A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation.

摘要: Abstract Atrial fibrillation (AF) represents the most common form of sustained cardiac arrhythmia and accounts for substantial morbidity mortality. Increasing evidence demonstrates that abnormal cardiovascular development is involved in pathogenesis AF. In this study, coding exons splice sites NKX2.5 gene, which encodes a homeodomain-containing transcription factor pivotal normal morphogenesis, were sequenced 110 unrelated index patients with familial The available relatives mutation carrier 200 ethnically-matched healthy individuals serving as controls subsequently genotyped. disease-causing potential identified variation was predicted by MutationTaster. functional characteristics mutant protein analyzed using dual-luciferase reporter assay system. As result, novel heterozygous mutation, p.F145S, family AF transmitted an autosomal dominant trait, co-segregated complete penetrance. detected substitution, altered amino acid completely conserved evolutionarily across species, absent 400 control chromosomes automatically to be causative. Functional analysis demonstrated associated significantly decreased transcriptional activity compared its wild-type counterpart. To best our knowledge, first report on association loss-of-function increased susceptibility findings present study provide insights into molecular mechanism underlying AF, suggesting implications early prophylaxis allele-specific therapy