Portal de Periódicos da CAPES

ANKRD1, the Gene Encoding Cardiac Ankyrin Repeat Protein, Is a Novel Dilated Cardiomyopathy Gene

2009; Elsevier BV; Volume: 54; Issue: 4 Linguagem: Inglês

10.1016/j.jacc.2009.02.076

1558-3597

Mousumi Moulik, Matteo Vatta, Stephanie H. Witt, Anita Arola, Ross T. Murphy, William J. McKenna, Aladin M. Boriek, Kazuhiro Oka, Siegfried Labeit, Neil E. Bowles, Takuro Arimura, Akinori Kimura, Jeffrey A. Towbin,

Cardiovascular Effects of Exercise

We evaluated ankyrin repeat domain 1 (ANKRD1), the gene encoding cardiac ankyrin repeat protein (CARP), as a novel candidate gene for dilated cardiomyopathy (DCM) through mutation analysis of a cohort of familial or idiopathic DCM patients, based on the hypothesis that inherited dysfunction of mechanical stretch-based signaling is present in a subset of DCM patients. CARP, a transcription coinhibitor, is a member of the titin-N2A mechanosensory complex and translocates to the nucleus in response to stretch. It is up-regulated in cardiac failure and hypertrophy and represses expression of sarcomeric proteins. Its overexpression results in contractile dysfunction. In all, 208 DCM patients were screened for mutations/variants in the coding region of ANKRD1using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct deoxyribonucleic acid sequencing. In vitro functional analyses of the mutation were performed using yeast 2-hybrid assays and investigating the effect on stretch-mediated gene expression in myoblastoid cell lines using quantitative real-time reverse transcription–polymerase chain reaction. Three missense heterozygous ANKRD1mutations (P105S, V107L, and M184I) were identified in 4 DCM patients. The M184I mutation results in loss of CARP binding with Talin 1 and FHL2, and the P105S mutation in loss of Talin 1 binding. Intracellular localization of mutant CARP proteins is not altered. The mutations result in differential stretch-induced gene expression compared with wild-type CARP. ANKRD1is a novel DCM gene, with mutations present in 1.9% of DCM patients. The ANKRD1mutations may cause DCM as a result of disruption of the normal cardiac stretch-based signaling.