Mutations in Cypher/ZASPin patients with dilated cardiomyopathy and left ventricular non-compaction

Abstract

We evaluated the role of Cypher/ZASPin the pathogenesis of dilated cardiomyopathy (DCM) with or without isolated non-compaction of the left ventricular myocardium (INLVM). Dilated cardiomyopathy, characterized by left ventricular dilation and systolic dysfunction with signs of heart failure, is genetically transmitted in 30% to 40% of cases. Genetic heterogeneity has been identified with mutations in multiple cytoskeletal and sarcomeric genes causing the phenotype. In addition, INLVM with a hypertrophic dilated left ventricle, ventricular dysfunction, and deep trabeculations, is also inherited, and the genes identified to date differ from those causing DCM. Cypher/ZASPis a newly identified gene encoding a protein that is a component of the Z-line in both skeletal and cardiac muscle. Diagnosis of DCM was performed by echocardiogram, electrocardiogram, and physical examination. In addition, levels of the muscular isoform of creatine kinase were measured to evaluate for skeletal muscle involvement. Cypher/ZASPwas screened by denaturing high performance liquid chromatography (DHPLC) and direct deoxyribonucleic acid sequencing. We identified and screened 100 probands with left ventricular dysfunction. Five mutations in six probands (6% of cases) were identified in patients with familial or sporadic DCM or INLVM. In vitro studies showed cytoskeleton disarray in cells transfected with mutated Cypher/ZASP. These data suggest that mutated Cypher/ZASPcan cause DCM and INLVM and identify a mechanistic basis.