Identification and functional analysis of a new candidate gene of nemaline myopathy

• Project/Area Number: 25860876
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Yokohama City University
• Principal Investigator: IMAMURA Eriko 横浜市立大学, 医学(系)研究科(研究院), 博士研究員 (80637877)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2013: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 先天性ミオパチー / エクソーム解析 / ゼブラフィッシュ / エキソーム解析

Outline of Final Research Achievements

By whole exome sequencing, compound heterozygous mutation was identified in new candidate gene KLHL40 from a Japanese family with nemaline myopathy (NEM). A multinational cohort of 143 severe NEM patients lacking genetic diagnosis revealed that 19 mutations in KLHL40 in 28 NEM family. Molecular modeling suggested that the missense mutations would destabilize the protein. Protein studies showed that KLHL40 is a skeletal muscle specific protein that is absent in patient skeletal muscle. In zebrafish, knockdown of klhl40 resulted in disruption of muscle structure. These results indicated that the mutations of KLHL40 gene caused NEM.

Research Products

• [Journal Article] Detecting copy-number variations in whole-exome sequencing data using the eXome Hidden Markov Model: an 'exome-first' approach. (2015)
  • Author(s): Miyatake S, Koshimizu E, Fujita A, Fukai R, Imagawa E, Ohba C, Kuki I, Nukui M, Araki A, Makita Y, Ogata T, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Matsumoto N
  • Journal Title: Journal of Human Genetics Volume: 60 Pages: 175-182
  • Peer Reviewed
• [Journal Article] De novo SOX11 mutations cause Coffin-Siris syndrome. (2014)
  • Author(s): Tsurusaki Y, Koshimizu E, Ohashi H, Phadke S, Kou I, Shiina M, Suzuki T, Okamoto N, Imamura S, Yamashita M, Watanabe S, Yoshiura K, Kodera H, Miyatake S, Nakashima M, Saitsu H, Ogata K, Ikegawa S, Miyake N, Matsumoto N
  • Journal Title: Nature Communications Volume: 5 Pages: 4011-4011
  • Peer Reviewed
• [Journal Article] Deep sequencing detects very-low-grade somatic mosaicism in the unaffected mother of siblings with nemaline myopathy (2014)
  • Author(s): Miyatake S, Koshimizu E, Hayashi YK, Miya K, Shiina M, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Ogata K, Nishino I, Matsumoto N
  • Journal Title: Neuromuscular Disorders Volume: 24 Pages: 642-647
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy (2013)
  • Author(s): Ravenscroft G, Miyatake S, Hayashi YK, Miyake N, Tsurusaki Y, Doi H, Saitsu H, Osaka H, Yamashita S, Ohya T, Sakamoto Y, Koshimizu E, Imamura S, Yamashita M, Ogata K, Shiina M, Bryson-Richardson RJ, Nishino I, Matsumoto N, Laing NG, et al
  • Journal Title: Am J Hum Genet Volume: 93 Pages: 6-18
  • Peer Reviewed
• [Journal Article] Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with autism spectrum disorder (2013)
  • Author(s): Koshimizu E, Miyatake S, Okamoto N, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Matsumoto N
  • Journal Title: PLoS One Volume: 8
  • Peer Reviewed
• [Journal Article] De Novo mutations in GNAO1, encoding a Gαo subunit of heterotrimeric G proteins, cause epileptic encephalopathy (2013)
  • Author(s): Nakamura K, Kodera H, Akita T, Shiina M, Kato M, Hoshino H, Terashima H, Osaka H, Nakamura S, Miyatake S, Koshimizu E, Nishiyama K, Nakashima M, Tsurusaki Y, Miyake N, Hayasaka K, Ogata K, Fukuda A, Matsumoto N, Saitsu H, et al
  • Journal Title: Am J Hum Genet Volume: 93 Pages: 496-505
  • Peer Reviewed
• [Journal Article] MLL2 and KDM6A mutations in patients with Kabuki syndrome (2013)
  • Author(s): Miyake N, Koshimizu E, Okamoto N, Mizuno S, Ogata T, Nagai T, Kosho T, Ohashi H, Kato M, Sasaki G, Kitanaka S, Matsubara Y, Makita T, Taguri M, Nakashima M, Tsurusaki Y, Saitsu H, Yoshiura K, Matsumoto N, Niikawa N, et al
  • Journal Title: Am J Med Genet A Volume: 161 Pages: 2234-2243
  • Peer Reviewed
• [Journal Article] Whole-exome sequencing identified a homozygous FNBP4 mutation in a family with a condition similar to microphthalmia with limb anomalies (2013)
  • Author(s): Kondo Y, Koshimizu E, Megarbane A, Hamanoue H, Okada I, Nishiyama K, Kodera H, Miyatake S, Tsurusaki Y, Nakashima M, Doi H, Miyake N, Saitsu H, Matsumoto N.
  • Journal Title: Am J Med Genet A Volume: 161 Pages: 1543-1546
  • Peer Reviewed
• [Presentation] 次世代シーケンサーを用いた超低頻度モザイク変異の検出：ネマリンミオパチーの一例. (2014)
  • Author(s): 輿水江里子, 宮武聡子, 林由起子, 宮一志, 椎名政昭, 中島光子, 鶴崎美徳, 三宅紀子, 才津浩智, 緒方一博, 西野一三, 松本直通
  • Organizer: 日本人類遺伝学会第59回大会
  • Place of Presentation: タワーホール船堀（東京）
  • Year and Date: 2014-11-19 – 2014-11-22
• [Presentation] Deep sequencing detects very low-grade somatic mosaicism in the unaffected mother of siblings with nemaline myopathy. (2014)
  • Author(s): Koshimizu E, Miyatake S, Hayashi K Y, Miya K, Shiina M, Nakashima, M, Tsurusaki Y, Miyake N, Saitsu H, Ogata K, Nishino I, Matsumoto N
  • Organizer: American Society of Human Genetics 64th Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 2014-10-18 – 2014-10-22
• [Presentation] Performance Evaluation of Bench-top Next Generation Sequencers Using Microdroplet PCR-Based Enrichment for Targeted Sequencing in Patients with Autism Spectrum Disorder (2013)
  • Author(s): Koshimizu E, Miyatake S, Okamoto N, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Matsumoto N
  • Organizer: American Society of Human Genetics 63rd Annual Meeting
  • Place of Presentation: Boston, USA
• [Presentation] 自閉症スペクトラム疾患を対象としたマルチプレックスPCR産物の次世代シーケンス法の確立 (2013)
  • Author(s): 輿水 江里子, 宮武 聡子, 岡本 伸彦, 三宅 紀子, 才津 浩智, 松本 直通
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 江陽グランドホテル (宮城県仙台市)
• [Presentation] ネマリンミオパチーの遺伝子変異解析 (2013)
  • Author(s): 林 由起子, 宮武 聡子, 輿水 江里子, 松本 直通, 野口 悟, 西野 一三
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 江陽グランドホテル (宮城県仙台市)
• [Presentation] ネマリンミオパチーの新規原因遺伝子KLHL40 の同定 (2013)
  • Author(s): 宮武 聡子, 輿水 江里子, 林 由起子, Gianina Ravenscroft, 三宅 紀子, 土井 宏, 鶴崎 美徳, 才津 浩智, 小坂 仁, 山下 純正, 大宅 喬, 増澤 祐子, 今村 伸太朗, 山下 倫明, 椎名 政昭, 緒方 一博, 西野 一三, Nigel Laing, 松本 直通
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 江陽グランドホテル (宮城県仙台市)
• [Remarks] 松本教授ら研究グループが、筋肉の障害、筋力低下をきたす『先天性ミオパチー』の新たな原因遺伝子を発見！
  • URL: http://www.yokohama-cu.ac.jp/univ/pr/press/130610.html