心臓イオンチャネルの遺伝子異常と機能破綻の分子基盤

2014 Fiscal Year Annual Research Report

• Project Area: Establishment of Integrative Multi-level Systems Biology and its Applications
• Project/Area Number: 22136007
• Research Institution: Nagasaki University
• Principal Investigator: 蒔田 直昌 長崎大学, 医歯薬学総合研究科(医学系), 教授 (00312356)
• Co-Investigator(Kenkyū-buntansha): 前村 浩二 長崎大学, 医歯薬学総合研究科(医学系), 教授 (90282649) ; 辻 幸臣 長崎大学, 医歯薬学総合研究科(医学系), 講師 (60432217)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Keywords: 洞不全症候群 / ミオシン重鎖 / サルコメア / 網羅的遺伝子解析 / ゼブラフィッシュ / 心拍数 / GWAS

Outline of Annual Research Achievements

家族性洞不全症候群(SSS)はまれな徐脈性不整脈で、一部の症例に心筋NaチャネルSCN5AやペースメーカチャネルHCN4の遺伝子変異が報告されているが、多くの症例では原因が未解明である。近年のゲノムワイド関連解析から心房型ミオシン重鎖遺伝子MYH6がSSSに関与していることが明らかとなり、本研究室ではSSS患者に新たなMYH6遺伝子変異を見出した。本研究の目的は、1)我々が日本人SSSに同定した新規MYH6アミノ酸欠損変異(delE933)の機能解析を行うこと、2)家族性SSSの網羅的遺伝子解析によって新規分子病態を探索することである。免疫沈降実験によって、MYH6-delE933はサルコメアの構造機能調節に必須のミオシン結合タンパクC(MyBP-C)との機能的結合異常を介してサルコメア構造の機能連関を乱すことが判明した。またゼブラフィッシに内因性myh6のノックダウンで徐脈がもたらされ、野生型ヒトMYH6はmyh6を補償できたが変異MYH6にはその効果がなく、delE933は心拍数に関して機能喪失型変異だと判明した。また心房筋細胞HL-1にMYH6を安定発現させ、64点電極上で活動電位伝導速度を測定したところ、delE933の細胞は伝導が障害されていた。以上の結果から、洞結節のexit blockによってSSSを発症するという新たな疾患メカニズムが明らかになった。次に、心疾患関連459遺伝子をターゲットとするエクソンキャプチャーで家族性SSS患者のDNA網羅的に解析を行ったところ、新たな原因遺伝子Xを見出した。その分子機序は既知の原因遺伝子とは異なるものであると推測され、網羅的遺伝子解析が新たな遺伝性不整脈の分子機序解明に有効であることが示された。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] A novel mutation in the α-myosin heavy chain gene is associated with sick sinus syndrome. (2015)
  • Author(s): Ishikawa T, Jou CJ, Nogami A, Kowase S, Arrington CB, Barnett SM, Harrell DT, Arimura T, Tsuji Y, Kimura A, Makita N.
  • Journal Title: Circ Arrhythm Electrophysiol. Volume: in press Pages: 印刷中
  • DOI: CIRCEP.114.002534
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of moderate-to-severe obstructive sleep apnea on the clinical manifestations of plaque vulnerability and the progression of coronary atherosclerosis in patients with acute coronary syndrome. (2015)
  • Author(s): Nakashima H, Kurobe M, Minami K, Furudono S, Uchida Y, Amenomori K, Nunohiro T, Takeshita S, Maemura K.
  • Journal Title: Eur Heart J Volume: 4 Pages: 75-84
  • DOI: 10.1177/2048872614530865
  • Peer Reviewed
• [Journal Article] Sinus arrest as a result of rivastigmine in an elderly dementia with Lewy bodies patient. (2015)
  • Author(s): Muto S, Kawano H, Nakatomi D, Yamasa T, Maemura K.
  • Journal Title: Geriatr Gerontol Int Volume: 15 Pages: 229-230
  • DOI: 10.1111/ggi.12311.
  • Peer Reviewed
• [Journal Article] Rivaroxaban therapy resulting in the resolution of right atrial thrombosis resistant to ordinary control with warfarin in a patient with atrial fibrillation. (2015)
  • Author(s): Kawano H, Kohno Y, Izumida S, Tsuneto A, Fukae S, Takeno M, Koide Y, Maemura K.
  • Journal Title: Intern Med Volume: 54 Pages: 601-604
  • DOI: 10.2169/internalmedicine.54.3003
  • Peer Reviewed
• [Journal Article] Molecular mechanisms of heart failure progression associated with implantable cardioverter-defibrillator shocks for ventricular tachyarrhythmias. (2014)
  • Author(s): Tsuji Y, Ishikawa T, Makita N.
  • Journal Title: J Arrhythmia. Volume: 30 Pages: 235-241
  • DOI: 10.1016/j.joa.2014.04.003
  • Peer Reviewed
• [Journal Article] A rare KCNE1 polymorphism, D85N, as a genetic modifier of long QT syndrome. (2014)
  • Author(s): Hasegawa K, Ohno S, Itoh H, Makiyama T, Aiba T, Nakano Y, Shimizu W, Matsuura H, Makita N, Horie M.
  • Journal Title: J Arrhythmia. Volume: 30 Pages: 161-166
  • DOI: 10.1016/j.joa.2013.08.004
  • Peer Reviewed
• [Journal Article] Normal dose of pilsicainide showed marked negative inotropic effects in a patient who had no underlying heart disease. (2014)
  • Author(s): Yoshida M, Ando S, Chishaki A, Makita N, Hasegawa Y, Narita S, Momii H, Kadokami T.
  • Journal Title: J Arrhythmia. Volume: 30 Pages: 68-70
  • Peer Reviewed
• [Journal Article] わが国における遺伝性不整脈診断・治療の今後の展望-欧米との違いも含めて. (2014)
  • Author(s): 清水渉, 蒔田直昌, 堀江稔, 相庭武司.
  • Journal Title: Cardiac Practice. Volume: 25 Pages: 65-72
• [Journal Article] 重症不整脈 electrical storm : 基礎研究からのアプローチ. (2014)
  • Author(s): 辻幸臣, 蒔田直昌.
  • Journal Title: 長崎市医師会報 Volume: 48 Pages: 7-11
• [Journal Article] 遺伝性不整脈の遺伝子診断の歴史. (2014)
  • Author(s): 蒔田直昌.
  • Journal Title: 呼吸と循環. Volume: 62 Pages: 827-831
• [Journal Article] Novel calmodulin mutations associated with congenital arrhythmia susceptibility. (2014)
  • Author(s): Makita N, Tsuji Y（39人中21番目）et al
  • Journal Title: Circ Cardiovasc Genet. Volume: 7 Pages: 466-474
  • DOI: 10.1161/CIRCGENETICS.113.000459
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics. (2014)
  • Author(s): Abe K, Machida T, Sumitomo N, Yamamoto H, Ohkubo K, Watanabe I, Makiyama T, Fukae S, Kohno M, Harrell DT, Ishikawa T, Tsuji Y, Nogami A, Watabe T, Oginosawa Y, Abe H, Maemura K, Motomura H, Makita N.
  • Journal Title: Circ Arrhythm Electrophysiol. Volume: 7 Pages: 511-517
  • DOI: 10.1161/CIRCEP.113.001340
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Right bundle branch block without overt heart disease predicts higher risk of pacemaker implantation: the study of atomic-bomb survivors. (2014)
  • Author(s): Kusumoto S, Kawano H, Makita N, Ichimaru S, Kaku T, Haruta D, Hida A, Sera N, Imaizumi M, Nakashima E, Maemura K, Akahoshi M.
  • Journal Title: Int J Cardiol. Volume: 174 Pages: 77-82
  • DOI: 10.1016/j.ijcard.2014.03.152
  • Peer Reviewed
• [Journal Article] Efficacy of bepridil to prevent ventricular fibrillation in severe form of early repolarization syndrome. (2014)
  • Author(s): Katsuumi G, Shimizu W, Watanabe H, Noda T, Nogami A, Ohkubo K, Makiyama T, Takehara N, Kawamura Y, Hosaka Y, Sato M, Fukae S, Chinushi M, Oda H, Okabe M, Kimura A, Maemura K, Watanabe I, Kamakura S, Horie M, Aizawa Y, Makita N, Minamino T.
  • Journal Title: Int J Cardiol. Volume: 172 Pages: 519-522
  • DOI: 10.1016/j.ijcard.2014.01.036
  • Peer Reviewed
• [Journal Article] Successful control of life-threatening polymorphic ventricular tachycardia by radiofrequency catheter ablation in an infant. (2014)
  • Author(s): Abe Y, Sumitomo N, Okuma H, Nakamura T, Fukuhara J, Ichikawa R, Matsumura M, Miyashita M, Kamiyama H, Ayusawa M, Watanabe M, Joo K, Makita N, Horie M.
  • Journal Title: Heart Vessels. Volume: 29 Pages: 422-426
  • DOI: 10.1007/s00380-013-0390-6
  • 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: 1646-1654
  • DOI: 10.1093/europace/eut382
  • Peer Reviewed
• [Journal Article] Adipose-derived regenerative cell therapy inhibits the progression of monocrotaline-induced pulmonary hypertension in rats. (2014)
  • Author(s): Eguchi M, Ikeda S, Kusumoto S, Sato D, Koide Y, Kawano H, Maemura K.
  • Journal Title: Life sci Volume: 118 Pages: 306-312
  • DOI: 10.1016/j.lfs.2014.05.008
  • Peer Reviewed
• [Journal Article] Longitudinal strain of right ventricular free wall by 2-dimensional speckle-tracking echocardiography is useful for detecting pulmonary hypertension (2014)
  • Author(s): Ikeda S, Tsuneto A, Kojima S, Koga S, Nakata T, Yoshida T, Eto M, Minami T, Yanagihara K, Maemura K.
  • Journal Title: Life sci Volume: 111 Pages: 12-17
  • DOI: 10.1016/j.lfs.2014.06.024
  • Peer Reviewed
• [Journal Article] Cardiac diastolic dysfunction predicts in-hospital mortality in acute ischemic stroke with atrial fibrillation. (2014)
  • Author(s): Tateishi Y, Tsujino A, Hamabe J, Tsuneto A, Maemura K, Tasaki O, Horie N, Izumo T, Hayashi K, Nagata I.
  • Journal Title: J Neurol Sci Volume: 345 Pages: 83-86
  • DOI: 10.1016/j.jns.2014.07.011
  • Peer Reviewed
• [Journal Article] Impairment of flow-mediated dilation correlates with aortic dilation in patients with Marfan syndrome. (2014)
  • Author(s): Takata M, Amiya E, Watanabe M, Omori K, Imai Y, Fujita D, Nishimura H, Kato M, Morota T, Nawata K, Ozeki A, Watanabe A, Kawarasaki S, Hosoya Y, Nakao T, Maemura K, Nagai R, Hirata Y, Komuro I.
  • Journal Title: Heart Vessels Volume: 29 Pages: 478-485
  • DOI: 10.1007/s00380-013-0393-3
  • Peer Reviewed
• [Journal Article] Honeycomb-like neointima of sirolimus-eluting stent in saphenous vein graft: insights from OCT and IVUS. (2014)
  • Author(s): Koga S, Ikeda S, Maemura K.
  • Journal Title: Int J Cardiol Volume: 172 Pages: 522-523
  • DOI: 10.1016/j.ijcard.2014.01.028
  • Peer Reviewed
• [Presentation] Emerging link between genetic variations of sodium channels and susceptibility to lethal arrhythmias. (2015)
  • Author(s): Makita N, Ishikawa T, Schott JJ, Bezzina CR
  • Organizer: 第88回日本薬理学会
  • Place of Presentation: 名古屋市、名古屋国際会議場
  • Year and Date: 2015-03-19
  • Invited
• [Presentation] Ventricular arrhythmias generated from purkinje fiber network with gap junction mutation －A simulation study－ (2015)
  • Author(s): Inada S, Harrell DT, Haraguchi R, Ashihara T, Makita N, Nakazawa K
  • Organizer: 多階層生体機能学「終了記念シンポジウム」
  • Place of Presentation: 大阪市、大阪大学中之島センター
  • Year and Date: 2015-03-06
• [Presentation] 心臓イオンチャネルの遺伝子異常と機能破綻の分子基盤 (2015)
  • Author(s): 蒔田直昌
  • Organizer: 多階層生体機能学「最終成果報告会」
  • Place of Presentation: 大阪市、大阪大学中之島センター
  • Year and Date: 2015-03-05
• [Presentation] Diverse Gender Difference of Arrhythmic Risk in Patients With Congenital Long QT Syndrome:From Japanese Congenital LQTS Multicenter Registry (2014)
  • Author(s): Aiba T, Makimoto H, Makiyama T, Watanabe H, Hayashi K, Nakano Y, Miyauchi Y, Morita H, Aonuma K, Hagiwara N, Fukuda K, Yoshinaga M, Horigome H, Sumitomo N, Tanaka T, Sekine A, Shiraishi I, Kusano K, Miyamoto Y, Kamakura S, Yasuda S, Ogawa H, Makita N, Horie M, Shimizu W
  • Organizer: American Heart Association Scientific Sessions
  • Place of Presentation: Chicago,USA
  • Year and Date: 2014-11-16
• [Presentation] Electrical storm: pathophysiological insights and therapeutic consequences (2014)
  • Author(s): Tsuji Y
  • Organizer: Asian Pacific Heart Rhythm Society
  • Place of Presentation: New Delhi, India
  • Year and Date: 2014-11-01
  • Invited
• [Presentation] A novel cardiac alpha-myosin heavy chain (MYH6) mutation impairing sarcomere structure responsible for familial sick sinus syndrome (2014)
  • Author(s): Ishikawa T, Nogami A, Kowase S, Harrell D, Tsuji Y, Arimura T, Kimura A, Makita N
  • Organizer: European Society of Cardiology
  • Place of Presentation: Barcelona,Spain
  • Year and Date: 2014-09-02
• [Presentation] Genetic modifiers in the long QT3/Brugada overlap-syndrome caused by E1784K. (2014)
  • Author(s): Muggenthaler M, Tanck MW, Schott JJ, Kyndt F, Borggrefe M, McKeown P, Makita N, Schwartz P, Roden D, Behr ER
  • Organizer: European Society of Cardiology
  • Place of Presentation: Barcelona,Spain
  • Year and Date: 2014-09-02
• [Presentation] Ethnicity and phenotype in the SCN5A E1784K mutation. (2014)
  • Author(s): Wijeyeratne Y, Probst V, Veltmann C, Shimizu W, Crotti L, Horie M, McKeown P, Makita N, Roden D, Behr ER
  • Organizer: European Society of Cardiology
  • Place of Presentation: Barcelona,Spain
  • Year and Date: 2014-08-31
• [Presentation] 不整脈の新規病因解明を目指す全エクソン解析とiPS技術のハイブリッドアプローチ (2014)
  • Author(s): 石川泰輔, 牧山武, 蒔田直昌
  • Organizer: 新学術研究領域「統合的多階層生体機能学領域の確立とその応用」
  • Place of Presentation: 秋田市、秋田大学
  • Year and Date: 2014-08-05
• [Presentation] A Novel Mutation in Atrial Myosin Heavy Chain Coding Gene MYH6 Causes Sick Sinus Syndrome (2014)
  • Author(s): Ishikawa T, Nogami A, Kowase S, Harrell DT, Arimura T, Tsuji Y, Kimura A, Makita N
  • Organizer: 第29回日本不整脈学会・第31回日本心電学会合同学術大会
  • Place of Presentation: 東京都港区、ザ・プリンスパークタワー東京
  • Year and Date: 2014-07-24
• [Presentation] Paradigm Shifts in the Genetics of Inherited Arrhythmias Brought on by High-throughput Sequencing and Genome-wide Association Studies (2014)
  • Author(s): Makita N
  • Organizer: 第29回日本不整脈学会・第31回日本心電学会合同学術大会
  • Place of Presentation: 東京都港区、ザ・プリンスパークタワー東京
  • Year and Date: 2014-07-24
  • Invited
• [Presentation] Role of Ca2+/calmodulin -dependent Protein Kinase ll in Atrial and Ventricular Remodeling and Arrhythmias (2014)
  • Author(s): Tsuji Y, Ishikawa T, Makita N
  • Organizer: 第29回日本不整脈学会・第31回日本心電学会合同学術大会
  • Place of Presentation: 東京都港区、ザ・プリンスパークタワー東京
  • Year and Date: 2014-07-24
  • Invited
• [Presentation] Electrical Storm in Inherited Arrhythmia Syndromes (2014)
  • Author(s): Tsuji Y, Ishikawa T, Makita N
  • Organizer: 第29回日本不整脈学会・第31回日本心電学会合同学術大会
  • Place of Presentation: 東京都港区、ザ・プリンスパークタワー東京
  • Year and Date: 2014-07-23
  • Invited
• [Presentation] Ventricular arrhythmia induced by the Purkinje network with reduced gap junction conductance - A simulation study - (2014)
  • Author(s): Inada S, Harrell DT, Haraguchi R, Ashihara T, Makita N, Nakazawa K
  • Organizer: 第53回日本生体医工学会
  • Place of Presentation: 仙台市、仙台国際センター
  • Year and Date: 2014-06-24
• [Presentation] Electrical storm: translational perspective on pathophysiology and therapy (2014)
  • Author(s): Tsuji Y
  • Organizer: Korea Heart Rhythm Symposium
  • Place of Presentation: Gyeonggi-do, Korea
  • Year and Date: 2014-06-14
  • Invited
• [Presentation] 遺伝性不整脈の病態における最近の知見 (2014)
  • Author(s): 蒔田直昌
  • Organizer: 第23回東葛地区不整脈研究会
  • Place of Presentation: 松戸市、松戸市立病院
  • Year and Date: 2014-05-31
  • Invited
• [Presentation] The Spectrum of Most Frequent Mutation in Short QT Syndrome (2014)
  • Author(s): Hu D, Zhang J, Li Y, Gollob M, Healey J, Harrell DT, Makita N, Abe H, Sun Y, Zhang L, Yan G, Mah D, Walsh E, Leopold H, Giustetto C, Gaita F, Martinez HB, Antzelevitch C
  • Organizer: 35th Annual Scientific Sessions, Heart Rhythm
  • Place of Presentation: San Francisco,USA
  • Year and Date: 2014-05-08
• [Presentation] A Novel Cardiac a-Myosin Heavy Chain (MYH6) Mutation Associated with Familial Sick Sinus Syndrome Altering Sarcomeric Organization (2014)
  • Author(s): Ishikawa T, Nogami A, Kowase S, Arimura T, Kimura A, Makita N
  • Organizer: 35th Annual Scientific Sessions,Heart Rhythm
  • Place of Presentation: San Francisco,USA
  • Year and Date: 2014-05-08
• [Presentation] Genotype-Phenotype Associations in Early Repolarization Syndrome (2014)
  • Author(s): Sonoda K, Watanabe H, Nogami A, Ohkubo K, Makiyama T, Takehara N, Kawamura Y, Hosaka Y, Sato M, Fukae S, Chinushi M, Oda H, Okabe M, Shimizu W, Kimura A, Maemura K, Watanabe I, Kamakura S, Burashnikov E, Antzelevitch C, Horie M, Aizawa Y, Minamino T, Makita N
  • Organizer: 35th Annual Scientific Sessions,Heart Rhythm
  • Place of Presentation: San Francisco,USA
  • Year and Date: 2014-05-08
• [Presentation] Genetic modifiers in carriers of the SCN5A E1784K mutation with variable phenotypic expression - Long QT3 / Brugada syndrome overlap disease (2014)
  • Author(s): Wileyeratne YD, Muggenthaler M, Tanck M, Schott JJ, Kyndt F, Probst V, Borggrefe M, McKeown P, Veltmann C, L C, Schwarts P, Sharma S, Makita N, Roden D, Behr ER
  • Organizer: British Cardiovascular Society annual meeting
  • Place of Presentation: Manchester,UK
  • Year and Date: 2014-05-01
• [Remarks] 長崎大学 分子生理学
  • URL: http://nagasaki-molphys.org/
• [Remarks] 長崎大学 循環器内科
  • URL: http://www.med.nagasaki-u.ac.jp/renew/information/intmed_3/index.html