A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy.
Circ Arrhythm Electrophysiol
; 3(6): 646-56, 2010 Dec.
Article
em En
| MEDLINE
| ID: mdl-20852297
ABSTRACT
BACKGROUND:
Dilated cardiomyopathy (DCM) is a primary disease of the heart muscle associated with sudden cardiac death secondary to ventricular tachyarrhythmias and asystole. However, the molecular pathways linking DCM to arrhythmias and sudden cardiac death are unknown. We previously identified a S196L mutation in exon 4 of LBD3-encoded ZASP in a family with DCM and sudden cardiac death. These findings led us to hypothesize that this mutation may precipitate both cytoskeletal and conduction abnormalities in vivo. Therefore, we investigated the role of the ZASP4 mutation S196L in cardiac cytoarchitecture and ion channel biology. METHODS ANDRESULTS:
We generated and analyzed transgenic mice with cardiac-restricted expression of the S196L mutation. We also performed cellular electrophysiological analysis on isolated S196L cardiomyocytes and protein-protein interaction studies. Ten month-old S196L mice developed hemodynamic dysfunction consistent with DCM, whereas 3-month-old S196L mice presented with cardiac conduction defects and atrioventricular block. Electrophysiological analysis on isolated S196L cardiomyocytes demonstrated that the L-type Ca(2+) currents and Na(+) currents were altered. The pull-down assay demonstrated that ZASP4 complexes with both calcium (Ca(v)1.2) and sodium (Na(v)1.5) channels.CONCLUSIONS:
Our findings provide new insight into the mechanisms by which mutations of a structural/cytoskeletal protein, such as ZASP, lead to cardiac functional and electric abnormalities. This work represents a novel framework to understand the development of conduction defects and arrhythmias in subjects with cardiomyopathies, including DCM.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Citoesqueleto
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DNA
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Cardiomiopatia Dilatada
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Proteínas de Transporte
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Proteínas de Homeodomínio
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Mutação de Sentido Incorreto
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Miócitos Cardíacos
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Sistema de Condução Cardíaco
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Circ Arrhythm Electrophysiol
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Estados Unidos