Neurology, Neurosurgery and Psychiatry

      Volume: - Issue: 8 Pages: 622-630

    • DOI

      10.1136/jnnp-2022-330769

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Novel PRPS1 Mutation in a Japanese Patient with CMTX52022

    • Author(s)
      Shirakawa Shunichi、Murakami Tatufumi、Hashiguchi Akihiro、Takashima Hiroshi、Hasegawa Hiroshi、Ichida Kimiyoshi、Sunada Yoshihide
    • Journal Title

      Internal Medicine

      Volume: 61 Issue: 11 Pages: 1749-1751

    • DOI

      10.2169/internalmedicine.8029-21

    • NAID

      130008119253

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2022-06-01
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] An MFN2-related Charcot-Marie-Tooth Disease Patient with Optic Nerve Atrophy, Neurogenic Bladder Dysfunction, and Diaphragmatic Weakness2022

    • Author(s)
      Kimura Yasuyoshi、Nishikawa Akira、Hashiguchi Akihiro、Etoh Masaki、Yoshimura Akiko、Asai Kanako、Miyashita Noriko、Takashima Hiroshi、Sumi Hisae、Naka Takashi
    • Journal Title

      Internal Medicine

      Volume: 61 Issue: 11 Pages: 1743-1747

    • DOI

      10.2169/internalmedicine.6487-20

    • NAID

      130008119239

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2022-06-01
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Clinical genetics of Charcot-Marie-Tooth disease2022

    • Author(s)
      Yujiro Higuchi and Hiroshi Takashima
    • Journal Title

      Journal of Human Genetics

      Volume: - Issue: 3 Pages: 199-214

    • DOI

      10.1038/s10038-022-01031-2

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel de novo POLR3B mutations responsible for demyelinating Charcot-Marie-Tooth disease in Japan2022

    • Author(s)
      Ando Masahiro、Higuchi Yujiro、Yuan Jun‐Hui、Yoshimura Akiko、Kitao Ruriko、Morimoto Takehiko、Taniguchi Takaki、Takeuchi Mika、Takei Jun、Hiramatsu Yu、Sakiyama Yusuke、Hashiguchi Akihiro、Okamoto Yuji、Mitsui Jun、Ishiura Hiroyuki、Tsuji Shoji、Takashima Hiroshi
    • Journal Title

      Annals of Clinical and Translational Neurology

      Volume: 9 Issue: 5 Pages: 747-755

    • DOI

      10.1002/acn3.51555

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Novel heterozygous variants of SLC12A6 in Japanese families with Charcot-Marie-Tooth disease.2022

    • Author(s)
      Ando Masahiro、Higuchi Yujiro、Yuan Junhui、Yoshimura Akiko、Taniguchi Takaki、Takei Jun、Takeuchi Mika、Hiramatsu Yu、Shimizu Fumitaka、Kubota Masaya、Takeshima Akari、et al.
    • Journal Title

      Annals of Clinical and Translational Neurology

      Volume: 9 Issue: 7 Pages: 902-911

    • DOI

      10.1002/acn3.51603

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Comprehensive Genetic Analyses of Inherited Peripheral Neuropathies in Japan: Making Early Diagnosis Possible2022

    • Author(s)
      Ando Masahiro、Higuchi Yujiro、Yuan Junhui、Yoshimura Akiko、Taniguchi Takaki、Kojima Fumikazu、Noguchi Yutaka、Hobara Takahiro、Takeuchi Mika、Takei Jun、Hiramatsu Yu、Sakiyama Yusuke、Hashiguchi Akihiro、Okamoto Yuji、Mitsui Jun、Ishiura Hiroyuki、Tsuji Shoji、Takashima Hiroshi
    • Journal Title

      Biomedicines

      Volume: 10 Issue: 7 Pages: 1546-1546

    • DOI

      10.3390/biomedicines10071546

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic and clinical features of cerebellar ataxia with RFC1 biallelic repeat expansions in Japan2022

    • Author(s)
      Ando Masahiro、Higuchi Yujiro、Yuan Junhui H.、Yoshimura Akiko、Higashi Shuntaro、Takeuchi Mika、Hobara Takahiro、Kojima Fumikazu、Noguchi Yutaka、Takei Jun、Hiramatsu Yu、Nozuma Satoshi、Sakiyama Yusuke、Hashiguchi Akihiro、Matsuura Eiji、Okamoto Yuji、Nagai Masahiro、Takashima Hiroshi
    • Journal Title

      Frontiers in Neurology

      Volume: 13 Pages: 952493-952493

    • DOI

      10.3389/fneur.2022.952493

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Multi-type RFC1 repeat expansions as the most common cause of hereditary sensory and autonomic neuropathy2022

    • Author(s)
      Yuan Jun-Hui、Higuchi Yujiro、Ando Masahiro、Matsuura Eiji、Hashiguchi Akihiro、Yoshimura Akiko、Nakamura Tomonori、Sakiyama Yusuke、Mitsui Jun、Ishiura Hiroyuki、Tsuji Shoji、Takashima Hiroshi
    • Journal Title

      Frontiers in Neurology

      Volume: 13

    • DOI

      10.3389/fneur.2022.986504

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Spinocerebellar Ataxia with Axonal Neuropathy Type 12022

    • Author(s)
      Salih MAM, Takashima H, Boerkoel CF.
    • Journal Title

      GeneReviews174; Seattle (WA):

      Volume: PMID: 20301284

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Complex hereditary peripheral neuropathies caused by novel variants in mitochondrial-related nuclear genes2022

    • Author(s)
      Hiramatsu Yu、Okamoto Yuji、Yoshimura Akiko、Yuan Jun-Hui、Ando Masahiro、Higuchi Yujiro、Hashiguchi Akihiro、Matsuura Eiji、Takashima Hiroshi et al.
    • Journal Title

      Journal of Neurology

      Volume: - Issue: 8 Pages: 4129-4140

    • DOI

      10.1007/s00415-022-11026-w

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A case of sporadic amyotrophic lateral sclerosis (ALS) with Senataxin (<i>SETX</i>) gene variant2022

    • Author(s)
      Beppu Shohei、Ikenaka Kensuke、Hashiguchi Akihiro、Takashima Hiroshi、Mochizuki Hideki et al.
    • Journal Title

      Rinsho Shinkeigaku

      Volume: 62 Issue: 3 Pages: 205-210

    • DOI

      10.5692/clinicalneurol.cn-001675

    • NAID

      130008163871

    • ISSN
      0009-918X, 1882-0654
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families2022

    • Author(s)
      Ando Masahiro、Higuchi Yujiro、Okamoto Yuji、Yuan Junhui、Yoshimura Akiko、Takei Jun、Taniguchi Takaki、Hiramatsu Yu、Sakiyama Yusuke、Hashiguchi Akihiro、Matsuura Eiji、Nakagawa Hiroto、Sonoda Ken、Yamashita Toru、Tamura Akiko、Terasawa Hideo、Mitsui Jun、Ishiura Hiroyuki、Tsuji Shoji、Takashima Hiroshi
    • Journal Title

      Journal of Human Genetics

      Volume: - Issue: 7 Pages: 399-403

    • DOI

      10.1038/s10038-022-01019-y

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The first case of infantile-onset multisystem neurologic, endocrine, and pancreatic disease caused by novel PTRH2 mutation in Japan2022

    • Author(s)
      Ando Masahiro、Higuchi Yujiro、Takeuchi Mika、Hashiguchi Akihiro、Takashima Hiroshi
    • Journal Title

      Neurological Sciences

      Volume: 43 Issue: 3 Pages: 2133-2136

    • DOI

      10.1007/s10072-021-05817-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Elderly patients with suspected Charcot-Marie-Tooth disease should be tested for the TTR gene for effective treatments2022

    • Author(s)
      Taniguchi Takaki、Ando Masahiro、Okamoto Yuji、Yoshimura Akiko、Higuchi Yujiro、Hashiguchi Akihiro、Matsuda Nozomu、Yamamoto Mamoru、Dohi Eisuke、Takahashi Makoto、Yoshino Masanao、Nomura Taichi、Matsushima Masaaki、Yabe Ichiro、Sanpei Yui、Ishiura Hiroyuki、Mitsui Jun、Nakagawa Masanori、Tsuji Shoji、Takashima Hiroshi
    • Journal Title

      Journal of Human Genetics

      Volume: - Issue: 6 Pages: 353-362

    • DOI

      10.1038/s10038-021-01005-w

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sibling Cases of Charcot-Marie-Tooth Disease Type 4H with a Homozygous <i>FGD4</i> Mutation and Cauda Equina Thickening2021

    • Author(s)
      Aoki Sho、Nagashima Kazuaki、Shibata Makoto、Kasahara Hiroo、Fujita Yukio、Hashiguchi Akihiro、Takashima Hiroshi、Ikeda Yoshio
    • Journal Title

      Internal Medicine

      Volume: 60 Issue: 24 Pages: 3975-3981

    • DOI

      10.2169/internalmedicine.7247-21

    • NAID

      130008129487

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2021-12-15
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pathological evidence of demyelination in the recurrent laryngeal, phrenic, and oculomotor nerves in Charcot-Marie-Tooth disease 4F2021

    • Author(s)
      Maeda Kengo、Yamamoto Yutaka、Ohuchi Masatsugu、Sakashita Takuto、Shiohara Masanori、Namura Tomo、Shintaku Masayuki、Matsuura Eiji、Takashima Hiroshi
    • Journal Title

      eNeurologicalSci

      Volume: 25 Pages: 100358-100358

    • DOI

      10.1016/j.ensci.2021.100358

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Prevalence of Fragile X-Associated Tremor/Ataxia Syndrome in Patients with Cerebellar Ataxia in Japan2021

    • Author(s)
      Higuchi Yujiro、Ando Masahiro、Yoshimura Akiko、Hakotani Satoshi、Koba Yuki、Sakiyama Yusuke、Hiramatsu Yu、Tashiro Yuichi、Maki Yoshimitsu、Hashiguchi Akihiro、Yuan Junhui、Okamoto Yuji、Matsuura Eiji、Takashima Hiroshi
    • Journal Title

      The Cerebellum

      Volume: - Issue: 5 Pages: 851-860

    • DOI

      10.1007/s12311-021-01323-x

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed

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Published: 2021-04-28   Modified: 2025-01-30  

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