2012 Fiscal Year Final Research Report
Molecular basis for cardiac muscle diseases caused by functional abnormalities of Z-disc
| Project/Area Number |
23659414
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
KIMURA Akinori 東京医科歯科大学, 難治疾患研究所, 教授 (60161551)
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| Project Period (FY) |
2011 – 2012
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| Keywords | 遺伝学 / 遺伝子 / ゲノム / 循環器・高血圧 |
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| 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.
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[Journal Article] Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations2012
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.
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Journal Title
Hum Mol Genet
Volume: 21(9)
Pages: 2039-2053
Peer Reviewed
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[Journal Article] Loss-of-function of hNav1.5 by ZASP1-D117N associated with intraventricular conduction disturbances in left ventricularnoncompaction2012
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
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Journal Title
Circ Arrhythm Electrophysiol
Volume: 5(5)
Pages: 1017-1026
Peer Reviewed
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[Journal Article] A novel disease gene for Brugada syndrome: sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.52012
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
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Journal Title
Circ Arrhythm Electrophysiol
Volume: 5(6)
Pages: 1098-1107
Peer Reviewed
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