Cardiac myosin binding protein–C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy

Abstract

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease characterized by a ventricular hypertrophy predominantly affecting the inter-ventricular septum and associated with a large extent of myocardial and myofibrillar disarray¹. It is the most common cause of sudden death in the young. In the four disease loci found, three genes have been identified which code for β-myosin heavy chain, cardiac tro-ponin T and α-tropomyosin^2–7. Recently the human cardiac myosin binding protein-C (MyBP-C) gene was mapped to chromosome 11p11.2 (ref. 8), making this gene a good candidate for the fourth locus, CMH4 (ref. 5). Indeed, MyBP-C is a substantial component of the myofibrils that interacts with several proteins of the thick filament of the sarcomere^9–13. In two unrelated French families linked to CMH4, we found a mutation in a splice acceptor site of the MyBP-C gene, which causes the skipping of the associated exon and could produce truncated cardiac MyBP-Cs. Mutations in the cardiac MyBP-C gene likely cause chromosome 11-linked hypertrophic cardiomyopathy, further supporting the hypothesis that hypertrophic cardiomyopathy results from mutations in genes encoding contractile proteins.