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Cardiac alpha-myosin (MYH6) is the predominant sarcomeric disease gene for familial atrial septal defects - PubMed

Cardiac alpha-myosin (MYH6) is the predominant sarcomeric disease gene for familial atrial septal defects

Maximilian G Posch et al. PLoS One. 2011.

Abstract

Secundum-type atrial septal defects (ASDII) account for approximately 10% of all congenital heart defects (CHD) and are associated with a familial risk. Mutations in transcription factors represent a genetic source for ASDII. Yet, little is known about the role of mutations in sarcomeric genes in ASDII etiology. To assess the role of sarcomeric genes in patients with inherited ASDII, we analyzed 13 sarcomeric genes (MYH7, MYBPC3, TNNT2, TCAP, TNNI3, MYH6, TPM1, MYL2, CSRP3, ACTC1, MYL3, TNNC1, and TTN kinase region) in 31 patients with familial ASDII using array-based resequencing. Genotyping of family relatives and control subjects as well as structural and homology analyses were used to evaluate the pathogenic impact of novel non-synonymous gene variants. Three novel missense mutations were found in the MYH6 gene encoding alpha-myosin heavy chain (R17H, C539R, and K543R). These mutations co-segregated with CHD in the families and were absent in 370 control alleles. Interestingly, all three MYH6 mutations are located in a highly conserved region of the alpha-myosin motor domain, which is involved in myosin-actin interaction. In addition, the cardiomyopathy related MYH6-A1004S and the MYBPC3-A833T mutations were also found in one and two unrelated subjects with ASDII, respectively. No mutations were found in the 11 other sarcomeric genes analyzed. The study indicates that sarcomeric gene mutations may represent a so far underestimated genetic source for familial recurrence of ASDII. In particular, perturbations in the MYH6 head domain seem to play a major role in the genetic origin of familial ASDII.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Family pedigrees of MYH6 mutation carriers.

Squares represent male and circles female subjects. The proband is marked by an arrow. Plus signs and minus signs depict mutation-positive and mutation-negative individuals, respectively. Crossed symbols represent deceased individuals.

Figure 2
Figure 2. Localization of all so far detected MYH6 mutations.

Centrally shown are the three main domains of alpha-myosin heavy chain (head, neck, and rod). Identified mutations in patients with cardiomyopathy are shown above the protein while mutations in patients with congenital heart disease (CHD) are shown below. Mutations found in this study are underlined. The interaction sites for alpha-actin, adenosine triphosphate (ATP), and regulatory myosin light chain (RLC) as well as the known coiled coil structure are indicated. The human cardiac phenotypes to each mutation are given in the table below. FDCM: familial DCM; IDCM: idiopathic DCM; TA: tricuspid atresia; TGA: transposition of the great arteries; PFO: patent foramen ovale; SAR: subaortic rim; AS: Aortic stenosis.

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