Role of abnormal RNA for the pathophysiology of hereditary muscle diseases

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591245
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Osaka University
• Principal Investigator: TAKAHASHI Masanori 大阪大学, 医学(系)研究科(研究院), 助教 (20359847)
• Project Period (FY): 2011 – 2013
• Keywords: 筋強直性ジストロフィー / イオンチャネル / スプライシング / mRNA / チャネル病

Research Abstract

Pathomechanism of hereditary skeletal muscle diseases, especially myotonic dystrophy (DM) and channelopathies of skeletal muscle were investigated in the light of RNA abnormality. Regarding DM, the pathomechanism of arrhythmia which is clinically important as a cause of sudden death in DM, was investigated. An mRNA missplicing of ion channel was identified in DM hearts and the subsequent electrophysiological analyses and in silico simulation revealed its link with arrhythmia. Regarding the channelopathies of skeletal muscle, the molecular mechanism of the splicing of minor AT-AC II intron was investigated for the first disease mutation identified recently. It should be of note that a novel causative gene for a channelopathy of muscle was identified.

Research Products

• [Journal Article] A Kir3.4 mutation causes Andersen–Tawil syndrome by an inhibitory effect on Kir2.1 (2014)
  • Author(s): Kokunai Y, Nakata T, Furuta M, Sakata S, Kimura H, Aiba T, Yoshinaga M, Osaki Y, Nakamori M, Itoh H, Sato T, Kubota T, Kadota K, Shindo K, Mochizuki H, Shimizu W, Horie M, Okamura Y, Ohno K, Takahashi MP
  • Journal Title: Neurology Volume: 82(12) Pages: 1058-64
  • DOI: 10.1212/WNL.0000000000000239
  • Peer Reviewed
• [Journal Article] Ultrasound-enhanced delivery of Morpholino with Bubble liposomes ameliorates the myotonia of myotonic dystrophy model mice (2013)
  • Author(s): Koebis M, Kiyatake T, Yamaura H, Nagano K, Higashihara M, Sonoo M, Hayashi Y, Negishi Y, Endo-Takahashi Y, Yanagihara D, Matsuda R, Takahashi MP, Nishino I, Ishiura S
  • Journal Title: Sci Rep Volume: 3 Pages: 2242
  • DOI: 10.1038/srep02242
  • Peer Reviewed
• [Journal Article] Manumycin A corrects aberrant splicing of Clcn1 in myotonic dystrophy type 1 (DM1) mice (2013)
  • Author(s): Oana K, Oma Y, Suo S, Takahashi MP, Nishino I, Takeda S, Ishiura S
  • Journal Title: Sci Rep Volume: 3 Pages: 2142
  • DOI: 10.1038/srep02142
  • Peer Reviewed
• [Journal Article] Muscleblind-like 2 mediated alternative splicing in the developing brain and dysregulation in myotonic dystrophy (2012)
  • Author(s): Charizanis K, Lee K-Y, Batra R, Goodwin M, Zhang C, Yuan Y, Shiue L, Cline M, Scotti MM, Xia G, Kumar A, Ashizawa T, Brent Clark H, Kimura T, Takahashi MP, Fujimura H, Jinnai K, Yoshikawa H, Gomes-Pereira M, Gourdon G, Sakai N, Nishino S, Ares Jr M, Darnell RB, Swanson M
  • Journal Title: Neuron Volume: 75(3) Pages: 437-50
  • DOI: 10.1016/j.neuron.2012.05.029
  • Peer Reviewed
• [Journal Article] A sodium channel myotonia due to a novel SCN4A mutation accompanied by acquired autoimmune myasthenia gravis (2012)
  • Author(s): Kokunai Y, Goto K, Kubota T, Fukuoka T, Sakoda S, Ibi T, Doyu M, Mochizuki H, Sahashi K, Takahashi MP
  • Journal Title: Neurosci Lett Volume: 519(1)(Epub 2012 May 14) Pages: 67-72
  • DOI: 10.1016/j.neulet.2012.05.023
  • Peer Reviewed
• [Journal Article] Muscleblind-like 1 Knockout Mice Reveal Novel Splicing Defects in the Myotonic Dystrophy Brain (2012)
  • Author(s): Suenaga K, Lee KY, Nakamori M, Tatsumi Y, Takahashi MP, Fujimura H, Jinnai K, Yoshikawa H, Du H, Ares M Jr, Swanson MS, Kimura T
  • Journal Title: PLoS One Volume: 7(3) Pages: e33218
  • DOI: 10.1371/journal.pone.0033218
  • Peer Reviewed
• [Journal Article] A novel mutation in SCN4A causes severe myotonia and school-age-onset paralytic episodes (2012)
  • Author(s): Yoshinaga Y. Sakoda S-I, Good JM, Takahashi MP, Kubota T, Arikawa-Hirasawa E, Nakata T, Ohno K, Kitamura T, Kobayashi K, Ohtsuka Y
  • Journal Title: J Neurol Sci Volume: 315(1-2) Pages: 15-9
  • DOI: 10.1016/j.jns.2011.12.015
  • Peer Reviewed
• [Journal Article] A novel mutation in the calcium channel gene in a family with hypokalemic periodic paralysis (2011)
  • Author(s): Hirano M, Kokunai Y, Nagai A, Nakamura Y, Saigoh K, Kusunoki S, Takahashi MP
  • Journal Title: J Neurol Sci Volume: 309(1-2) Pages: 9-11
  • DOI: 10.1016/j.jns.2011.07.046
  • Peer Reviewed
• [Journal Article] Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy (2011)
  • Author(s): Rau F, Freyermuth F, Fugier C, Villemin JP, Fischer MC, Jost B, Dembele D, Gourdon G, Nicole A, Duboc D, Wahbi K, Day JW, Fujimura H, Takahashi MP, Auboeuf D, Dreumont N, Furling D, Charlet-Berguerand N
  • Journal Title: Nat Struct Mol Biol Volume: 18(7) Pages: 840-5
  • DOI: 10.1038/nsmb.2067
  • Peer Reviewed
• [Journal Article] Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy (2011)
  • Author(s): Fugier C, Klein AF, Hammer C, Vassilopoulos S, Ivarsson Y, Toussaint A, Tosch V, Vignaud A, Ferry A, Messaddeq N, Kokunai Y, Tsuburaya R, de la Grange P, Dembele D, Francois V, Precigout G, Boulade-Ladame C, Hummel MC, de Munain AL, Sergeant N, Laquerrière A, Thibault C, Deryckere F, Auboeuf D, Garcia L, Zimmermann P, Udd B, Schoser B, Takahashi MP, Nishino I, Bassez G, Laporte J, Furling D, Charlet-Berguerand N
  • Journal Title: Nature Medicine Volume: 17(6) Pages: 720-5
  • DOI: 10.1038/nm.2374
  • Peer Reviewed
• [Journal Article] A mutation in a rare type of intron in a sodium-channel gene results in aberrant splicing and causes myotonia (2011)
  • Author(s): KubotaT, Roca X, Kimura T, Kokunai Y, Nishino I, Sakoda S, Krainer AR, and Takahashi MP
  • Journal Title: Human Mutation Volume: 32(7) Pages: 773-82
  • DOI: 10.1002/humu.21501
  • Peer Reviewed
• [Presentation] Altered splicing of cardiac sodium channel might be responsible for cardiac conduction defects in myotonic dystrophy (2013)
  • Author(s): Kokunai Y, Itoh H, Kino Y, Li M, Nakamori M, Kimura T, Matsumura T, Fujimura H, Nukina N, Mochizuki H, Sakoda S, Horie M, Ishiura S, Imoto K, Swanson MS, Charlet Berguerand N, Takahashi MP
  • Organizer: 9th International Myotonic Dystrophy Consortium Meeting
  • Place of Presentation: Donostia San Sebastian, Spain
  • Year and Date: 2013-10-17
• [Presentation] RNA mis-splicing in myotonic disorders (2012)
  • Author(s): Takahashi MP
  • Organizer: The 9th Japanese-French Symposium for'muscular dystrophy'
  • Place of Presentation: 東京
  • Year and Date: 2012-09-07
• [Presentation] Symposium - Frontiers of Neurogenetics and Neuroscience Myotonic dystrophy and RNA story. Myotonic Dystrophy Overview and the pathomechanism as an mRNA disease (2012)
  • Author(s): Takahashi MP
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京(東京国際フォーラム)
  • Year and Date: 2012-05-23
• [Book] 筋強直性ジストロフィー筋疾患診療ハンドブック(青木正志編集) (2013)
  • Author(s): 中森雅之、高橋正紀
  • Total Pages: 176-181
  • Publisher: 中外医学社
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/neurol/myweb6/group04.html