ALTERED CARDIAC TROPONIN-T IN-VITRO FUNCTION IN THE PRESENCE OF A MUTATION IMPLICATED IN FAMILIAR HYPERTROPHIC CARDIOMYOPATHY

Familial hypertrophic cardiomyopathy (HCM) can be caused by dominant m issense mutations in cardiac troponin T (TnT), alpha-tropomyosin, C-pr otein, or cardiac myosin heavy chain genes. The myosin mutations are k nown to impair function, but any functional consequences of the TnT mu tations are unknown. This report describes the in vitro function of tr oponin containing an Ile91Asn mutation in rat cardiac TnT, correspondi ng to the HCM-causing Ile79Asn mutation in man. Mutant and wild-type T nT cDNAs were expressed in bacteria and the proteins purified and reco nstituted with the other troponin subunits. The mutation had no effect on troponin's affinity for tropomyosin, troponin-induced binding of t ropomyosin to actin, cooperative binding of myosin subfragment 1 to th e thin filament, Ca2+-sensitive regulation of thin filament-myosin sub fragment 1 ATPase activity, or the Ca2+ concentration dependence of th is regulation, However, the mutation resulted in 50% faster thin filam ent movement over a surface coated with heavy meromyosin in in vitro m otility assays, The increased sliding speed suggests an unexpected rol e for the amino terminal region of TnT in which this mutation occurs, The relationship between this faster motility and altered cardiac cont raction in patients with HCM is discussed.