Pathogenesis of Charcot-Marie-Tooth disease

• Project/Area Number: 25461537
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Yamagata University
• Principal Investigator: HAYASAKA Kiyoshi 山形大学, 医学部, 名誉教授 (20142961)
• Co-Investigator(Kenkyū-buntansha): NUMAKURA Chikahiko 山形大学, 医学部, 講師 (00400549) ; ABE Akiko 山形大学, 医学部, 非常勤講師 (10536949) ; TAKAHASHI Nobuya 山形大学, 医学部, 医員 (20536958)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 遺伝性ニューロパチー / Charcot-Marie-Tooth病 / 軸索型 / 混合型 / チトクロームオキシダーゼ / COX6A1 / cytochrome c oxidase / respiratory complex IV / 軸索 / 連鎖解析 / 呼吸鎖複合体 / 次世代シークエンサー / エクソーム解析

Outline of Final Research Achievements

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy, but causing gene mutation is not unknown in half of the patients. We studied two consanguineous families with CMT (axonal and mixed phenotypes) by SNP array and whole-genome sequencing analyses and finally detected a disease-specific 5 bp deletion (c.247-10_247-6delCACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1). Functional analysis showed that expression of COX6A1 in peripheral white blood cells from the affected individuals and COX activity in their EB-virus-transformed lymphoblastoid cell lines were significantly reduced. In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking. Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT.

Research Products

• [Journal Article] A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease. (2014)
  • Author(s): Tamiya G, Makino S, Hayashi M, Abe A, Numakura C, Ueki M, Tanaka A, Ito C, Toshimori K, Ogawa N, Terashima T, Maegawa H, Yanagisawa D, Tooyama I, Tada M, Onodera O, Hayasaka K.
  • Journal Title: Am J Hum Genet. Volume: 95 Issue: 3 Pages: 294-300
  • DOI: 10.1016/j.ajhg.2014.07.013
  • Peer Reviewed / Open Access
• [Journal Article] Molecular analysis of the genes causing recessive demyelinating Charcot-Marie-Tooth disease in Japan. (2013)
  • Author(s): Hayashi M, Abe A, Murakami T, Yamao S, Arai H, Hattori H, Iai M, Watanabe K, Oka N, Chida K, Kishikawa Y, Hayasaka K.
  • Journal Title: J Hum Genet. Volume: 58 Issue: 5 Pages: 273-278
  • DOI: 10.1038/jhg.2013.15
  • NAID: 10031177222
  • Peer Reviewed
• [Journal Article] INF2 mutationsin Charcot-Marie-Tooth disease complicated with focal segmental glomerulosclerosis. (2013)
  • Author(s): Toyota K, Ogino D, Hayashi M, Taki M, Saito K, Abe A, Hashimoto T, Umetsu K, Tsukaguchi H, Hayasaka K.
  • Journal Title: J Peripher Nerv Syst. Volume: 18(1) Issue: 1 Pages: 97-98
  • DOI: 10.1111/jns5.12014
  • Peer Reviewed
• [Journal Article] The first Japanese case of Charcot-Marie-Tooth disease type 4H with a novel FGD4 c.837-1G>A mutation. (2013)
  • Author(s): Arai H, Hayashi M, Hayasaka K, Kanda T, Tanabe Y.
  • Journal Title: Neuromuscul Disord. Volume: 23 Issue: 8 Pages: 652-655
  • DOI: 10.1016/j.nmd.2013.04.010
  • Peer Reviewed
• [Presentation] 劣性軸索型および混合型Charcot-Marie-Tooth病における新規病因遺伝子COX6A1の同定 (2015)
  • Author(s): 早坂清，田宮元，牧野悟士，沼倉周彦，林真貴子，阿部暁子，植木優夫，田中敦，他田正義，小野寺理
  • Organizer: 第57回日本先天代謝異常学会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2015-11-14
• [Book] シャルコー・マリー・トゥース病診療マニュアル改訂２版 (2015)
  • Author(s): CMT診療マニュアル編集委員会
  • Total Pages: 181
  • Publisher: 金芳堂出版