TBX5 mutations contribute to early-onset atrial fibrillation in Chinese and Caucasians

Atrial fibrillation (AF) is a common arrhythmia with an important heritable aspect. The genetic factors underlying AF have not been fully elucidated.

We screened six candidate genes (CAV1, KCNJ2, KCNQ1, NKX2.5, PITX2, and TBX5) for novel mutations in 139 patients of Chinese descent with early-onset AF and 576 controls. Four missense TBX5 mutations, p.R355C, p.Q376R, p.A428S, and p.S372L, were identified in evolutionarily conserved regions. We did not find any mutations in CAV1, KCNJ2, KCNQ1, NKX2.5, and PITX2. These mutations increased the expression of atrial natriuretic peptide (ANP) and connexin-40 (CX40) in the primarily cultured rat atrial myocytes but did not alter the expression of cardiac structural genes, atrial myosin heavy chain-α (MHC-α) and myosin light chain-2α (MLC-2α). Overexpression of p.R355C developed an atrial arrhythmia suggestive of paroxysmal AF in the zebrafish model. To replicate our findings, we screened TBX5 in 527 early-onset AF cases from the Massachusetts General Hospital AF study. A novel TBX5 deletion (ΔAsp118, p.D118del) was identified, while no TBX5 mutations were identified in 1176 control subjects.

Our results provide both genetic and functional evidence to support the contribution of TBX5 gene in the pathogenesis of AF. The potential mechanism of arrhythmia may be due in part to the disturbed expression of ANP and CX40.