title: Characterization of troponin T dilated cardiomyopathy mutations in the fetal troponin isoform.
abstract: The major goal of this study was to elucidate how troponin T (TnT) dilated cardiomyopathy (DCM) mutations in fetal TnT and fetal troponin affect the functional properties of the fetal heart that lead to infantile cardiomyopathy. The DCM mutations R141W and DeltaK210 were created in the TnT1 isoform, the primary isoform of cardiac TnT in the embryonic heart. In addition to a different TnT isoform, a different troponin I (TnI) isoform, slow skeletal TnI (ssTnI), is the dominant isoform in the embryonic heart. In skinned fiber studies, TnT1-wild-type (WT)-treated fibers reconstituted with cardiac TnI.troponin C (TnC) or ssTnI.TnC significantly increased Ca(2+) sensitivity of force development when compared with TnT3-WT-treated fibers at both pH 7.0 and pH 6.5. Porcine cardiac fibers treated with TnT1 that contained the DCM mutations (R141W and DeltaK210), when reconstituted with either cardiac TnI.TnC or ssTnI.TnC, significantly decreased Ca(2+) sensitivity of force development compared with TnT1-WT at both pH values. The R141W mutation, which showed no significant change in the Ca(2+) sensitivity of force development in the TnT3 isoform, caused a significant decrease in the TnT1 isoform. The DeltaK210 mutation caused a greater decrease in Ca(2+) sensitivity and maximal isometric force development compared with the R141W mutation in both the fetal and adult TnT isoforms. When complexed with cardiac TnI.TnC or ssTnI.TnC, both TnT1 DCM mutations strongly decreased maximal actomyosin ATPase activity as compared with TnT1-WT. Our results suggest that a decrease in maximal actomyosin ATPase activity in conjunction with decreased Ca(2+) sensitivity of force development may cause a severe DCM phenotype in infants with the mutations.
authors.affiliation: Department of Molecular and Cellular Pharmacology and Physiology and Biophysics, University of Miami School of Medicine, Miami, Florida 33101, USA.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Venkatraman
authors.forename: Aldrin V
authors.initials: AV
authors.lastname: Gomes
authors.forename: W Glenn L
authors.initials: WG
authors.lastname: Kerrick
authors.forename: James D
authors.initials: JD
authors.lastname: Potter
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D005318:Fetal Heart / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D009154:Mutation; D020033:Protein Isoforms / Q000235:genetics; D011817:Rabbits; D013552:Swine; D020107:Troponin T / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; D020107:Troponin T