Cardiomyopathy, Dilated, 1w

A number sign (#) is used with this entry because this form of dilated cardiomyopathy is caused by mutation in the gene encoding metavinculin (VCL; 193065).

For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200).

Olson et al. (2002) used SSCP to analyze the VCL gene, which maps to chromosome 10q, in 350 unrelated patients with sporadic or familial dilated cardiomyopathy who were negative for mutations in the ACTC (102540) and TPM1 (191010) genes, and identified heterozygosity for a 3-bp in-frame deletion (L954del; 193065.0001) and a missense mutation (R975W; 193065.0002) in 2 patients, respectively. Neither mutation was found in 500 controls. A potential risk-conferring polymorphism, A934V, was identified in heterozygosity in a 30-year-old man with dilated cardiomyopathy who died 2 years after diagnosis of progressive heart failure; this variant was also found in 1 of 500 controls, a 67-year-old woman in whom electrocardiography showed abnormal T waves but echocardiogram was nondiagnostic for dilated cardiomyopathy. All 3 variants were located in exon 19, the metavinculin-specific exon of the VCL gene. Low-shear viscometry studies revealed variable reductions in viscosity associated with the variants, with greater reductions caused by the L954del and R975W mutants. Fluorescence microscopy confirmed the viscosity findings, with actin organization by the A934V variant similar to wildtype, although the network appeared coarser; more prominent bundles were observed for L954del, and R975W showed the highest bundling activity. Electron microscopy of cardiac myocytes from a patient with the R975W mutation showed irregular and fragmented intercalated discs, with intact sarcomeric thin and thick filaments.