Functional analyses of troponin T mutations that cause hypertrophic cardiomyopathy: insights into disease pathogenesis and troponin function.
Mutations in a number of cardiac sarcomeric protein genes cause hypertrophic cardiomyopathy (HCM). Previous findings indicate that HCM-causing mutations associated with a truncated cardiac troponin T (TnT) and missense mutations in the beta-myosin heavy chain share abnormalities in common, acting as dominant negative alleles that impair contractile performance. In contrast, Lin et al. [Lin, D., Bobkova, A., Homsher, E. & Tobacman, L. S. (1996) J. Clin. Invest. 97, 2842-2848] characterized a TnT point mutation (Ile79Asn) and concluded that it might lead to hypercontractility and, thus, potentially a different mechanism for HCM pathogenesis. In this study, three HCM-causing cardiac TnT mutations (Ile79Asn, Arg92Gln, and DeltaGlu160) were studied in a myotube expression system. Functional studies of wild-type and mutant transfected myotubes revealed that all three mutants decreased the calcium sensitivity of force production and that the two missense mutations (Ile79Asn and Arg92Gln) increased the unloaded shortening velocity nearly 2-fold. The data demonstrate that TnT can alter the rate of myosin cross-bridge detachment, and thus the troponin complex plays a greater role in modulating muscle contractile performance than was recognized previously. Furthermore, these data suggest that these TnT mutations may cause disease via an increased energetic load on the heart. This would represent a second paradigm for HCM pathogenesis.
Sweeney
H L
HL
Department of Physiology, A700 Richards Building, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6085, USA. lsweeney@mail.med.upenn.edu
Feng
H S
HS
Yang
Z
Z
Watkins
H
H
D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian; D006801:Humans; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology*; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000235:genetics; D017354:Point Mutation; D011784:Quail; D011994:Recombinant Proteins / Q000096:biosynthesis; D012518:Sarcomeres / Q000502:physiology / Q000648:ultrastructure; D017384:Sequence Deletion; D014162:Transfection; D020107:Troponin T / Q000096:biosynthesis / Q000235:genetics*
D011994:Recombinant Proteins; D020107:Troponin T; D018995:Myosin Heavy Chains