Molecular basis for cardiac muscle diseases caused by functional abnormalities of Z-disc

• Project/Area Number: 23659414
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Circulatory organs internal medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: KIMURA Akinori 東京医科歯科大学, 難治疾患研究所, 教授 (60161551)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 遺伝学 / 遺伝子 / ゲノム / 循環器・高血圧 / Ｚ帯 / 循環器疾患 / 心筋症 / 不整脈 / 遺伝子変異 / SLMAP / ZASP / 細胞内輸送障害 / Z帯 / 機能連関 / Naチャネル / ストレス反応 / ストレッチ反応

Research Abstract

In this study, we investigated functional role of Z-disc in the molecular pathogenesis of cardiomyopathy and arrhythmia to develop a novel strategy for the diseases via modifying the Z-disc function. It was deciphered that mutations in ZASP caused cardiomyopathy accompanied by ventricular arrhythmia via impairing the function of INa through affecting expression of cardiac sodium channel Nav1.5. In addition, we revealed that the mutations in SLMAP gene encoding for a Z-disc protein of unknown function. It was found that SLMAP mutations impaired INa function via inhibiting intracellular trafficking of Nav1.5. Moreover, we also revealed that a SCN3B mutation inhibited intracellular trafficking of Nav1.5 and affected INa function. These observations have indicated that the intracellular trafficking of Nav1.5 is in part controlled by Z-disc elements. On the other hand, we found that a heart-specific small subunit of myosin phosphatase, M21, localized at Z-disc and increased the phosphorylation of a large subunit of myosin phosphatase, M110, which resulted in increased calcium sensitivity of cardiac muscle contraction. Inhibition of binding between M21 and M110 suppressed the phosphorylation of M110. M21 also bound to a Rho-kinase and enhanced its kinase activity, suggesting that inhibition of rho-kinase would be useful in modulation of calcium sensitivity of cardiac muscle contraction.

Research Products

• [Journal Article] Impact of ANKRD1 mutations associated with hypertrophic cardiomyopathy on contraction parameters of engineered heart tissue (2013)
  • Author(s): Crocini C, Arimura T, Reischmann S, Eder A, Braren I, Hansen A, Eschenhagen T, Kimura A, Carrier L
  • Journal Title: Basic Res Cardiol Volume: (in press) Issue: 3 Pages: 349-349
  • DOI: 10.1007/s00395-013-0349-x
  • Peer Reviewed
• [Journal Article] Novel <i>SCN3B</i> Mutation Associated With Brugada Syndrome Affects Intracellular Trafficking and Function of Nav1.5 (2013)
  • Author(s): Ishikawa T
  • Journal Title: Circulation Journal Volume: 77 Issue: 4 Pages: 959-967
  • DOI: 10.1253/circj.CJ-12-0995
  • NAID: 10031138998
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations (2012)
  • Author(s): Purevjav E, Arimura T, Augustin S, Huby A-C, Takagi K, Nunoda S, Kearney DL, Taylor MD, Terasaki F, Bos JM, Ommen SR, Shibata H, Takahashi M, Itoh-Satoh M, McKenna W, Murphy RT, Labeit S, Yamanaka Y, Machida N, Park JE,Alexander PMA, Weintraub RG, Kitaura Y, Ackerman MJ, Kimura A, Towbin JA.
  • Journal Title: Hum Mol Genet Volume: 21(9) Pages: 2039-2053
  • Peer Reviewed
• [Journal Article] Loss-of-function of hNav1.5 by ZASP1-D117N associated with intraventricular conduction disturbances in left ventricularnoncompaction (2012)
  • Author(s): Xi Y, Ai T, De Lange E, Li Z, Wu G, Brunelli L, Kyle WB, Cheng J, Ackerman MJ, Kimura A, Weiss JN, Qu Z, Kim JJ, Faulkner G, Vatta M
  • Journal Title: Circ Arrhythm Electrophysiol Volume: 5(5) Pages: 1017-1026
  • Peer Reviewed
• [Journal Article] A novel disease gene for Brugada syndrome: sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5 (2012)
  • Author(s): Ishikawa T, Sato A, Marcou CA, Tester DJ, Ackerman MJ, Crotti L, Schwartz PJ, On YK, Park JE, Nakamura K, Hiraoka M,Nakazawa K, Sakurada H, Arimura T, Makita N, Kimura A
  • Journal Title: Circ Arrhythm Electrophysiol Volume: 5(6) Pages: 1098-1107
  • Peer Reviewed
• [Journal Article] Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations. (2012)
  • Author(s): Purevjav E
  • Journal Title: Hum Mol Genet Volume: 21 Issue: 9 Pages: 2039-2053
  • DOI: 10.1093/hmg/dds022
  • Peer Reviewed
• [Journal Article] Loss-of-function of hNav1.5 by ZASP1-D117N associated with intraventricular conduction disturbances in left ventricular noncompaction (2012)
  • Author(s): Xi Y
  • Journal Title: Circ Arrhythm Electrophysiol Volume: 5 Issue: 5 Pages: 1017-1026
  • DOI: 10.1161/circep.111.969220
  • Peer Reviewed
• [Journal Article] A novel disease gene for Brugada syndrome: sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5 (2012)
  • Author(s): Ishikawa T
  • Journal Title: Circ Arrhythm Electrophysiol Volume: 5 Issue: 6 Pages: 1098-1107
  • DOI: 10.1161/circep.111.969972
  • Peer Reviewed
• [Journal Article] Prevalence and Distribution of Sarcomeric Gene Mutations in Japanese Patients With Familial Hypertrophic Cardiomyopathy (2012)
  • Author(s): Otsuka H, Arimura T, Abe T, Kawai H, Aizawa Y, Kubo T, Kitaoka H, Nakamura H, Nakamura K, Okamoto H, Ichida F, Ayusawa M, Nunoda S, Isobe M, Matsuzaki M, Doi YL, Fukuda K, Sasaoka T, Izumi T, Ashizawa N, Kimura A
  • Journal Title: Circulation Journal Volume: 76 Issue: 2 Pages: 453-461
  • DOI: 10.1253/circj.CJ-11-0876
  • NAID: 10030035969
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Contribution of genetic factors to the pathogenesis of dilated cardiomyopathy: the cause of dilated cardiomyopathy: genetic or acquired? (genetic-side) (2011)
  • Author(s): Kimura A
  • Journal Title: Circ J Volume: 75(7) Pages: 1756-1765
  • NAID: 10029127069
  • Peer Reviewed
• [Journal Article] Dilatedcardiomyopathy-associated BAG3 mutations impair the Z-disc assembly and enhance the sensitivity to apoptosis in cardiomyocytes (2011)
  • Author(s): Arimura T, Ishikawa T, Nunoda S, KawaiS, Kimura A
  • Journal Title: Hum Mutat Volume: 32(12) Pages: 1481-1491
  • Peer Reviewed
• [Journal Article] Dilated cardiomyopathy-associated BAG3 mutations impair the Z-disc as sembly and enhance the sensitivity to apoptosis in cardiomyocytes (2011)
  • Author(s): Arimura T, Ishikawa T, Nunoda S, Kawai S, Kimura A
  • Journal Title: Hum Mutat Volume: 32 Issue: 12 Pages: 1481-1491
  • DOI: 10.1002/humu.21603
  • Peer Reviewed
• [Journal Article] Electrocardiographic Characteristics and SCN5A Mutations in Idiopathic Ventricular Fibrillation Associated with Early Repolarization (2011)
  • Author(s): Watanabe H, Nogami A, Ohkubo K, Kawata H, Hayashi Y, Ishikawa T, Makiyama T, Nagao S, Yagihara N, Takehara N, Kawamura Y, Sato A, Okamura K, Hosaka Y, Sato M, Fukae S, Chinushi M, Oda H, Okabe M, Kimura A, Maemura K, Watanabe I, Kamakura S, Horie M, Aizawa Y, Shimizu W, Makita N
  • Journal Title: Circ Arrhythm Electrophysiol Volume: 4 Issue: 6 Pages: 874-881
  • DOI: 10.1161/circep.111.963983
  • Peer Reviewed
• [Presentation] 肥大型心筋症および拡張型心筋症におけるタイチンA/M帯変異の意義 (2012)
  • Author(s): 有村卓朗,石川泰輔,木村彰方
  • Organizer: 第57回日本人類遺伝学会
  • Place of Presentation: 東京
  • Year and Date: 2012-10-26
• [Presentation] ブルガダ症候群患者に見出されたSLMAP変異とその機能解析 (2012)
  • Author(s): 石川泰輔,佐藤光希,有村卓朗,蒔田直昌,木村彰方
  • Organizer: 第57回日本人類遺伝学会
  • Place of Presentation: 東京
  • Year and Date: 2012-10-26
• [Presentation] Impact of testosterone on progression of dilated cardiomyopathy in a Lmna-mutation knock-in mouse model (2012)
  • Author(s): Arimura T, Bonne G, Kimura A
  • Organizer: The 9th Japanese-French Symposium for "Muscular Dystrophy"
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2012-09-08
• [Presentation] Dilatedcardiomyopathy-associated BAG3 mutations impair the Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes (2012)
  • Author(s): Arimura T, Ishikawa T, Nunoda S, KawaiS, Kimura A
  • Organizer: The 76th Annual Meeting of the Japanese Circulation Society
  • Place of Presentation: Fukuoka
  • Year and Date: 2012-03-17
• [Presentation] A novel mechanism of Brugada syndrome: Mutation of sarcolemmalmembrane-associated protein (SLMAP)gene impaired hNav1.5 function (2012)
  • Author(s): Ishikawa T, Sato A, Arimura T, Sakurada H, Makita N, Kimura A
  • Organizer: The76th Annual Meeting of the Japanese Circulation Society
  • Place of Presentation: Fukuoka, Japan
  • Year and Date: 2012-03-16
• [Presentation] Cardiomyopathy as a disease of abnormalities in sensing for stretch and metabolic stress in cardiac sarcomere (2012)
  • Author(s): Kimura A
  • Organizer: 4th Sensing Biology Symposium
  • Place of Presentation: Tokyo
  • Year and Date: 2012-01-30
• [Presentation] Novel molecular mechanisms of idiopathic cardiomyopathy (2011)
  • Author(s): Arimura T, Kimura A
  • Organizer: 第28回国際心臓研究学会日本部会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2011-12-03
• [Presentation] Role of sarcolemmal membrane-associated protein (SLMAP) gene in Brugadasyndrome (2011)
  • Author(s): Ishikawa T, Arimura T, Kimura A
  • Organizer: The 14th Cardiovascular Genomics and Atherosclerosis Symposium
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2011-11-28
• [Presentation] 遺伝子異常からみた分子病態 (2011)
  • Author(s): 木村彰方.心筋症
  • Organizer: 第20回小児心筋疾患学会ランチョンセミナー
  • Place of Presentation: 東京
  • Year and Date: 2011-11-19
• [Presentation] BAG3変異は心筋細胞のZ帯整合性異常とアポトーシス感受性増強を介して拡張型心筋症を引き起こす (2011)
  • Author(s): 有村卓朗,石川泰輔,布田伸一,河合祥雄,木村彰方
  • Organizer: 第56回日本人類遺伝学会
  • Place of Presentation: 幕張
  • Year and Date: 2011-11-10
• [Presentation] Dilated cardiomyopathy-associated BAG3 mutations impair the sarcomere assembly and increase the sensitivity to apoptosis (2011)
  • Author(s): Arimura T, Ishikawa T, Kimura A
  • Organizer: The 14th Cardiovascular Genomics and Atherosclerosis Symposium
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2011-10-28
• [Presentation] Heart-specific Small Subunit of Myosin Light Chain Phosphatase Activates Rho-associated Kinase and Regulates Phosphorylationof Myosin Phosphatase Target Subunit 1 (2011)
  • Author(s): Arimura T, Kimura A
  • Organizer: 第75回日本循環器学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2011-08-03
• [Presentation] 心筋症の遺伝子異常と分子病態 (2011)
  • Author(s): 木村彰方
  • Organizer: 第73回東京心臓の会
  • Place of Presentation: 東京
  • Year and Date: 2011-06-11
• [Presentation] Role of sarcolemmal membrane-associated protein (SLMAP) gene in Brugada syndrome. (2011)
  • Author(s): Ishikawa T, Arimura T, Kimura A
  • Organizer: The 14th Cardiovascular Genomics and Atherosclerosis Symposium
  • Place of Presentation: Seoul, Korea
• [Presentation] ブルガダ症候群患者に見出されたSCN3B遺伝子V110I変異とその機能解析 (2011)
  • Author(s): 石川泰輔， 有村卓朗， 蒔田直昌， 木村彰方
  • Organizer: 第56回日本人類遺伝学会
  • Place of Presentation: 幕張
• [Presentation] 心筋症：遺伝子異常からみた分子病態 (2011)
  • Author(s): 木村彰方
  • Organizer: 第20回小児心筋疾患学会
  • Place of Presentation: 東京
• [Presentation] Novel molecular mechanisms of idiopathic cardiomyopathy (2011)
  • Author(s): Arimura T， Kimura A
  • Organizer: 第28回国際心臓研究学会日本部会
  • Place of Presentation: 東京
• [Presentation] ブルガダ症候群患者に見出されたSLMAP変異とその機能解析
  • Author(s): 石川泰輔
  • Organizer: 第57回日本人類遺伝学会
  • Place of Presentation: 東京
• [Remarks]
  • URL: http://www.tmd.ac.jp/mri/mri-mpath/index_j.html