Abstract 2822: Mutations in the New Z-disk Protein ZF125 cause Dilated Cardiomyopathy in Humans and Zebrafish
Heart failure due to idiopathic dilated cardiomyopathy (DCM) is among the most common causes of cardiovascular mortality. At least 30% of DCM cases are inherited and an even larger portion is believed to be caused by sporadic gene mutations. However, due to the lack of large DCM families, suitable for classical linkage analysis, only a few DCM genes have been described to date. In a bioinformatical screen for novel cardiac transcripts we have identified ZF125 as a novel Z-disk protein of heart and skeletal muscle. Antisense oligonucleotide mediated inactivation of the zf125 gene in zebrafish leads to destruction of cardiac Z-disks and consecutively progressive DCM. Mutation analysis of the zf125 gene in familial and sporadic cases of DCM reveals several disease causing mutations, indicating that zf125 mutations account for a significant proportion of genetic DCM cases. Strikingly, heart tissue of affected patients unveils ultrastructural alterations identical to the ones observed in zf125-deficient zebrafish hearts. Consistent with an autosomal-dominant mode of inheritance, overexpression of mutant ZF125 in zebrafish disrupts sarcomere integrity in a dominant-negative manner. Furthermore, increasing mechanical strain in zf125-deficient heart and skeletal muscle aggravates sarcomere damage, providing insight into a possible physiologic function for ZF125 in protecting Z-disks from mechanical trauma. Accordingly, Z-disk instability might be a major molecular trigger for cardiomyopathies.