Abstract 11437: A Cardiac a-Myosin Heavy Chain (MYH6) Mutation Impairing Sarcomere Structure Responsible for Familial Sick Sinus Syndrome
Background: Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or underlying structural heart diseases, but it may occur in a familial form. Mutations responsible for familial SSS have been demonstrated in several genes including SCN5A and HCN4, and a recent genome-wide association study has shown a rare variation (R721W) in the α-myosin heavy chain (α-MHC) gene (MYH6) increasing susceptibility to SSS. Because MYH6 is primarily expressed in adult atrium, it is a possible candidate for familial SSS.
Methods: We genetically screened MYH6 in genotype-negative SSS families (n=9) using PCR direct sequencing strategy. Since the mutations in MYH6 are linked to cardiomyopathy and a variety of congenital heart diseases (CHD) and known to impair the myofibril formation, we assessed the morphological changes of sarcomere attributable to MYH6 mutations.
Results: A novel in-frame 3bp deletion mutation E933del (c.2797_2799delGAG) was identified in the exon 22 of MYH6 in a 62 year-old female who had a pacemaker implanted with a diagnosis of SSS. Her deceased mother also had a pacemaker implanted due to SSS. E933del was not identified in 400 healthy Japanese control subjects as well as in 1000 Genomes database or dbSNP. The proband did not carry the variation MYH6-R721W. Echocardiography showed mild dilatation of left ventricle and right atrium, but there was no sign of cardiomyopathy, CHD, or cardiac dysfunction. Immunofluorescent imaging of neonatal rat cardiomyocytes transfected with MYH6-E933del showed brightly fluorescent speckles of α-MHC and lack of organized repeating units characteristics of myofibrils, demonstrating markedly impaired sacromeric structural integrity. The residue E933 of MYH6 is located in a highly conserved region across different species for both α- and β-MHC isoforms. A homologous mutation in the β-MHC gene (MYH7-E931del), corresponding to MYH6-E933del, was previously demonstrated in hypertrophic cardiomyopathy, suggesting that the MYH6-E933del may disrupt the sarcomeric architecture primarily at the atrium.
Conclusion: MYH6 is a novel candidate gene for familial SSS. The MYH6 mutation E933del may directly or indirectly disrupt sarcomere structure of atrial tissues sounding sinus node, leading to manifest SSS.
- © 2013 by American Heart Association, Inc.