A Novel Mutation in the α-Myosin Heavy Chain Gene Is Associated with Sick Sinus Syndrome

BACKGROUND: -Recent genome-wide association studies have demonstrated an association between MYH6, the gene encoding α-myosin heavy chain (α-MHC), and sinus node function in the general population. Moreover, a rare MYH6 variant, R721W, predisposing susceptibility to sick sinus syndrome (SSS) has been identified. However, the existence of disease-causing MYH6 mutations for familial SSS and their underlying mechanisms remain unknown. METHODS AND RESULTS: -We screened nine genotype-negative probands with SSS families for mutations in MYH6, and identified an in-frame 3-bp deletion predicted to delete one residue (delE933) at the highly conserved coiled-coil structure within the binding motif to myosin-binding protein C (MyBP-C) in one patient. Co-immunoprecipitation analysis revealed enhanced binding of delE933 α-MHC to MyBP-C. Irregular fluorescent speckles retained in the cytoplasm with substantially disrupted sarcomere striation were observed in neonatal rat cardiomyocytes transfected with α-MHC mutants carrying delE933 or R721W. In addition to the sarcomere impairments, delE933 α-MHC exhibited electrophysiological abnormalities both in vitro and in vivo. The atrial cardiomyocyte cell line HL-1 stably expressing delE933 α-MHC showed a significantly slower conduction velocity on multi-electrode array than those of wild-type α-MHC or control plasmid transfected cells. Furthermore, targeted morpholino knock-down of MYH6 in zebrafish significantly reduced the heart rate, which was rescued by co-expressed wild-type human α-MHC but not by delE933 α-MHC. CONCLUSIONS: -The novel MYH6 mutation delE933 causes both structural damage of the sarcomere and functional impairments on atrial action propagation. This report reinforces the relevance of MYH6 for sinus node function and identifies a novel pathophysiology underlying familial SSS.