TY - JOUR
T1 - Identification of a metavinculin missense mutation, R975W, associated with both hypertrophic and dilated cardiomyopathy
AU - Vasile, Vlad C.
AU - Will, Melissa L.
AU - Ommen, Steve R.
AU - Edwards, William D.
AU - Olson, Timothy M.
AU - Ackerman, Michael J.
N1 - Funding Information:
Funding: This study was supported by a Mayo Foundation Clinician Research award to M.J.A. M.J.A. is an established investigator of the American Heart Association.
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. Correspondence should be addressed to M.J.A ( ackerman.michael@mayo.edu ). We take this opportunity to express our gratitude to Ms. Linda M. Murphy, from the Mayo Foundation Tissue and Cell Molecular Analysis Laboratory, for her help and expertise in immunohistochemistry.
PY - 2006/2
Y1 - 2006/2
N2 - 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.
AB - 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.
KW - Genetics
KW - Hypertrophic cardiomyopathy
KW - Metavinculin
KW - Molecular biology
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U2 - 10.1016/j.ymgme.2005.08.006
DO - 10.1016/j.ymgme.2005.08.006
M3 - Article
C2 - 16236538
AN - SCOPUS:32044458438
SN - 1096-7192
VL - 87
SP - 169
EP - 174
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 2
ER -