Familial Hypertrophic Cardiomyopathy: a Genetic Model of Cardiac Hypertrophy

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.