Molecular pathology of familial hypertrophic cardiomyopathy caused by mutations in the cardiac myosin binding protein C gene.

Abstract

DNA studies in familial hypertrophic cardiomyopathy (FHC) have shown that it is caused by mutations in genes coding for proteins which make up the muscle sarcomere. The majority of mutations in the FHC genes result from missense changes, although one of the most recent genes to be identified (cardiac myosin binding protein C gene, MYBPC3) has predominantly DNA mutations which produce truncated proteins. Both dominant negative and haploinsufficiency models have been proposed to explain the molecular changes in FHC. This study describes two Australian families with FHC caused by different mutations in MYBPC3. The first produces a de novo Asn755Lys change in a cardiac specific domain of MYBPC3. The second is a Gln969X nonsense mutation which results in a truncated protein. Neither mutation has previously been found in the MYBPC3 gene. The consequences of DNA changes on the function of cardiac myosin binding protein C are discussed in relation to current molecular models for this disorder. (J Med Genet 1998;35:205-2 10)

Myosin binding protein C: Structural abnormalities in familial hypertrophic cardiomyopathy

“…The N755K point mutation in Motif 5 exhibits a severe phenotype and lies in the highly conserved position 1 of a Type 1 β-turn connecting the F and G strands of the IgI domain. It was predicted that this highly conserved β-turn is stabilized by hydrogen bonding between N755 and G758 at position 4 of this β-turn [64]. Circular dichroism and NMR have confirmed that this N755K mutant is unstable and largely unfolded compared to the wild-type Motif 5, due to the loss of several key interactions [59,65].…”

“…A large majority of FHC mutations result in the premature termination of translation of the C-terminus of MyBPC, thus eliminating the titin and/or myosin binding sites [26,32,64,76,77]. This probably results in minimal or no incorporation of these truncated mutant proteins into the sarcomere [32].…”

“…FnIII modules Motifs 6 and 7 are reasonably homologous to similar FnIII domain pairs found in titin and fibronectin [63][64][65][66][67][68][69]. This homology includes a short linker region between the domains.…”

A Novel Variant of Cardiac Myosin-binding Protein-C That Is Unable to Assemble into Sarcomeres Is Expressed in the Aged Mouse Atrium

“…Mutations in the gene MYBPC3, encoding human cardiactype MyBP-C, have been identified to cause modest and late-onset familial hypertrophic cardiomyopathy (Bonne et al, 1995;Watkins et al, 1995;Carrier et al, 1997;Rottbauer et al, 1997;Yu et al, 1998). Familial hypertrophic cardiomyopathy is an autosomal dominant disease with typical morphological changes, including cardiomyocyte hypertrophy and/or myofibrillar disarray with fibrosis (Maron et al, 1987a,b;Seidman and Seidman, 2001).…”

Hypertrophic cardiomyopathy: from gene defect to clinical disease

“…During cardiac embryogenesis, cardiac myosin-binding protein C may participate in the alignment of thick filaments [21] whereas in the adult myocardium, phosphory- [19], [20], [23]. As in cardiac troponin T defects, penetranceis often incomplete, and is strikingly age-dependent [20].…”