Diastolic dysfunction caused by titin mutation
| Project/Area Number |
24390201
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Partial Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Keio University |
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Principal Investigator |
Makino Shinji 慶應義塾大学, 医学部, 准教授 (20306707)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAGISHI TAKAYUKI 慶應義塾大学, 医学部, 准教授 (40255500)
ARIMURA TAKURO 東京医科歯科大学, 難治疾患研究所, 助教 (50342887)
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| Project Period (FY) |
2012-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2014: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2013: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2012: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
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| Keywords | 家族性心筋症 / 拡張不全 / メダカ変異体 / タイチン / 小型魚類変異体 / メダカ |
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| Outline of Final Research Achievements |
Hypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by cardiac hypertrophy with diastolic dysfunction. We generated a cardiovascular-mutant medaka fish non-spring heart (nsh), which showed diastolic dysfunction and hypertrophic myocardium. The nsh had expressed pathologically stiffer titin isoforms. The nsh heterozygotes showed M-line disassembly. Positional cloning revealed a missense mutation in an immunoglobulin domain located in the M-line-A-band transition zone of titin. Screening of mutations in 96 unrelated patients with familial HCM, who had no previously implicated mutations in known sarcomeric gene candidates, identified two mutations in Ig domains close to the M-line region of titin. The mutations found in both medaka fish and in familial HCM increased binding of titin to MURF1 and enhanced titin degradation by ubiquitination. These findings implicate an impaired interaction between titin and MURF1 as a novel mechanism underlying the pathogenesis of HCM.
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Report
(5 results)
Research Products
(38 results)
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[Journal Article] ET-1 induces myofibrillar disarray and contractile vector in hypertrophic cardiomyopathy-iPS cell-derived cardiomyocytes2014
Author(s)
Tanaka A, Yuasa S, Mearini G, Egashira T, Seki T, Kodaira M, Kusumoto D, Kuroda Y, Okata S, Suzuki T, Arimura T, Makino S, Kimura K, Kimura A, Furukawa T, Carrier L, Nobe K, Fukuda K
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Journal Title
J Am Heart Assoc
Volume: 3
Issue: 6
Pages: 1-25
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Wnt2 accelerates cardiac myocyte differentiation from ES-cell derived mesodermal cells via non-canonical pathway.2012
Author(s)
Onizuka T, Yuasa S, Kusumoto D, Shimoji K, Egashira T, Ohno Y, Kageyama T, Tanaka T, Hattori F, Fujita J, Ieda M, Kimura K, Makino S, Sano M, Kudo A, Fukuda K
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Journal Title
J Mol Cell Cardiol.
Volume: 52
Pages: 650-659
Related Report
Peer Reviewed
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[Journal Article] Genetic analysis of essential cardiac transcription factors in 256 patients with non-syndromic congenital heart defects.2012
Author(s)
Kodo K, Nishizawa T, Furutani M, Arai S, Ishihara K, Oda M, Makino S, Fukuda K, Takahashi T, Matsuoka R, Nakanishi T, Yamagishi H.
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Journal Title
Circ J.
Volume: 76
Pages: 1703-1711
NAID
Related Report
Peer Reviewed
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[Journal Article] miR-142-3p is essential for hematopoiesis and affects cardiac cell fate in zebrafish.2012
Author(s)
Nishiyama T, Kaneda R, Ono T, Tohyama S, Hashimoto H, Endo J, Tsuruta H, Yuasa S, Ieda M, Makino S, Fukuda K
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Journal Title
Biochem Biophys Res Commun.
Volume: 425
Pages: 755-761
Related Report
Peer Reviewed
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