Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy

Background: The molecular basis of idiopathic dilated cardiomyopathy, a pri mary myocardial disorder that results in reduced contractile function, is l argely unknown. Some cases of familial dilated cardiomyopathy are caused by mutations in cardiac cytoskeletal proteins; this finding implicates defect s in contractile-force transmission as one mechanism underlying this disord er. To elucidate this important cause of heart failure, we investigated oth er genetic causes of dilated cardiomyopathy. Methods: Clinical evaluations were performed in 21 kindreds with familial d ilated cardiomyopathy. A genome-wide linkage study prompted a search of the genes encoding beta -myosin heavy chain, troponin T, troponin I, and alpha -tropomyosin for disease-causing mutations. Results: A genetic locus for mutations associated with dilated cardiomyopat hy was identified at chromosome 14q11.2-13 (maximal lod score, 5.11; theta =0), where the gene for cardiac beta -myosin heavy chain is encoded. Analys es of this and other genes for sarcomere proteins identified disease-causin g dominant mutations in four kindreds. Cardiac beta -myosin heavy-chain mis sense mutations (Ser532Pro and Phe764Leu) and a deletion in cardiac troponi n T (Delta Lys210) caused early-onset ventricular dilatation (average age a t diagnosis, 24 years) and diminished contractile function and frequently r esulted in heart failure. Affected persons had neither antecedent cardiac h ypertrophy (average maximal left-ventricular-wall thickness, 8.5 mm) nor hi stopathological findings characteristic of hypertrophy. Conclusions: Mutations in sarcomere protein genes account for approximately 10 percent of cases of familial dilated cardiomyopathy and are particularl y prevalent in families with early-onset ventricular dilatation and dysfunc tion. Because distinct mutations in sarcomere proteins cause either dilated or hypertrophic cardiomyopathy, the effects of mutant sarcomere proteins o n muscle mechanics must trigger two different series of events that remodel the heart. (N Engl J Med 2000;343:1688-96.) (C) 2000, Massachusetts Medica l Society.