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.