Familial hypertrophic cardiomyopathy: a genetic model of cardiac hypertrophy

Abstract

Familial hypertrophic cardiomyopathy is an autosomal dominant disorder manifesting as cardiac hypertrophy in the absence of increased cardiac work load, which has been studied as a model of myocardial hypertrophy in humans. Hypertrophic cardiomyopathy is genetically heterogeneous with three known disease-genes and two further mapped loci. The disease-genes encode contractile proteins of the thick and thin filaments of the sarcomere: the beta cardiac myosin heavy chain gene on chromosome 14q11, the alpha tropomyosin gene on chromosome 15q2 and the cardiac troponin T gene on chromosome 1q3. Other disease loci have been mapped to chromosome 11p13-q13 and 7q3. In each known disease-gene a number of different mutations have been identified; these are missense mutations, or mutations leading to modest alterations of peptide structure, but not null alleles. Specific mutations are associated with different disease severity and may provide diagnostic and prognostic information not available from clinical assessment. Genetic and functional data suggest that mutations which cause hypertrophic cardiomyopathy act as dominant negative alleles that impair cross-bridge cycling and contractile function and interfere with sarcomere assembly.

Molecular genetics of familial hypertrophic cardiomyopathy (FHC)

“…These include -cardiac myosin heavy chain (MYH7) (Geisterfer-Lowrance et al 1990;Watkins et al 1992), cardiac myosin-binding protein C (MyBPC-3) (Watkins et al 1995a), cardiac troponin T (TnT2) (Thierfelder et al 1994), Recently, two families were shown to harbor mutations in the light meromyosin domain in the rod region of the protein (Blair et al 2002). The MYH7 mutations account for about 30% of the reported FHC cases (Table 1) (Watkins et al 1995c). To date more than 70 different mutations have been identified in the MYH7 gene (Table 1).…”

Mutations in the motor domain modulate myosin activity and myofibril organization

“…Mutations in the structural components of muscle are directly responsible for a class of human disease, familial hypertrophic cardiomyopathy (FHC) (Bonne et al, 1998;Seidman and Seidman, 2001;Watkins et al, 1995c). The disease is characterized by cardiac hypertrophy primarily affecting the left ventricle and the intraventricular septum that occurs in the absence of other known conditions leading to hypertrophy.…”

Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy

“…For example, most of the mutations in the β-MyHC are missense mutations, whereas mutations in the cTnT and myosin-binding protein C genes can be splice-site mutations, deletions of codons, and missense mutations. The disease is also clinically heterogeneous, with some mutant alleles resulting in a poor clinical prognosis, whereas others are associated with a good prognosis (2). In general, mutations in the β-MyHC gene are associated with moderate to severe ventricular hypertrophy and variable sudden death, whereas mutations in cTnT are associated with mild or no hypertrophy and a high incidence of sudden death.…”