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A novel GATA4 loss-of-function mutation responsible for familial dilated cardiomyopathy.
Zhao, Lan; Xu, Jia-Hong; Xu, Wen-Jun; Yu, Hong; Wang, Qian; Zheng, Hong-Zhen; Jiang, Wei-Feng; Jiang, Jin-Fa; Yang, Yi-Qing.
Afiliação
  • Zhao L; Department of Cardiology, Yantaishan Hospital, Yantai, Shandong 264001, P.R. China.
  • Xu JH; Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
  • Xu WJ; Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
  • Yu H; Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
  • Wang Q; Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
  • Zheng HZ; Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
  • Jiang WF; Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
  • Jiang JF; Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
  • Yang YQ; Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
Int J Mol Med ; 33(3): 654-60, 2014 Mar.
Article em En | MEDLINE | ID: mdl-24366163
Dilated cardiomyopathy (DCM) is the most common form of primary myocardial disorder and is associated with substantial morbidity and mortality. Increasing evidence suggests that genetic risk factors play an important role in the pathogenesis of idiopathic DCM. However, DCM is a genetically heterogeneous disease, and the genetic defects responsible for DCM in an overwhelming majority of cases remain to be identified. In the present study, the entire coding region and the splice junction sites of the GATA4 gene, which encodes a cardiac transcription factor essential for cardiogenesis, were sequenced in 150 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped. The functional characteristics of the mutant GATA4 were delineated in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 mutation, p.V291L, was identified in a family with DCM inherited in an autosomal dominant pattern, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes, and the altered amino acid was completely conserved evolutionarily among species. Functional analysis revealed that the GATA4 mutant was associated with significantly diminished transcriptional activity. The findings expand the mutational spectrum of GATA4 linked to DCM and provide novel insight into the molecular etiology involved in DCM, suggesting the potential implications in the early prophylaxis and allele-specific treatment for this common type of cardiomyopathy.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cardiomiopatia Dilatada / Predisposição Genética para Doença / Mutação de Sentido Incorreto / Fator de Transcrição GATA4 Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Int J Mol Med Assunto da revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cardiomiopatia Dilatada / Predisposição Genética para Doença / Mutação de Sentido Incorreto / Fator de Transcrição GATA4 Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Int J Mol Med Assunto da revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Ano de publicação: 2014 Tipo de documento: Article