NOVEL SPLICE DONOR SITE MUTATION IN THE CARDIAC MYOSIN-BINDING PROTEIN-C GENE IN FAMILIAL HYPERTROPHIC CARDIOMYOPATHY - CHARACTERIZATION OFCARDIAC TRANSCRIPT AND PROTEIN

Familial hypertrophic cardiomyopathy is a disease generally believed t o be caused by mutations in sarcomeric proteins. In a family with hype rtrophic cardiomyopathy linked to polymorphic markers on chromosome 11 , we found a new mutation of a splice donor site of the cardiac myosin -binding protein-C gene, This mutation causes the skipping of the asso ciated exon in mRNA from lymphocytes and myocardium, Skipping of the e xon with a consecutive reading frame shift leads to premature terminat ion of translation and is thus expected to produce a truncated cardiac myosin-binding protein-C with loss of the myosin- and titin-binding C OOH terminus, However, Western blot analysis of endomyocardial biopsie s from histologically affected left ventricular myocardium failed to s how the expected truncated protein. These data show for the first time that a splice donor site mutation in the myosin-binding protein-C gen e is transcribed to cardiac mRNA, Truncated cardiac myosin-binding pro tein-C does not act as a ''poison polypeptide,'' since it seems not to be incorporated into the sarcomere in significant amounts, The absenc e of mutant protein and of significantly reduced amounts of wild-type protein in the presence of the mutated mRNA argues against the ''poiso n protein'' and the ''null allele'' hypotheses and suggests yet unknow n mechanisms relevant to the genesis of chromosome-11-associated famil ial hypertrophic cardiomyopathy.