PITX2 Loss-of-Function Mutation Contributes to Congenital Endocardial Cushion Defect and Axenfeld-Rieger Syndrome

摘要: Congenital heart disease (CHD), the most common type of birth defect, is still leading non-infectious cause infant morbidity and mortality in humans. Aggregating evidence demonstrates that genetic defects are involved pathogenesis CHD. However, CHD genetically heterogeneous components underpinning an overwhelming majority patients remain unclear. In present study, coding exons flanking introns PITX2 gene, which encodes a paired-like homeodomain transcription factor 2essential for cardiovascular morphogenesis as well maxillary facial development, was sequenced 196 unrelated with subsequently mutation carrier's family members available. As result, novel heterozygous mutation, p.Q102X PITX2a, or p.Q148X PITX2b, p.Q155X PITX2c, identified endocardial cushion defect (ECD) Axenfeld-Rieger syndrome (ARS). Genetic analysis pedigree showed nonsense co-segregated ECD ARS transmitted autosomal dominant pattern complete penetrance. The absent 800 control chromosomes from ethnically matched population. Functional by using dual-luciferase reporter assay system revealed mutant had no transcriptional activity eliminated synergistic activation between NKX2.5, another pivotal cardiogenesis. To our knowledge, this first report on association loss-of-function increased susceptibility to ARS. findings provide insight into molecular mechanisms ARS, suggesting potential implications antenatal prophylaxis personalized treatment