title: Alpha-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.
authors.affiliation: Institute of Genetics, School of Biology, Queen’s Medical Centre, University of Nottingham, Nottingham, UK.
authors.forename: Javier T
authors.initials: JT
authors.lastname: Granados-Riveron
authors.forename: Tushar K
authors.initials: TK
authors.lastname: Ghosh
authors.forename: Mark
authors.initials: M
authors.lastname: Pope
authors.forename: Frances
authors.initials: F
authors.lastname: Bu'Lock
authors.forename: Christopher
authors.initials: C
authors.lastname: Thornborough
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Eason
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Kirk
authors.forename: Diane
authors.initials: D
authors.lastname: Fatkin
authors.forename: Michael P
authors.initials: MP
authors.lastname: Feneley
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harvey
authors.forename: John A L
authors.initials: JA
authors.lastname: Armour
authors.forename: J
authors.initials: J
authors.lastname: David Brook
mesh_terms: D000818:Animals; D024722:Cardiac Myosins / Q000235:genetics* / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D056726:Genetic Association Studies; D006330:Heart Defects, Congenital / Q000235:genetics*; D006344:Heart Septal Defects, Atrial / Q000235:genetics*; D006801:Humans; D051379:Mice; D009154:Mutation; D032446:Myoblasts / Q000166:cytology; D009210:Myofibrils / Q000235:genetics / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids; D014162:Transfection
chemical_list: C094239:MYH6 protein, human; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains