title: Novel mutation in the α-myosin heavy chain gene is associated with sick sinus syndrome.
abstract: 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 has been identified. However, the existence of disease-causing MYH6 mutations for familial sick sinus syndrome and their underlying mechanisms remain unknown.
  
  
  RESULTS
  We screened 9 genotype-negative probands with sick sinus syndrome 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 in one patient. Co-immunoprecipitation analysis revealed enhanced binding of delE933 α-MHC to myosin-binding protein 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 multielectrode array than those of wild-type α-MHC or control plasmid transfected cells. Furthermore, targeted morpholino knockdown of MYH6 in zebrafish significantly reduced the heart rate, which was rescued by coexpressed 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 sick sinus syndrome.
authors.affiliation: From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama (A.N., S.K.); and Department of Veterinary Medicine, Kagoshima University, Kagoshima, Japan (T.A.).
authors.forename: Taisuke
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama (A.N., S.K.); and Department of Veterinary Medicine, Kagoshima University, Kagoshima, Japan (T.A.).
authors.forename: Chuanchau J
authors.initials: CJ
authors.lastname: Jou
authors.affiliation: From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama (A.N., S.K.); and Department of Veterinary Medicine, Kagoshima University, Kagoshima, Japan (T.A.).
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nogami
authors.affiliation: From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama (A.N., S.K.); and Department of Veterinary Medicine, Kagoshima University, Kagoshima, Japan (T.A.).
authors.forename: Shinya
authors.initials: S
authors.lastname: Kowase
authors.affiliation: From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama (A.N., S.K.); and Department of Veterinary Medicine, Kagoshima University, Kagoshima, Japan (T.A.).
authors.forename: Cammon B
authors.initials: CB
authors.lastname: Arrington
authors.affiliation: From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama (A.N., S.K.); and Department of Veterinary Medicine, Kagoshima University, Kagoshima, Japan (T.A.).
authors.forename: Spencer M
authors.initials: SM
authors.lastname: Barnett
authors.affiliation: From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama (A.N., S.K.); and Department of Veterinary Medicine, Kagoshima University, Kagoshima, Japan (T.A.).
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Harrell
authors.affiliation: From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama (A.N., S.K.); and Department of Veterinary Medicine, Kagoshima University, Kagoshima, Japan (T.A.).
authors.forename: Takuro
authors.initials: T
authors.lastname: Arimura
authors.affiliation: From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama (A.N., S.K.); and Department of Veterinary Medicine, Kagoshima University, Kagoshima, Japan (T.A.).
authors.forename: Yukiomi
authors.initials: Y
authors.lastname: Tsuji
authors.affiliation: From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama (A.N., S.K.); and Department of Veterinary Medicine, Kagoshima University, Kagoshima, Japan (T.A.). makitan@nagasaki-u.ac.jp akitis@mri.tmd.ac.jp.
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.affiliation: From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama (A.N., S.K.); and Department of Veterinary Medicine, Kagoshima University, Kagoshima, Japan (T.A.). makitan@nagasaki-u.ac.jp akitis@mri.tmd.ac.jp.
authors.forename: Naomasa
authors.initials: N
authors.lastname: Makita
mesh_terms: D000200:Action Potentials; D000818:Animals; D000831:Animals, Newborn; D024722:Cardiac Myosins / Q000235:genetics* / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D004252:DNA Mutational Analysis; D015716:Electrocardiography, Ambulatory; D005260:Female; D055785:Gene Knockdown Techniques; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D008875:Middle Aged; D060172:Morpholinos / Q000378:metabolism; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D012518:Sarcomeres / Q000378:metabolism / Q000473:pathology; D012804:Sick Sinus Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D014162:Transfection; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C094239:MYH6 protein, human; D060172:Morpholinos; D029961:Zebrafish Proteins; C481025:myh6 protein, zebrafish; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains
keywords: MYH6; genetics; myosin heavy chain; sick sinus syndrome; sinus node dysfunction