Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype.
J Biol Chem
; 280(31): 28498-506, 2005 Aug 05.
Article
en En
| MEDLINE
| ID: mdl-15923195
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 11 ratio of mutant/wild-type proteins (the likely in vivo ratio), all showed reduced Ca(2+) sensitivity of activation in ATPase and motility assays, and except for one alpha-tropomyosin mutant showed lower maximum Ca(2+) activation. Incorporation of either of two troponin T mutants in skinned cardiac trabeculae also decreased Ca(2+) 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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tropomiosina
/
Troponina
/
Cardiomiopatía Dilatada
/
Subfragmentos de Miosina
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2005
Tipo del documento:
Article
País de afiliación:
Reino Unido