Dilated cardiomyopathy associated with deficiency of the cytoskeletal protein metavinculin

Background: The cytoskeleton plays an important role in maintaining cell structure and integrity. Defects in cytoskeletal proteins can cripple cell strength and may cause cardiomyopathy. We analyzed heart tissues from subjects with dilated cardiomyopathy for abnormalities in the cardiac cytoskeleton. Metavinculin, a cardiac isoform of the cytoskeletal protein vinculin, connects actin microfilaments to the intercalated disk and membrane costameres of the heart. Methods and Results: Metavinculin and vinculin transcripts and protein were analyzed by polymerase chain reaction (PCR) and Western blotting. Thirty three human heart specimens were studied, including 5 normal controls, 4 subjects with ischemic cardiomyopathy, 1 with X-linked cardiomyopathy, and 23 with idiopathic dilated cardiomyopathy (IDC). PCR of cardiac cDNA detected absence of the metavinculin transcript in cardiac tissue from a subject with IDC. PCR of genomic DNA showed that the metavinculin exon was present but not utilized in the cardiac transcript. Western blot analysis demonstrated absence of metavinculin protein in the heart from this subject. Immunostaining of cardiac vinculin in this heart showed disorganized intercalated disk structures. Metavinculin deficiency was associated with normal cardiac expression of the cytoskeletal proteins vinculin, α-actinin, and dystrophin. Normal metavinculin expression in the other heart specimens suggests that the defect is specific in the IDC subject identified. Conclusions: These results demonstrate an association between metavinculin deficiency and dilated cardiomyopathy due to a defect in alternative mRNA splicing.