Elucidation of pathology by molecular genetic approach in Charcot-Marie-Tooth disease

• Project/Area Number: 18H02742
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Kagoshima University
• Principal Investigator: Takashima Hiroshi 鹿児島大学, 医歯学域医学系, 教授 (80372803)
• Co-Investigator(Kenkyū-buntansha): 岡本 裕嗣 鹿児島大学, 医歯学域医学系, 教授 (60709658) ; 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): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 遺伝性ニューロパシー / Charcot-Marie-Tooth病 / 遺伝子診断 / 脊髄小脳失調症 / シャルコー・マリー・トゥース病 / 遺伝性ニューロパチー / ゲノム解析 / 遺伝性運動性ニューロパチー / シャルコー・マリー・トーゥス病 / 遺伝子ニューロパチー / 分子疫学

Outline of Final Research Achievements

Charcot-Marie-Tooth disease (CMT) is a common hereditary peripheral neuropathy. Our CMT genetic diagnosis was able to diagnose 10 of 2481 ATTR-FAP patients and provided effective treatment. From 2007 to the end of 2019, 2481 CMT comprehensive genetic tests were performed to determine the genetic cause in 51.2% of demyelinated and 32.5% axonal patients. In addition, we reported in JNNP the detailed analysis results of comprehensive CMT genetic diagnosis for 1005 consecutive cases. It was an important report for considering the overall measures of CMT by analyzing the frequency and clinical characteristics of each causative gene from various aspects.

Academic Significance and Societal Importance of the Research Achievements

日本において、包括的で詳細なCMTの遺伝子診断を年間約250名に行っている。2018年には、連続1005症例について世界で最も詳細に調べた包括的なCMT遺伝子診断の詳細な解析結果をJNNP誌に報告し、原因遺伝子別の頻度や臨床的な特徴について多方面から解析を行い、CMT研究全体を俯瞰するうえでの最も重要な報告のひとつとなっている。
さらにミトコンドリア関連遺伝子COA7が軸索型末梢神経障害を伴う小脳失調症をSCAN3 （spinocerebellar ataxia with axonal neuropathy 3：新疾患）の原因となることを突き止め、動物モデルの解析とともに報告した。

Research Products

• [Journal Article] Genetic spectrum of Charcot-Marie-Tooth disease associated with myelin protein zero gene variants in Japan (2021)
  • Author(s): Takaki Taniguchi, Masahiro Ando, Yuji Okamoto, Akiko Yoshimura, Yujiro Higuchi, Akihiro Hashiguchi, Kensuke Shiga, Arisa Hayashida, Taku Hatano, Hiroyuki Ishiura, Jun Mitsui, Nobutaka Hattori, Toshiki Mizuno, Masanori Nakagawa, Shoji Tsuji, Hiroshi Takashima
  • Journal Title: Clinical Genetics Volume: 99 Issue: 3 Pages: 359-375
  • DOI: 10.1111/cge.13881
  • Peer Reviewed / Open Access
• [Journal Article] Phenotypic and molecular diversities of spinocerebellar ataxia type 2 in Japan (2021)
  • Author(s): Inada R, Hirano M, Oka N, Samukawa M, Saigoh K, Suzuki H, Udaka F, Hashiguchi A, Takashima H, Hamada Y, Nakamura Y, Kusunoki S.
  • Journal Title: J Neurol. Volume: Feb 24 Issue: 8 Pages: 2933-2942
  • DOI: 10.1007/s00415-021-10467-z
  • Peer Reviewed / Open Access
• [Journal Article] The First Case of Spinocerebellar Ataxia Type 8 in Monozygotic Twins (2020)
  • Author(s): Sawada J, Katayama T, Tokashiki T, Kikuchi S, Kano K, Takahashi K, Saito T, Adachi Y, Okamoto Y, Yoshimura A, Takashima H, Hasebe N.
  • Journal Title: Internal Medicine Volume: 59 Issue: 2 Pages: 277-283
  • DOI: 10.2169/internalmedicine.2905-19
  • NAID: 130007785008
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-01-15
  • Peer Reviewed / Open Access
• [Journal Article] Clinical features of inherited neuropathy with BSCL2 mutations in Japan. (2020)
  • Author(s): Ishihara S, Okamoto Y, Tanabe H, Yoshimura A, Higuchi Y, Yuan JH, Hashiguchi A, Ishiura H, Mitsui J, Suwazono S, Oya Y, Sasaki M, Nakagawa M, Tsuji S, Ohya Y, Takashima H
  • Journal Title: J Peripher Nerv Syst Volume: - Issue: 2 Pages: 000-001
  • DOI: 10.1111/jns.12369
  • Peer Reviewed / Open Access
• [Journal Article] A case of spastic paraplegia 48 with a novel mutation in the AP5Z1 gene (2020)
  • Author(s): Maruta K, Ando M, Otomo T, Takashima H.
  • Journal Title: Rinsho Shinkeigaku. Volume: Aug 7;60(8) Issue: 8 Pages: 543-548
  • DOI: 10.5692/clinicalneurol.60.cn-001419
  • NAID: 130007885763
  • Peer Reviewed / Open Access
• [Journal Article] A case of motor and sensory polyneuropathy and respiratory failure with novel heterozygous mutation of the senataxin gene (2020)
  • Author(s): Kitao R, Honma Y, Hashiguchi A, Mizoguchi K, Takashima H, Komori T.
  • Journal Title: Rinsho Shinkeigaku Volume: 60 Issue: 7 Pages: 466-472
  • DOI: 10.5692/clinicalneurol.60.cn-001415
  • NAID: 130007882483
  • ISSN: 0009-918X, 1882-0654
  • Peer Reviewed / Open Access
• [Journal Article] Charcot-Marie-Tooth disease with a mutation in FBLN5 accompanying with the small vasculitis and widespread onion-bulb formations (2020)
  • Author(s): Yamagishi Y, Samukawa M, Kuwahara M, Takada K, Saigoh K, Mitsui Y, Oka N, Hashiguchi A, Takashima H, Kusunoki S.
  • Journal Title: J Neurol Sci Volume: 410 Pages: 000-001
  • DOI: 10.1016/j.jns.2019.116623
  • Peer Reviewed / Open Access
• [Journal Article] Effect of direct oral anticoagulant for acute major cerebral artery occlusion in cardioembolic stroke/transient ischemic attack patients with non-valvular atrial fibrillation. (2019)
  • Author(s): Tomari Shinya, Arima Junnosuke, Yoshida Takashi, Yamashita Hitomi, Sata Reiko, Hamada Rikuzo, Kanda Naoaki, Takashima Hiroshi.
  • Journal Title: Journal of the neurological sciences Volume: 402 Pages: 162-166
  • DOI: 10.1016/j.jns.2019.05.023
  • Peer Reviewed / Open Access
• [Journal Article] Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease (2019)
  • Author(s): Sone Jun、Mitsuhashi Satomi et al.
  • Journal Title: Nature Genetics Volume: 51 Issue: 8 Pages: 1215-1221
  • DOI: 10.1038/s41588-019-0459-y
  • Peer Reviewed / Open Access
• [Journal Article] Muscle pathology of hereditary motor and sensory neuropathy with proximal dominant involvement with TFG mutation. (2019)
  • Author(s): Yamashita S, Kimura E, Zhang Z, Tawara N, Hara K, Yoshimura Akiko, Takashima Hiroshi, Ando Y.
  • Journal Title: Muscle Nerve. Volume: 60 Issue: 6 Pages: 739-744
  • DOI: 10.1002/mus.26683
  • Peer Reviewed / Open Access
• [Journal Article] A novel homozygous mutation of the TFG gene in a patient with early onset spastic paraplegia and later onset sensorimotor polyneuropathy (2019)
  • Author(s): Miyabayashi T, Ochiai T, Suzuki N, Aoki M, Inui T, Okubo Y, Sato R, Togashi N, Takashima H, Ishiura H, Tsuji S, Koh K, Takiyama Y, Haginoya K
  • Journal Title: J Hum Genet Volume: 64 Issue: 2 Pages: 171-176
  • DOI: 10.1038/s10038-018-0538-4
  • Peer Reviewed
• [Journal Article] Genetic profile and onset features of 1005 patients with Charcot-Marie-Tooth disease in Japan (2018)
  • Author(s): Yoshimura Akiko、Yuan Jun-Hui、Hashiguchi Akihiro、Ando Masahiro、Higuchi Yujiro、Nakamura Tomonori、Okamoto Yuji、Nakagawa Masanori、Takashima Hiroshi
  • Journal Title: Journal of Neurology, Neurosurgery & Psychiatry Volume: 90 Issue: 2 Pages: 195-202
  • DOI: 10.1136/jnnp-2018-318839
  • Peer Reviewed / Open Access
• [Journal Article] Genetic and phenotypic profile of 112 patients with X-linked Charcot-Marie-Tooth disease type 1 (2018)
  • Author(s): Yuan J.-H.、Sakiyama Y.、Hashiguchi A.、Ando M.、Okamoto Y.、Yoshimura A.、Higuchi Y.、Takashima H.
  • Journal Title: European Journal of Neurology Volume: 25 Issue: 12 Pages: 1454-1461
  • DOI: 10.1111/ene.13750
  • Peer Reviewed / Open Access
• [Journal Article] Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy (2018)
  • Author(s): Higuchi Yujiro、Ohtake Akira、Matsuura Eiji、Ueda Takehiro、Toda Tatsushi、Yamashita Sumimasa、Yamada Kenichiro、Koide Takashi、Yaguchi Hiroaki、Mitsui Jun、Ishiura Hiroyuki、Yoshimura Jun、Doi Koichiro、Morishita Shinichi、Sato Ken、Nakagawa Masanori、Yamaguchi Masamitsu、Tsuji Shoji、Takashima Hiroshi
  • Journal Title: Brain Volume: 印刷中 Issue: 6 Pages: 1622-1636
  • DOI: 10.1093/brain/awy104
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] KIF5A遺伝子変異を認めた若年性筋萎縮性側索硬化症の1例 (2021)
  • Author(s): 神田佳樹，湯治美佳，安藤匡宏，平松 有，田邊 肇，田代雄一，﨑山祐介，松浦英治，髙嶋 博
  • Organizer: 第332回日本内科学会九州地方会
• [Presentation] 小脳性運動失調症と主徴としたコケイン症候群の姉妹例 (2021)
  • Author(s): 高橋信敬，三嶋崇靖，藤岡伸助，髙嶋 博，泉浩太郎，坪井義夫
  • Organizer: 第231回日本神経学会九州地方会
• [Presentation] ニューロパチーの遺伝学最新の知見（シンポジウム 日本初 遺伝性神経筋疾患 最新の発見） (2020)
  • Author(s): 樋口雄二郎，橋口昭大，岡本裕嗣，髙嶋 博
  • Organizer: 第61回日本神経学会学術総会
• [Presentation] 次世代シーケンサーを利用した神経感染症のショットガンメタゲノム解析 (2020)
  • Author(s): 﨑山佑介，吉村明子，湯地美佳，安藤匡宏，平松 有，田代雄一，樋口雄二郎，荒田 仁，松浦英治，髙嶋 博
  • Organizer: 第61回日本神経学会学術総会
• [Presentation] 精神運動発達遅滞にてんかんと舞踏様運動を合併した GNAO1 変異によるてんかん性脳症の一例 (2020)
  • Author(s): 久保純平，足立拓馬, 神田佳樹, 湯地美佳，安藤匡宏，平松 有, 田代雄一, 﨑山佑介，髙嶋 博
  • Organizer: 第229回日本神経学会九州地方会
• [Book] 難病と在宅ケア (2021)
  • Author(s): 樋口雄二郎，髙嶋 博
  • Publisher: 日本プランニングセンター
• [Book] 生体の科学 (2020)
  • Author(s): 樋口雄二郎，髙嶋 博
  • Publisher: 医学書院