β-Myosin Heavy Chain Gene Mutations in Familial Hypertrophic Cardiomyopathy

Familial hypertrophic cardiomyopathy (FHC) is a genetic disorder arising from mutations in sarcomeric protein genes. Human genetic studies have implicated at least 9 different genes in FHC, emphasizing the enormous genetic and allelic heterogeneity associated with FHC.1 β-Myosin heavy chain (βMyHC, MYH7 ) is the most commonly mutated gene in FHC, and at least 60 different MYH7 gene mutations have been described in human FHC subjects.2 The vast majority of these are single base pair mutations that produce missense amino acid substitutions. Myosin is a hexamer composed of 2 heavy chains and 2 each of the regulatory and essential light chains (see Figure). Myosin is a highly asymmetric protein with a long rod domain and 2 globular heads. The globular domain of myosin, heavy meromyosin (HMM), can be proteolyzed into subfragment 1 (S1) and subfragment 2 (S2). The S1 head is the enzymatic “business” end of the molecule in that it possesses actin-activated ATPase activity and is capable of directing the sliding of actin filaments in vitro. The crystal structure of S1 has been determined, shedding light on the potential conformational changes that occur in response to ATP hydrolysis and that ultimately are responsible for myocyte shortening, skeletal muscle movement, and the beating of our hearts.3 Myosin was one of the first proteins to be purified and proteolytically separated into distinct functional domains contributing to the domain theory of proteins. Similarly for human genetic studies, the domain structure of myosin has proved useful because all the reported missense mutations in βMyHC map to the head and neck region, a region of the rod most proximal to the globular head. Within the S1 head, FHC mutations cluster to …