Functional Analysis of a Unique Troponin C Mutation, GLY159ASP, that Causes Familial Dilated Cardiomyopathy, Studied in Explanted Heart Muscle

DOI Web Site 被引用文献2件
  • Emma C. Dyer
    From the NHLI (E.C.D., A.M.J., C.E.G., A.E.M., S.B.M.), Imperial College London; Cardiovascular Division (A.C.H., J.C.K.), King’s College London; Great Ormond St Hospital (M.B.); University College London (J.P.K.); and School of Cancer Sciences (D.G.W.), Birmingham University, Birmingham, London, United Kingdom.
  • Adam M. Jacques
    From the NHLI (E.C.D., A.M.J., C.E.G., A.E.M., S.B.M.), Imperial College London; Cardiovascular Division (A.C.H., J.C.K.), King’s College London; Great Ormond St Hospital (M.B.); University College London (J.P.K.); and School of Cancer Sciences (D.G.W.), Birmingham University, Birmingham, London, United Kingdom.
  • Anita C. Hoskins
    From the NHLI (E.C.D., A.M.J., C.E.G., A.E.M., S.B.M.), Imperial College London; Cardiovascular Division (A.C.H., J.C.K.), King’s College London; Great Ormond St Hospital (M.B.); University College London (J.P.K.); and School of Cancer Sciences (D.G.W.), Birmingham University, Birmingham, London, United Kingdom.
  • Douglas G. Ward
    From the NHLI (E.C.D., A.M.J., C.E.G., A.E.M., S.B.M.), Imperial College London; Cardiovascular Division (A.C.H., J.C.K.), King’s College London; Great Ormond St Hospital (M.B.); University College London (J.P.K.); and School of Cancer Sciences (D.G.W.), Birmingham University, Birmingham, London, United Kingdom.
  • Clare E. Gallon
    From the NHLI (E.C.D., A.M.J., C.E.G., A.E.M., S.B.M.), Imperial College London; Cardiovascular Division (A.C.H., J.C.K.), King’s College London; Great Ormond St Hospital (M.B.); University College London (J.P.K.); and School of Cancer Sciences (D.G.W.), Birmingham University, Birmingham, London, United Kingdom.
  • Andrew E. Messer
    From the NHLI (E.C.D., A.M.J., C.E.G., A.E.M., S.B.M.), Imperial College London; Cardiovascular Division (A.C.H., J.C.K.), King’s College London; Great Ormond St Hospital (M.B.); University College London (J.P.K.); and School of Cancer Sciences (D.G.W.), Birmingham University, Birmingham, London, United Kingdom.
  • Juan Pablo Kaski
    From the NHLI (E.C.D., A.M.J., C.E.G., A.E.M., S.B.M.), Imperial College London; Cardiovascular Division (A.C.H., J.C.K.), King’s College London; Great Ormond St Hospital (M.B.); University College London (J.P.K.); and School of Cancer Sciences (D.G.W.), Birmingham University, Birmingham, London, United Kingdom.
  • Michael Burch
    From the NHLI (E.C.D., A.M.J., C.E.G., A.E.M., S.B.M.), Imperial College London; Cardiovascular Division (A.C.H., J.C.K.), King’s College London; Great Ormond St Hospital (M.B.); University College London (J.P.K.); and School of Cancer Sciences (D.G.W.), Birmingham University, Birmingham, London, United Kingdom.
  • Jonathan C. Kentish
    From the NHLI (E.C.D., A.M.J., C.E.G., A.E.M., S.B.M.), Imperial College London; Cardiovascular Division (A.C.H., J.C.K.), King’s College London; Great Ormond St Hospital (M.B.); University College London (J.P.K.); and School of Cancer Sciences (D.G.W.), Birmingham University, Birmingham, London, United Kingdom.
  • Steven B. Marston
    From the NHLI (E.C.D., A.M.J., C.E.G., A.E.M., S.B.M.), Imperial College London; Cardiovascular Division (A.C.H., J.C.K.), King’s College London; Great Ormond St Hospital (M.B.); University College London (J.P.K.); and School of Cancer Sciences (D.G.W.), Birmingham University, Birmingham, London, United Kingdom.

この論文をさがす

説明

<jats:p> <jats:bold> <jats:italic>Background—</jats:italic> </jats:bold> Familial dilated cardiomyopathy can be caused by mutations in the proteins of the muscle thin filament. In vitro, these mutations decrease Ca <jats:sup>2+</jats:sup> sensitivity and cross-bridge turnover rate, but the mutations have not been investigated in human tissue. We studied the Ca <jats:sup>2+</jats:sup> -regulatory properties of myocytes and troponin extracted from the explanted heart of a patient with inherited dilated cardiomyopathy due to the cTnC G159D mutation. </jats:p> <jats:p> <jats:bold> <jats:italic>Methods and Results—</jats:italic> </jats:bold> Mass spectroscopy showed that the mutant cTnC was expressed approximately equimolar with wild-type cTnC. Contraction was compared in skinned ventricular myocytes from the cTnC G159D patient and nonfailing donor heart. Maximal Ca <jats:sup>2+</jats:sup> -activated force was similar in cTnC G159D and donor myocytes, but the Ca <jats:sup>2+</jats:sup> sensitivity of cTnC G159D myocytes was higher (EC <jats:sub>50</jats:sub> G159D/donor=0.60). Thin filaments reconstituted with skeletal muscle actin and human cardiac tropomyosin and troponin were studied by in vitro motility assay. Thin filaments containing the mutation had a higher Ca <jats:sup>2+</jats:sup> sensitivity (EC <jats:sub>50</jats:sub> G159D/donor=0.55�0.13), whereas the maximally activated sliding speed was unaltered. In addition, the cTnC G159D mutation blunted the change in Ca <jats:sup>2+</jats:sup> sensitivity when TnI was dephosphorylated. With wild-type troponin, Ca <jats:sup>2+</jats:sup> sensitivity was increased (EC <jats:sub>50</jats:sub> P/unP=4.7�1.9) but not with cTnC G159D troponin (EC <jats:sub>50</jats:sub> P/unP=1.2�0.1). </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusions—</jats:italic> </jats:bold> We propose that uncoupling of the relationship between phosphorylation and Ca <jats:sup>2+</jats:sup> sensitivity could be the cause of the dilated cardiomyopathy phenotype. The differences between these data and previous in vitro results show that native phosphorylation of troponin I and troponin T and other posttranslational modifications of sarcomeric proteins strongly influence the functional effects of a mutation. </jats:p>

収録刊行物

被引用文献 (2)*注記

もっと見る

詳細情報 詳細情報について

問題の指摘

ページトップへ