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Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype

Mirza, M; Marston, S; Willott, R; Ashley, C; Mogensen, J; McKenna, W; Robinson, P; ... Watkins, H; + view all (2005) Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype. J BIOL CHEM , 280 (31) 28498 - 28506. 10.1074/jbc.M412281200.

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Abstract

Dilated cardiomyopathy ( DCM), characterized by cardiac dilatation and contractile dysfunction, is a major cause of heart failure. Inherited DCM can result from mutations in the genes encoding cardiac troponin T, troponin C, and alpha-tropomyosin; different mutations in the same genes cause hypertrophic cardiomyopathy. To understand how certain mutations lead specifically to DCM, we have investigated their effect on contractile function by comparing wild-type and mutant recombinant proteins. Because initial studies on two troponin T mutations have generated conflicting findings, we analyzed all eight published DCM mutations in troponin T, troponin C, and alpha-tropomyosin in a range of in vitro assays. Thin filaments, reconstituted with a 1: 1 ratio of mutant/wild-type proteins ( the likely in vivo ratio), all showed reduced Ca2+ sensitivity of activation in ATPase and motility assays, and except for one alpha-tropomyosin mutant showed lower maximum Ca2+ activation. Incorporation of either of two troponin T mutants in skinned cardiac trabeculae also decreased Ca2+ sensitivity of force generation. Structure/function considerations imply that the diverse thin filament DCM mutations affect different aspects of regulatory function yet change contractility in a consistent manner. The DCM mutations depress myofibrillar function, an effect fundamentally opposite to that of hypertrophic cardiomyopathy-causing thin filament mutations, suggesting that decreased contractility may trigger pathways that ultimately lead to the clinical phenotype.

Type: Article
Title: Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype
DOI: 10.1074/jbc.M412281200
Keywords: CARDIAC TROPONIN-T, VITRO MOTILITY ASSAY, FAMILIAL HYPERTROPHIC CARDIOMYOPATHY, ALPHA-TROPOMYOSIN, HEART-FAILURE, CA2+ SENSITIVITY, ACTIN-FILAMENTS, BINDING-SITE, MUTANT, DISEASE
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
URI: http://discovery.ucl.ac.uk/id/eprint/41101
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