Mutations in the cardiac myosin binding protein–C gene on chromosome 11 cause familial hypertrophic cardiomyopathy

Abstract

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disorder manifesting as cardiac hypertrophy with myocyte disarray and an increased risk of sudden death^1,2. Mutations in five different loci cause FHC and 3 disease genes have been identified: β cardiac myosin heavy chain³, α tropomyosin and cardiac troponin T^4,5. Because these genes encode contractile proteins, other FHC loci are predicted also to encode sar-comere components⁴. Two further FHC loci have been mapped to chromosomes 11p13–q13 (CMH4, ref. 6) and 7q3 (ref. 7). The gene encoding the cardiac isoform of myosin binding protein-C (cardiac MyBP-C) has recently been assigned to chromosome 11 p11.2 and proposed as a candidate FHC gene⁸. Cardiac MyBP-C is arrayed transversely in sarcomere A-bands and binds myosin heavy chain in thick filaments and titin in elastic filaments. Phosphorylation of MyBP-C appears to modulate contraction^8–10. We report that cardiac MyBP-C is genetically linked to CMH4 and demonstrate a splice donor mutation in one family with FHC and a duplication mutation in a second. Both mutations are predicted to disrupt the high affinity, C-terminal, myosin-binding domain of cardiac MyBP-C. These findings define cardiac MyBP-C mutations as the cause of FHC on chromosome 11 p and reaffirm that FHC is a disease of the sarcomere.