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Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia and is associated with substantially increased morbidity and mortality rates. Aggregating evidence demonstrates that genetic defects are involved in the pathogenesis of AF and a number of AF-associated genes have been identified. Nevertheless, AF is a genetically heterogeneous disorder and the genetic components underpinning AF in an overwhelming majority of patients remain unclear. In this study, the entire coding exons and splice junction sites of the NK2 homeobox 6 (NKX2-6) gene, which encodes a homeodomain transcription factor important for cardiovascular development, were sequenced in 150 unrelated patients with lone AF, and a novel heterozygous NKX2-6 mutation, p.Q175H, was identified in an index patient. Genetic analysis of the available family members of the mutation carrier revealed that the mutation co-segregated with AF transmitted in an autosomal dominant pattern. The missense mutation was absent in the 200 unrelated ethnically matched healthy individuals used as controls and the altered amino acid was completely conserved evolutionarily among species. Due to unknown transcriptional targets of NKX2-6, the functional characteristics of the mutation as regards transcriptional activity were analyzed using NKX2-5 as a surrogate. Alignment between human NKX2-6 and NKX2-5 proteins displayed that the Q175H-mutant NKX2-6 was equivalent to the Q181H-mutant NKX2-5, and the introduction of Q181H into NKX2-5 significantly decreased its transcriptional activity at the atrial natriuretic factor promoter. The present study firstly associates genetically defective NKX2-6 with enhanced susceptibility to AF, providing novel insight into the molecular mechanisms underlying AF and suggesting potential strategies for the antenatal prophylaxis and personalized treatment of AF.

NKX2-6 mutation predisposes to familial atrial fibrillation