Alpha-cardiac actin mutations produce atrial septal defects

Atrial septal defect (ASD) is one of the most frequent congenital heart defects (CHD) with a variable phenotypic effect depending on the size of the septal shunt. We identified two pedigrees comprising 20 members segregating isolated autosomal dominant secundum ASD. By genetic mapping we identified the gene encoding alpha cardiac actin (ACTC1), which is essential for cardiac contraction, as the likely candidate. A mutation screen of the coding regions of ACTC1 revealed a founder mutation predicting a M123V substitution in affected individuals of both pedigrees. Functional analysis of ACTC1 with a M123V substitution shows a reduced affinity for myosin but with retained actomyosin motor properties. We also screened 408 sporadic patients with congenital heart defects and identified a case with ASD and a 17-bp deletion in ACTC1 predicting a non-functional protein. Morpholino knockdown of ACTC1 in chick embryos produces delayed looping and reduced atrial septa supporting a developmental role for this protein. The combined results indicate for the first time that ACTC1 mutations or reduced ACTC1 levels may lead to ASD without signs of cardiomyopathy.