DILATED CARDIOMYOPATHY ASSOCIATED WITH DEFICIENCY OF THE CYTOSKELETALPROTEIN METAVINCULIN

Background The cytoskeleton plays an important role in maintaining cel l structure and integrity. Defects in cytoskeletal proteins can crippl e cell strength and may cause cardiomyopathy. We analyzed heart tissue s from subjects with dilated cardiomyopathy for abnormalities in the c ardiac cytoskeleton. Metavinculin, a cardiac isoform of the cytoskelet al protein vinculin, connects actin microfilaments to the intercalated disk and membrane costameres of the heart. Methods and Results Metavi nculin and vinculin transcripts and protein were analyzed by polymeras e chain reaction (PCR) and Western blotting. Thirty-three human heart specimens were studied, including 5 normal controls, 4 subjects with i schemic cardiomyopathy, 1 with X-linked cardiomyopathy, and 23 with id iopathic dilated cardiomyopathy (IDC). PCR of cardiac cDNA detected ab sence of the metavinculin transcript in cardiac tissue from a subject with IDC. PCR of genomic DNA showed that the metavinculin exon was pre sent but not utilized in the cardiac transcript. Western blot analysis demonstrated absence of metavinculin protein in the heart from this s ubject. Immunostaining of cardiac vinculin in this heart showed disorg anized intercalated disk structures. Metavinculin deficiency was assoc iated with normal cardiac expression of the cytoskeletal proteins vinc ulin, alpha-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 asso ciation between metavinculin deficiency and dilated cardiomyopathy due to a defect in alternative mRNA splicing.