MOLECULAR PATHOLOGY OF FAMILIAL HYPERTROPHIC CARDIOMYOPATHY CAUSED BYMUTATIONS IN THE CARDIAC MYOSIN BINDING-PROTEIN C-GENE

DNA studies in familial hypertrophic cardiomyopathy (FHC) have shown t hat it is caused by mutations in genes coding for proteins which make up the muscle sarcomere. The majority of mutations in the FHC genes re sult from missense changes, although one of the most recent genes to b e identified (cardiac myosin binding protein C gene, MYBPC3) has predo minantly 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 fami lies with FHC caused by different mutations in MYBPC3. The first produ ces a de novo Asn755Lys change in a cardiac specific domain of MYBPC3. The second is a Gln969X nonsense mutation which results in a truncate d protein. Neither mutation has previously been found in the MYBPC3 ge ne. The consequences of DNA changes on the function of cardiac myosin binding protein C are discussed in relation to current molecular model s for this disorder.