Molecular diagnosis of Charcot-Marie-Tooth disease in Japan: quantitative alterations in the major causative genes

• Project/Area Number: 25860842
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Yamagata University
• Principal Investigator: ABE Akiko 山形大学, 医学部, 非常勤講師 (10536949)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: Charcot-Marie-Tooth病 / 遺伝性ニューロパチー / MLPA法

Outline of Final Research Achievements

To determine the mechanisms of pathogenesis for Charcot-Marie-Tooth disease (CMT), we examined the genes that had already been known to be responsible for the development of CMT. In addition, we studied two families affected with autosomal-recessive (AR)-axonal CMT by a parametric linkage analysis using genome-wide SNP microarray and whole-genome analysis (WGA) using a next-generation sequencing. We detected the autosomal-dominant gene mutations as follows: 14 cases of MFN2 mutation, 1 of GARS, 5 of MPZ, 5 of GDAP1, 6 of GJB1, and 1 of PRPS1. Compound heterozygous OPA1 mutations were detected in the siblings who showed variable clinical symptoms. We also found a novel AR-causative gene, COX6A1 in two families. The homozygous COX6A1 mutation is a cause of autosomal-recessive axonal CMT or intermediate CMT. Since the causative genes have not yet been detected in most Japanese patients with CMT, WGA by using a next-generation sequencer would be useful for molecular diagnosis of 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] Charcot-Marie-Tooth病type 4B1とmyelin outfoldings． (2014)
  • Author(s): 村上龍文，久徳弓子，西村広健，林真貴子，阿部暁子，早坂清，砂田芳秀
  • Journal Title: 末梢神経 Volume: 25 Pages: 52-58
  • Peer Reviewed
• [Journal Article] Mild phenotype of Charcot-Marie-Tooth disease type 4B1 (2013)
  • Author(s): Tatsufumi Murakami, Yumiko Kutoku, Hirotake Nishimura, Makiko Hayashi, Akiko Abe, Kiyoshi Hayasaka, Yoshihide Sunada
  • Journal Title: Journal of the Neurological Sciences Volume: 334 Issue: 1-2 Pages: 176-179
  • DOI: 10.1016/j.jns.2013.08.001
  • 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] 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
• [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 改定２版 (2015)
  • Author(s): 阿部暁子，早坂清,大竹弘哲,岡本裕嗣,小野寺理，小林庸子,滋賀健介,高嶋博,辻有希子,中川正法,能登祐一,橋口昭大,蜂須賀明子,蜂須賀研二,服部直樹,松嶋康之,宮口琢磨,山下敏彦,山田隆司,和田郁雄,渡邉耕太
  • Total Pages: 181
  • Publisher: 金芳堂