Molecular pathology of the familial cardiomyopathy caused by lamin A/C gene mutation
| Project/Area Number |
15590716
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Tohoku University |
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Principal Investigator |
KARIBE Akihiko Tohoku University, Graduate School of Medicine, Research Associate, 大学院・医学系研究科, 助手 (80359504)
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| Co-Investigator(Kenkyū-buntansha) |
KAGAYA Yuttaka Tohoku University, Hospital, Lecture, 病院・講師 (90250779)
WATANABE Jun Tohoku University, Graduate School of Medicine, Assistant Professor, 大学院・医学研究科, 助教授 (90210905)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2003: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Keywords | Nuclear proteins / Idiopathic cardiomyopathy / Cardiac conduction system / 刺激伝達系 |
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| Research Abstract |
We identified five new families with progressive conduction defect and dilated cardiomyopathy. In the three of five families, we detected novel mutations in lamin A/C gene (LMNA). We analyzed a family with 21 affected members for detailed clinical phenotypes. The first clinical manifestation was lo w grade AV block or atrial fibrillation, which developed in affected members aged over 30 years old. We observed that the AV block progressed to third-degree within about six years. Three affected members died suddenly and two affected members died of heart failure and/or ventricular tachycardia. The electrophysiological studies revealed an impairment of intra-AV nodal conduction. Post-mortem examinations showed conspicuous fibrofatty degeneration of the AV node. Endomyocardial biopsies showed remarkably deformed nuclei and substantial deposits in the subsarcolemma.
To reveal a molecular pathology in the familial cardiomyopathy caused by LMNA mutations, we further investigated mouse lamin A/C
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gene (lmna) function in the mouse cultured cardiomyocytes model system. Real time quantitative RT-PCR showed that the lmna has been expressed before birth and is increased after birth. Interestingly, expression of the lamin B1 gene was decreased after birth. Expression of the lamin A/C protein is increase significantly after birth as indicating the importance in post-translational regulation. We constructed that a vector which express the truncated mutated lamin A/C protein with GFP expression marker using the site-directed mutagenesis. We also prepared siRNA vectors that specifically suppress the lmna. We studied the effects of the both vectors in the primally cultured cardiomyocytes from 14 days old mice. Immunoblotting and immunohistochemistry showed that the both vectors suppressed the lamin A/C proteins in the cardiomyocytes. Most important effects of the lamin A/C protein supressionwere the decreased expression of the phosphorelated retinoblastoma proteins and the increase in the number of the apoptotic cardiomyocytes. Less
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Report
(3 results)
Research Products
(2 results)
