title: Alpha-cardiac actin mutations produce atrial septal defects.
abstract: 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.
authors.affiliation: Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Matsson
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Eason
authors.forename: Carol S
authors.initials: CS
authors.lastname: Bookwalter
authors.forename: Joakim
authors.initials: J
authors.lastname: Klar
authors.forename: Peter
authors.initials: P
authors.lastname: Gustavsson
authors.forename: Jan
authors.initials: J
authors.lastname: Sunnegårdh
authors.forename: Henrik
authors.initials: H
authors.lastname: Enell
authors.forename: Anders
authors.initials: A
authors.lastname: Jonzon
authors.forename: Miikka
authors.initials: M
authors.lastname: Vikkula
authors.forename: Ilse
authors.initials: I
authors.lastname: Gutierrez
authors.forename: Javier
authors.initials: J
authors.lastname: Granados-Riveron
authors.forename: Mark
authors.initials: M
authors.lastname: Pope
authors.forename: Frances
authors.initials: F
authors.lastname: Bu'Lock
authors.forename: Jane
authors.initials: J
authors.lastname: Cox
authors.forename: Thelma E
authors.initials: TE
authors.lastname: Robinson
authors.forename: Feifei
authors.initials: F
authors.lastname: Song
authors.forename: David J
authors.initials: DJ
authors.lastname: Brook
authors.forename: Steven
authors.initials: S
authors.lastname: Marston
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Trybus
authors.forename: Niklas
authors.initials: N
authors.lastname: Dahl
mesh_terms: D000199:Actins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D002642:Chick Embryo; D002675:Child, Preschool; D005260:Female; D017353:Gene Deletion; D006321:Heart / Q000196:embryology; D006344:Heart Septal Defects, Atrial / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D016297:Mutagenesis, Site-Directed; D009218:Myosins / Q000378:metabolism; D010375:Pedigree
chemical_list: C526913:ACTC1 protein, human; D000199:Actins; D009218:Myosins