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Dilated cardiomyopathy and hypertrophic cardiomyopathy (HCM) can be caused by mutations in thin filament regulatory proteins of the contractile apparatus. In vitro functional assays show that, in general, the presence of dilated cardiomyopathy mutations decreases the Ca(2+) sensitivity of contractility, whereas HCM mutations increase it. To assess whether this functional phenomenon was a direct result of altered Ca(2+) affinity or was caused by altered troponin-tropomyosin switching, we assessed Ca(2+) binding of the regulatory site of cardiac troponin C in wild-type or mutant troponin complex and thin filaments using a fluorescent probe (2-[4'-{iodoacetamido}aniline]-naphthalene-6-sulfonate) attached to Cys35 of cardiac troponin C. The Ca(2+)-binding affinity (pCa(50)=6.57+/-0.03) of reconstituted troponin complex was unaffected by all of the HCM and dilated cardiomyopathy troponin mutants tested, with the exception of the troponin I Arg145Gly HCM mutation, which caused an increase (DeltapCa(50)=+0.31+/-0.05). However, when incorporated into regulated thin filaments, all but 1 of the 10 troponin and alpha-tropomyosin mutants altered Ca(2+)-binding affinity. Both HCM mutations increased Ca(2+) affinity (DeltapCa(50)=+0.41+/-0.02 and +0.51+/-0.01), whereas the dilated cardiomyopathy mutations decreased affinity (DeltapCa(50)=-0.12+/-0.04 to -0.54+/-0.04), which correlates with our previous functional in vitro assays. The exception was the troponin T Asp270Asn mutant, which caused a significant decrease in cooperativity. Because troponin is the major Ca(2+) buffer in the cardiomyocyte sarcoplasm, we suggest that Ca(2+) affinity changes caused by cardiomyopathy mutant proteins may directly affect the Ca(2+) transient and hence Ca(2+)-sensitive disease state remodeling pathways in vivo. This represents a novel mechanism for this class of mutation.

circulation research

Dilated and Hypertrophic Cardiomyopathy Mutations in Troponin and α-Tropomyosin Have Opposing Effects on the Calcium Affinity of Cardiac Thin Filaments