α-Cardiac myosin heavy chain (MYH6) mutations affecting myofibril formation are associated with congenital heart defects

Abstract

Congenital heart defects (CHD) are collectively the most common form of congenital malformation. Studies of human cases and animal models have revealed that mutations in several genes are responsible for both familial and sporadic forms of CHD. We have previously shown that a mutation in MYH6 can cause an autosomal dominant form of atrial septal defect (ASD), whereas others have identified mutations of the same gene in patients with hypertrophic and dilated cardiomyopathy. In the present study, we report a mutation analysis of MYH6 in patients with a wide spectrum of sporadic CHD. The mutation analysis of MYH6 was performed in DNA samples from 470 cases of isolated CHD using denaturing high-performance liquid chromatography and sequence analysis to detect point mutations and small deletions or insertions, and multiplex amplifiable probe hybridization to detect partial or complete copy number variations. One non-sense mutation, one splicing site mutation and seven non-synonymous coding mutations were identified. Transfection of plasmids encoding mutant and non-mutant green fluorescent protein-MYH6 fusion proteins in mouse myoblasts revealed that the mutations A230P and A1366D significantly disrupt myofibril formation, whereas the H252Q mutation significantly enhances myofibril assembly in comparison with the non-mutant protein. Our data indicate that functional variants of MYH6 are associated with cardiac malformations in addition to ASD and provide a novel potential mechanism. Such phenotypic heterogeneity has been observed in other genes mutated in CHD.

Malformations of the Left Ventricle

“…Mutations in genes encoding sarcomere proteins have been identified in a significant proportion of LVNC patients, 1,2 as well as in association with congenital heart defects (CHDs). [3][4][5] The presence of sarcomere mutations suggest an underlying cohesiveness of cardiomyopathy and structural CHDs, supporting the essential role for normal sarcomere function during cardiac development. In this issue of Circulation Cardiovascular Genetics, 2 papers 6,7 report on the results of whole exome sequencing and whole genome sequencing (WGS) in patients with LVNC and HLH, respectively.…”

“…[3][4][5] Dominant heterozygous MYH6 mutations with variable penetrance were described in atrial septal defect and other CHD. In addition, other rare heterozygous MYH6 variants were identified in dilated and hypertrophic cardiomyopathy.…”

“…23 MYH6 mutations found in patients with CHD have been shown to disrupt myofibril formation in vitro. 4 In the chick animal model of HLH, it was demonstrated that ligation of the left atrium, which decreased blood prograde flow to the LV, caused LV hypoplasia. 24 They also showed that…”

Genetik der angeborenen Herzfehler

“…Als wichtigste Vertreter dieser Gruppe sind hier MYH6, MYH7, MYH11 (kardiale Muskelbestandteile) und ACTC1 (kardiales Aktin) zu nennen, die insbesondere bei der EbsteinAnomalie [20], ASD [21] oder anderen Herzfehlbildungen [22] gefunden werden können. Vor allem die kardialen Strukturproteine zeigen eine große Überlappung mit den Kardiomyopathien.…”

The Impact of Mechanical Forces in Heart Morphogenesis

“…We 21,[23][24][25] and others 22,26 have shown that in humans, mutations of genes encoding contractile proteins expressed in the developing heart and great vessels can cause a wide spectrum of CHD (Table). Mutations of the ␣-cardiac actin (ACTC1) 21 and ␣-cardiac myosin heavy chain (MYH6) [23][24][25] genes have been found in families with autosomal dominant forms of atrial septal defect and in sporadic cases of other cardiac malformation.…”