TY - JOUR
T1 - A missense mutation in a ubiquitously expressed protein, vinculin, confers susceptibility to hypertrophic cardiomyopathy
AU - Vasile, Vlad C.
AU - Ommen, Steve R.
AU - Edwards, William D.
AU - Ackerman, Michael J.
N1 - Funding Information:
M.J.A.’s research program is supported by the Mayo Clinic College of Medicine, the Doris Duke Charitable Foundation, the American Heart Association, and the National Institutes of Health. We thank Ms. Linda M. Murphy, from the Mayo Foundation Tissue and Cell Molecular Analysis Laboratory, for her help and expertise in immunohistochemistry.
PY - 2006/7/7
Y1 - 2006/7/7
N2 - 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.
AB - 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.
KW - Cell biology
KW - Genetics
KW - Hypertrophic cardiomyopathy
KW - Molecular biology
KW - Vinculin
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U2 - 10.1016/j.bbrc.2006.04.151
DO - 10.1016/j.bbrc.2006.04.151
M3 - Article
C2 - 16712796
AN - SCOPUS:33646850881
SN - 0006-291X
VL - 345
SP - 998
EP - 1003
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -