title: A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation.
abstract: Defined as clinically unexplained hypertrophy of the left ventricle, hypertrophic cardiomyopathy (HCM) is traditionally understood as a disease of the cardiac sarcomere. Mutations in TNNC1-encoded cardiac troponin C (cTnC) are a relatively rare cause of HCM. Here, we report clinical and functional characterization of a novel TNNC1 mutation, A31S, identified in a pediatric HCM proband with multiple episodes of ventricular fibrillation and aborted sudden cardiac death. Diagnosed at age 5, the proband is family history-negative for HCM or sudden cardiac death, suggesting a de novo mutation. TnC-extracted cardiac skinned fibers were reconstituted with the cTnC-A31S mutant, which increased Ca(2+) sensitivity with no effect on the maximal contractile force generation. Reconstituted actomyosin ATPase assays with 50% cTnC-A31S:50% cTnC-WT demonstrated Ca(2+) sensitivity that was intermediate between 100% cTnC-A31S and 100% cTnC-WT, whereas the mutant increased the activation of the actomyosin ATPase without affecting the inhibitory qualities of the ATPase. The secondary structure of the cTnC mutant was evaluated by circular dichroism, which did not indicate global changes in structure. Fluorescence studies demonstrated increased Ca(2+) affinity in isolated cTnC, the troponin complex, thin filament, and to a lesser degree, thin filament with myosin subfragment 1. These results suggest that this mutation has a direct effect on the Ca(2+) sensitivity of the myofilament, which may alter Ca(2+) handling and contribute to the arrhythmogenesis observed in the proband. In summary, we report a novel mutation in the TNNC1 gene that is associated with HCM pathogenesis and may predispose to the pathogenesis of a fatal arrhythmogenic subtype of HCM.
authors: Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
authors: Michelle S
authors: MS
authors: Parvatiyar
authors: Andrew P
authors: AP
authors: Landstrom
authors: Cicero
authors: C
authors: Figueiredo-Freitas
authors: James D
authors: JD
authors: Potter
authors: Michael J
authors: MJ
authors: Ackerman
authors: Jose Renato
authors: JR
authors: Pinto
mesh_terms: D000483:Alleles; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000503:physiopathology; D002942:Circular Dichroism; D003001:Cloning, Molecular; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008968:Molecular Conformation; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D009210:Myofibrils / Q000378:metabolism; D009218:Myosins / Q000737:chemistry; D019209:Troponin C / Q000235:genetics* / Q000378:metabolism*; D014693:Ventricular Fibrillation / Q000235:genetics* / Q000503:physiopathology
chemical_list: D019209:Troponin C; D009218:Myosins; D002118:Calcium