We tested the hypothesis that perturbations in
metavinculin may provide a pathogenic substrate for
hypertrophic cardiomyopathy (HCM). HCM and
dilated cardiomyopathy (DCM) are partially allelic disorders whereby identical genes have been implicated in the pathogenesis of both diseases. Mutations in
metavinculin, a muscle-specific
isoform of
vinculin, were identified previously in DCM and shown to alter in vitro organization of actin filaments. Using denaturing high performance liquid chromatography and direct
DNA sequencing, mutational analysis of the
metavinculin-specific exon of
vinculin (VCL, exon 19) was performed in a cohort of 389 unrelated patients with clinical HCM, previously genotyped for the 8 most common HCM-associated myofilament-encoding genes. Overall, 3 non-synonymous single nucleotide polymorphisms (A934V, P943A, and R975W) were detected in 4 patients. One patient with severely obstructive, mid-ventricular and apical
hypertrophy harbored the previously published DCM-associated mutation, R975W. R975 is a highly conserved residue and R975W was absent in over 1400 reference alleles. Immunohistochemical analysis of the proband's myectomy specimen revealed a paucity of
vinculin/
metavinculin in the intercalated discs.
Metavinculin mutations are pathogenic substrates for both HCM and DCM, further highlighting the allelic nature of these
cardiomyopathies. Mutations in functionally distinct regions of certain
cardiomyopathy-associated genes may have a dominant effect in determining a remodeling pathway of either maladaptive
hypertrophy or dilation. However, this study demonstrates that the same fundamental mutation in humans can yield either cardiomyopathic phenotype, underscoring a critical role for modifier genes and/or environmental stressors in cardiac remodeling.