title: A missense mutation in a ubiquitously expressed protein, vinculin, confers susceptibility to hypertrophic cardiomyopathy.
abstract: The R975W mutation, in the alternatively spliced exon 19 of vinculin (VCL) which yields the isoform metavinculin, was associated previously with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), and shown to alter in vivo organization of intercalated discs. We tested the hypothesis that alterations in the ubiquitously expressed, VCL-encoded protein, vinculin, may provide a pathogenic substrate for HCM. Comprehensive mutational analysis of VCL's 22 translated exons was performed in a cohort of 228 unrelated patients with genotype negative HCM, having no identifiable mutations in 12 HCM-associated myofilament/Z-disc-encoding genes. A novel missense mutation, L277M-VCL, involving a conserved residue was identified in a patient with severely obstructive, mid-ventricular hypertrophy. This mutation was not detected in 400 reference alleles. Immunohistochemical analysis of the proband's myectomy specimen demonstrated markedly reduced vinculin levels in the intercalated discs. We provide the first report of a cardiomyopathy associated mutation in vinculin. Despite its ubiquitous expression, the HCM-associated VCL mutation clinically yielded a cardiac-specific phenotype.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Vlad C
authors.initials: VC
authors.lastname: Vasile
authors.forename: Steve R
authors.initials: SR
authors.lastname: Ommen
authors.forename: William D
authors.initials: WD
authors.lastname: Edwards
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D016596:Vinculin / Q000235:genetics*
chemical_list: D016596:Vinculin