Human Molecular Genetics Advance Access originally published online on October 18, 2007
Human Molecular Genetics 2008 17(2):256-265; doi:10.1093/hmg/ddm302
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Alpha-cardiac actin mutations produce atrial septal defects
1 Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala, Sweden 2 Institute of Genetics, University of Nottingham, Queen’s Medical Centre, NG7 2UH Nottingham, UK 3 Department of Molecular Physiology and Biophysics, University of Vermont, VT 05405 Burlington, USA 4 The Queen Silvia Children’s Hospital, S-416 85 Göteborg, Sweden 5 Department of Pedriatics, County Hospital of Halmstad, S-301 85 Halmstad, Sweden 6 Children’s Hospital, Uppsala University, S-75185 Uppsala, Sweden 7 Human Molecular Genetics (GEHU), Christian de Duve Institute, Université catholique de Louvain, B-1200 Brussels, Belgium 8 Department of Pediatric Cardiology, Glenfield Hospital, LE3 9QP Leicester, UK 9 National Heart and Lung Institute, Imperial College, SW3 6LY London, UK
* To whom correspondence should be addressed at: Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden. Tel: +46 18 611 2799; Fax: +46 18 554025; Email: niklas.dahl{at}genpat.uu.se
Received August 28, 2007; Accepted October 10, 2007
Atrial septal defect (ASD) is one of the most frequent congenital heart defects (CHDs) 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 an M123V substitution in affected individuals of both pedigrees. Functional analysis of ACTC1 with an M123V substitution shows a reduced affinity for myosin, but with retained actomyosin motor properties. We also screened 408 sporadic patients with CHDs and identified a case with ASD and a 17-bp deletion in ACTC1 predicting a non-functional protein. Morpholino (MO) 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.