心筋イオンチャネル病の遺伝疫学と生殖に関する研究

2013 Fiscal Year Research-status Report

• Project/Area Number: 25460406
• Research Category: Grant-in-Aid for Scientific Research (C)
• Research Institution: Shiga University of Medical Science
• Principal Investigator: 伊藤 英樹 滋賀医科大学, 医学部, 助教 (30402738)
• Co-Investigator(Kenkyū-buntansha): 堀江 稔 滋賀医科大学, 医学部, 教授 (90183938)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Keywords: イオンチャネル / 遺伝子 / 変異 / QT延長症候群 / 機能

Research Abstract

心筋イオンチャネルの遺伝子異常は心臓不整脈の原因のみならず、心臓以外の臓器の変化をきたす場合がある。これは心筋イオンチャネルが多臓器に発現し機能していることの証拠である。心筋カリウムチャネル遺伝子変異によるQT延長症候群に女性が多いことが共同研究者のGuicheney教授らのグループから報告されており、生殖に関与するイオンチャネル群を明らかにし、そのメカニズムを解明することで、遺伝カウンセリングや生殖医療へ応用が期待されるものと考えている。本年は心筋ナトリウムチャネル遺伝子に変異を有するブルガダ症候群の家系調査を行った。ブルガダ症候群は男性患者が全体の9割を占めており、当施設とパリ第6大学の34家系120例のブルガダ症候群の男女差、変異アレルの伝達を検討した。発端者を除外した男性の割合は53%、父親から変異アレルの伝達は54%であり、大きな性差は認めなかった。心筋ナトリウム遺伝子の変異を有するQT延長症候群においても男女差、変異アレルの遺伝子伝達に関して乖離が認められなかった。ブルガダ症候群の原因となる遺伝子変異はloss of function(機能喪失型)タイプの機能変化をおこす一方、QT延長症候群の原因となる変異はgain of function(機能亢進型)タイプの機能変化をきたすが、これらの異なった機能変化を有する疾患群において有意な変異アレルの伝達変化を認めなかったことから、心筋ナトリウム電流は生殖への関与は薄いことが考えられた。

Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

臨床遺伝学的検討に関しては概ね良好である。

Strategy for Future Research Activity

心筋カリウムチャネルの関与が大きいことが予想されるため、本年度はアンダーセン症候群の家族調査を行う予定である。また、KCNQ1遺伝子変異の機能解析を行い、臨床像と遺伝子伝達、男女差を機能変化毎に検討する予定である。

Research Products

• [Journal Article] Nonsense-mediated mRNA decay due to a CACNA1C splicing mutation in a patient with Brugada syndrome. (2014)
  • Author(s): Fukuyama M, Ohno S, Wang Q, Shirayama T, Itoh H, Horie M.
  • Journal Title: Heart Rhythm Volume: 11 Pages: 629-34
  • DOI: 10.1016/j.hrthm.2013.12.011.
  • Peer Reviewed
• [Journal Article] Exon 3 deletion of RYR2 encoding cardiac ryanodine receptor is associated with left ventricular non-compaction. (2014)
  • Author(s): Ohno S, Omura M, Kawamura M, Kimura H, Itoh H, Makiyama T, Ushinohama H, Makita N, Horie M.
  • Journal Title: Europace Volume: 16 Pages: 1646-54
  • DOI: 10.1093/europace/eut382.
  • Peer Reviewed
• [Journal Article] Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes. (2014)
  • Author(s): Fukuyama M, Wang Q, Kato K, Ohno S, Ding WG, Toyoda F, Itoh H, Kimura H, Makiyama T, Ito M, Matsuura H, Horie M.
  • Journal Title: Europace Volume: 16 Pages: 1828-37
  • DOI: 10.1093/europace/euu063.
  • Peer Reviewed
• [Journal Article] Mosaic KCNJ2 Mutation in Andersen-Tawil syndrome: Targeted Deep Sequencing is Useful for the Detection of Mosaicism. (2014)
  • Author(s): Hasegawa K, Ohno S, Kimura H, Itoh H, Makiyama T, Yoshida Y, Horie M.
  • Journal Title: Clin Genet Volume: in press Pages: in press
  • DOI: 10.1111/cge.12357
  • Peer Reviewed
• [Journal Article] Gain-of-Function KCNH2 Mutations in Patients with Brugada Syndrome. (2014)
  • Author(s): Wang Q, Ohno S, Ding WG, Fukuyama M, Miyamoto A, Itoh H, Makiyama T, Wu J, Bai J, Hasegawa K, Shinohara T, Takahashi N, Shimizu A, Matsuura H, Horie M.
  • Journal Title: J Cardiovasc Electrophysiol Volume: 25 Pages: 522-30
  • DOI: 10.1111/jce.12361
  • Peer Reviewed
• [Journal Article] Cardiac channelopathies associated with infantile fatal ventricular arrhythmias: from the cradle to the bench. (2014)
  • Author(s): Kato K, Makiyama T, Wu J, Ding WG, Kimura H, Naiki N, Ohno S, Itoh H, Nakanishi T, Matsuura H, Horie M.
  • Journal Title: J Cardiovasc Electrophysiol Volume: 25 Pages: 66-73
  • DOI: 10.1111/jce.12270
  • Peer Reviewed
• [Journal Article] A novel KCNQ1 missense mutation identified in a patient with juvenile-onset atrial fibrillation causes constitutively open IKs channels. (2014)
  • Author(s): Hasegawa K, Ohno S, Ashihara T, Itoh H, Ding WG, Toyoda F, Makiyama T, Aoki H, Nakamura Y, Delisle BP, Matsuura H, Horie M.
  • Journal Title: Heart Rhythm Volume: 11 Pages: 67-75
  • DOI: 10.1016/j.hrthm.2013.09.073
  • Peer Reviewed
• [Journal Article] Long-term Pharmacological Therapy of Brugada Syndrome: Is Attenuation of J waves a Marker of Drug Efficacy? (2014)
  • Author(s): Hasegawa K, Ashihara T, Kimura H, Jo Hikari, Itoh H, Yamamoto T, Aizawa Y, Horie M.
  • Journal Title: Internal Med Volume: in press Pages: in press
  • Peer Reviewed
• [Journal Article] A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1. (2013)
  • 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 Pages: 1058-64
  • DOI: 10.1212/WNL.0000000000000239
  • Peer Reviewed
• [Journal Article] Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome. (2013)
  • Author(s): Duchatelet S, Crotti L, Peat RA, Denjoy I, Itoh H, Berthet M, Ohno S, Fressart V, Monti MC, Crocamo C, Pedrazzini M, Dagradi F, Vicentini A, Klug D, Brink PA, Goosen A, Swan H, Toivonen L, Lahtinen AM, Kontula K, Shimizu W, Horie M, George AL Jr, Tregouet DA, Guicheney P, Schwartz PJ.
  • Journal Title: Circ Cardiovasc Genet Volume: 6 Pages: 354-61
  • DOI: 10.1161/CIRCGENETICS.113.000023
  • Peer Reviewed
• [Journal Article] Genetic background of catecholaminergic polymorphic ventricular tachycardia in Japan. (2013)
  • Author(s): Kawamura M, Ohno S, Naiki N, Nagaoka I, Dochi K, Wang Q, Hasegawa K, Kimura H, Miyamoto A, Mizusawa Y, Itoh H, Makiyama T, Sumitomo N, Ushinohama H, Oyama K, Murakoshi N, Aonuma K, Horigome H, Honda T, Yoshinaga M, Ito M, Horie M.
  • Journal Title: Circ J Volume: 77 Pages: 1705-13
  • Peer Reviewed
• [Journal Article] L-type calcium channel mutations in Japanese patients with inherited arrhythmias. (2013)
  • Author(s): Fukuyama M, Ohno S, Wang Q, Kimura H, Makiyama T, Itoh H, Ito M, Horie M.
  • Journal Title: Circ J Volume: 77 Pages: 1534-42
  • Peer Reviewed
• [Presentation] Kir3.4変異はKir2.1に対する抑制作用を通してAndersen-Tawil 症候群を引き起こす (2014)
  • Author(s): 田充、殻内洋介、中田智彦、坂田宗平、木村紘美、相庭武司、吉永正夫、大崎裕亮、中森雅之、伊藤秀樹、佐藤貴子、久保田智哉、門田一繁、進藤克郎、望月秀樹、清水渉、堀江稔、岡村康司、大野欽司、高橋正紀
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡
  • Year and Date: 20140521-20140524
• [Presentation] Both Gain- and Loss-of-Function SCN5A Mutations Associated with Infantile Fatal Ventricular Arrhythmias (2014)
  • Author(s): Koichi Kato, Takeru Makiyama, Jie Wu, Wei-Guang Ding, Hiromi Kimura, Nobu Naiki, Seiko Ohno, Hideki Itoh, Toshio Nakanishi, Hiroshi Matsuura, Minoru Horie
  • Organizer: ACC 2014
  • Place of Presentation: Washington
  • Year and Date: 20140329-20140331
• [Presentation] 後天性QT延長症候群の発症病態 (2014)
  • Author(s): 伊藤英樹、Crotti Lia、Schwartz J Peter、林研至、中島忠、大野聖子、牧山武、山岸正和、井本敬二、Pascale Guicheney、堀江稔
  • Organizer: 第91回日本生理学会大会
  • Place of Presentation: 鹿児島
  • Year and Date: 20140316-20140318
  • Invited
• [Presentation] VerapamilがVF stormに有効であった突発性心室細動の１例 (2013)
  • Author(s): 藤居祐介、伊藤英樹、服部哲久、小澤友哉、芦原貴司、児玉健二、高橋宏明、福沢綾子、冨田行則、八木典章、松本祐一、内貴乃生、木村紘美、酒井 宏、山本 孝、伊藤 誠、堀江 稔
  • Organizer: 第75回滋賀県循環器疾患研究会
  • Place of Presentation: 滋賀
  • Year and Date: 20131221-20131221
• [Presentation] short-coupled variant of torsade de pointes の遺伝的背景 (2013)
  • Author(s): 堀本かんな、伊藤英樹、小澤友哉、内貴乃生、冨田行則、藤居祐介、八木典章、服部哲久、木村紘美、芦原貴司、松本祐一、酒井 宏、山本 孝、伊藤 誠、堀江 稔
  • Organizer: 第116回日本循環器学会近畿地方会
  • Place of Presentation: 大阪
  • Year and Date: 20131130-20131130
• [Presentation] The High Prevalence of Early Repolarization in Genotyped Long QT Syndrome. (2013)
  • Author(s): Hasegawa K, Watanabe H, Ohno S, Itoh H, Makiyama T, Ashihara T, Hayashi H, Horie M.
  • Organizer: AHA Scientific Sessions 2013
  • Place of Presentation: Dallas, USA
  • Year and Date: 20131116-20131120
• [Presentation] Altered splicing of cardiac sodium channel might be responsible for cardiac conduction defects in myotonic dystrophy. (2013)
  • Author(s): Kokunai Y, Kino Y, Li M, Itoh H, Nakamori M, Kimura T, Matsumura T, Fujimura H, Nukina N, Sakoda S, Horie M, Imoto K, Ishiura S, Swanson MS, Charlet-Berguerand N, Takahashi MP.
  • Organizer: The 9th International Myotonic Dystrophy Consortium
  • Place of Presentation: Basque, Spain
  • Year and Date: 20131016-20131016
• [Presentation] 若年時に診断された催不整脈性右室心筋症・異形成（ARVC/D）患者の臨床的および遺伝的特徴 (2013)
  • Author(s): 大野聖子、福山 恵、長谷川奏恵、木村紘美、伊藤英樹、牧山 武、堀江 稔
  • Organizer: 第30回日本心電学会
  • Place of Presentation: 青森
  • Year and Date: 20131011-20131012
• [Presentation] Phenotypic characterization of three patients with lethal arrhythmia related to KCNH2-R148W missense mutation. (2013)
  • Author(s): Ohno S, Wang Q, Hasegwas K, Itoh H, Makiyama T, Horie M.
  • Organizer: 6th APHRS & CardioRhythm 2013
  • Place of Presentation: Hong Kong, China
  • Year and Date: 20131003-20131006
• [Presentation] Copy number variation in KCNQ1 gene were frequently identified in the pediatric patients of long QT syndrome and caused exercise related QT prolongation. (2013)
  • Author(s): Ohno S, Fukuyama M, Itoh H, Makiyama T, Horie M.
  • Organizer: ESC CONGRESS 2013
  • Place of Presentation: Amsterdam, the Netherlands
  • Year and Date: 20130831-20130904
• [Presentation] Novel CACNA1C mutations in Long QT syndrome patients- The subtype of Long QT syndrome type 8. (2013)
  • Author(s): Fukuyama M, Wang Q, Kato K, Ohno S, Kimura H, Makiyama T, Itoh H, Ito M, Matsuura H, Horie M.
  • Organizer: Denis Escande Symposium 2013
  • Place of Presentation: Amsterdam, the Netherlands
  • Year and Date: 20130830-20130831
• [Presentation] Underlying Mechanisms in Forme Fruste Long QT Syndrome Manifested by Acquired Factors. (2013)
  • Author(s): Itoh H.
  • Organizer: The 2nd HD Physiology International Symposium
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 20130628-20130629
• [Presentation] Exon-3 deletion of RyR2 encoding cardiac ryanodine receptor related to left ventricular non-compaction (LVNC) with ventricular arrhythmia and bradycardia. (2013)
  • Author(s): Ohno S, Omura M, Kawamura M, Kimura H, Itoh H, Makiyama T, Ushinohama H, Makita N, Horie M.
  • Organizer: EHRA EUROPACE 2013
  • Place of Presentation: Athens, Greek
  • Year and Date: 20130623-20130626
• [Presentation] 心室細動後の12誘導心電図で広範囲なST上昇を認めたJ wave syndromeの一例 (2013)
  • Author(s): 冨田行則、服部哲久、伊藤英樹、児玉 健二、福沢綾子、高橋宏明、八木典章、木村紘美、山科 聡、酒井 宏、小澤友哉、山本 孝、伊藤 誠、堀江 稔
  • Organizer: 第115回日本循環器学会近畿地方会
  • Place of Presentation: 京都
  • Year and Date: 20130615-20130615
• [Presentation] KCNH2遺伝子変異による徐脈性QT延長症候群の一家系 (2013)
  • Author(s): 中泉伸彦、伊藤英樹、児玉 浩、富田行則、八木典章、服部哲久、木村紘美、酒井 宏、小澤友哉、山本 孝、伊藤 誠、堀江 稔、椙本 晃
  • Organizer: 第115回日本循環器学会近畿地方会
  • Place of Presentation: 京都
  • Year and Date: 20130615-20130615
• [Presentation] Asymmetry of parental origin in Long QT syndrome. European Human Genetics Conference (2013)
  • Author(s): Itoh H, Berthet M, Fressart V, Denjoy I , Maugenre S, Klug D, Mizusawa Y, Makiyama T, Hofman N, Husemann A, Shimizu W, Wilde AA , Schulze-Bahr E, Horie M, du Montcel ST, Guicheney P.
  • Organizer: European Human Genetics Conference
  • Place of Presentation: Paris, France
  • Year and Date: 20130608-20130611
• [Book] 見逃すな！薬物中毒と電解質異常. レジデントノート 心電図の読み方トレニーング (2013)
  • Author(s): 伊藤英樹
  • Total Pages: 88-94
  • Publisher: 羊土社