Alpha-cardiac actin mutations produce atrial septal defects.
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.
Matsson
Hans
H
Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala, Sweden.
Eason
Jacqueline
J
Bookwalter
Carol S
CS
Klar
Joakim
J
Gustavsson
Peter
P
Sunnegårdh
Jan
J
Enell
Henrik
H
Jonzon
Anders
A
Vikkula
Miikka
M
Gutierrez
Ilse
I
Granados-Riveron
Javier
J
Pope
Mark
M
Bu'Lock
Frances
F
Cox
Jane
J
Robinson
Thelma E
TE
Song
Feifei
F
Brook
David J
DJ
Marston
Steven
S
Trybus
Kathleen M
KM
Dahl
Niklas
N
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
C526913:ACTC1 protein, human; D000199:Actins; D009218:Myosins