A Novel Alpha Cardiac Actin (ACTC1) Mutation Mapping to a Domain in Close Contact with Myosin Heavy Chain Leads to a Variety of Congenital Heart Defects, Arrhythmia and Possibly Midline Defects

Abstract

Background: A Lebanese Maronite family presented with 13 relatives affected by various congenital heart defects (mainly atrial septal defects), conduction tissue anomalies and midline defects. No mutations were found in GATA4 and NKX2-5.

Methods and results: A set of 399 poly(AC) markers was used to perform a linkage analysis which peaked at a 2.98 lod score on the long arm of chromosome 15. The haplotype analysis delineated a 7.7 meganucleotides genomic interval which included the alpha-cardiac actin gene (ACTC1) among 36 other protein coding genes. A heterozygous missense mutation was found (c.251T>C, p.(Met84Thr)) in the ACTC1 gene which changed a methionine residue conserved up to yeast. This mutation was absent from 1000 genomes and exome variant server database but segregated perfectly in this family with the affection status. This mutation and 2 other ACTC1 mutations (p.(Glu101Lys) and p.(Met125Val)) which result also in congenital heart defects are located in a region in close apposition to a myosin heavy chain head region by contrast to 3 other alpha-cardiac actin mutations (p.(Ala297Ser),p.(Asp313His) and p.(Arg314His)) which result in diverse cardiomyopathies and are located in a totally different interaction surface.

Conclusions: Alpha-cardiac actin mutations lead to congenital heart defects, cardiomyopathies and eventually midline defects. The consequence of an ACTC1 mutation may in part be dependent on the interaction surface between actin and myosin.

Fig 1. Pedigree of the family with recurrent cardiopathies.

Squares (males) and circle (females), crossed symbols (deceased), empty symbols (unaffected) and filled symbols (affected), arrow (proband). AF: atrial fibrillation; AR: aortic regurgitation; AS: aortic stenosis; ASD-OS: atrial septal defect ostium secundum type; LAH: left anterior hemiblock; LV: left ventricle; PAH: pulmonary artery hypertension; PS: pulmonary stenosis; RBBB: right bundle branch block; SB: sinus bradycardia; VSD: ventricular septal defect; WPW: Wolff Parkinson White.

Fig 2. Molecular representation of the PDB 4A7L complex, displaying an actin fiber (blue and green monomers, with ADP molecules in purple) with myosin heads (brown monomers).

Actin and myosin amino acid numbers are according to human numbering (A) Backbone representation of an actin fiber in complex with 3 myosin heads, showing secondary structure elements. The backbone atoms of the 3 amino acids altered by mutations causing atrial septal defects (residues 84, 101, and 125) are shown by red spheres on every actin monomer. (B) Close up on the interaction between the region spanning residues 84, 101 and 125 of an F-actin monomer and a very close loop of the myosin head. The actin monomer is shown in green, the myosin head is shown in brown. The interatomic distances measured in the complex between residues 84, 101 and 125 and the myosin surface typically range from 3 to 10 Å. The 562–571 region of the myosin head makes numerous contacts with the surface of the actin filament, and interacts closely with residues 84, 101 and 125 on the surface of actin. (C) Close up showing one myosin head interacting with the region 84, 101, and 125 region of the actin monomer, and the 297, 313 and 314 region of an adjacent actin monomer. The 562–571 region of the myosin head closely interacts with residues whose mutation leads to atrial septal defects (84, 101, and 125, in red), whereas the 367–365 region (human numbering) of the same myosin head interacts directly with an adjacent actin monomer (residues 297, 313, 314, in green), whose mutation leads to cardiomyopathies. The orientation of the actin monomers in panel A and B is similar whereas the molecules in panel C have been rotated for a better view of the interaction with residues 297, 313, and 314.