TBX5 loss-of-function mutation contributes to familial dilated cardiomyopathy

• DOI: 10.1016/j.bbrc.2015.02.094
• Publication Date: 2015-02-26T02:49:00Z
• Authors: Xian-Ling Zhang; Xing-Biao Qiu; Fang Yuan; Juan Wang; Cui-Mei Zhao; Ruo-Gu Li; Lei Xu; Ying-Jia Xu; Hong-Yu Shi; Xu-Min Hou; Xin-Kai Qu; Ya-Wei Xu; Yi-Qing Yang
• Keywords: GATA4; Penetrance; Dilated Cardiomyopathy; Loss function

The cardiac T-box transcription factor TBX5 is crucial for proper cardiovascular development, and mutations in have been associated with various congenital heart diseases arrhythmias humans. However, whether mutated contributes to dilated cardiomyopathy (DCM) remains unclear. In this study, the coding exons flanking introns of gene were sequenced 190 unrelated patients idiopathic DCM. available family members index patient carrying an identified mutation 200 ethnically matched healthy individuals used as controls genotyped TBX5. functional characteristics mutant explored contrast its wild-type counterpart by using a dual-luciferase reporter assay system. As result, novel heterozygous mutation, p.S154A, was DCM inherited autosomal dominant pattern, which co-segregated complete penetrance. missense absent 400 control chromosomes altered amino acid completely conserved evolutionarily across species. Functional assays revealed that had significantly decreased transcriptional activity. Furthermore, markedly diminished synergistic activation NKX2-5 or GATA4, other two factors causatively linked This study firstly associates loss-of-function enhanced susceptibility DCM, providing insight into molecular mechanisms suggesting potential implications development new treatment strategies common form myocardial disorder.