Functional consequences of troponin T mutations found in hypertrophic cardiomyopathy.
Missense mutations in the cardiac thin filament protein troponin T (TnT) are a cause of familial hypertrophic cardiomyopathy (FHC). To understand how these mutations produce dysfunction, five TnTs were produced and purified containing FHC mutations found in several regions of TnT. Functional defects were diverse. Mutations F110I, E244D, and COOH-terminal truncation weakened the affinity of troponin for the thin filament. Mutation DeltaE160 resulted in thin filaments with increased calcium affinity at the regulatory site of troponin C. Mutations R92Q and F110I resulted in impaired troponin solubility, suggesting abnormal protein folding. Depending upon the mutation, the in vitro unloaded actin-myosin sliding speed showed small increases, showed small decreases, or was unchanged. COOH-terminal truncation mutation resulted in a decreased thin filament-myosin subfragment 1 MgATPase rate. The results indicate that the mutations cause diverse immediate effects, despite similarities in disease manifestations. Separable but repeatedly observed abnormalities resulting from FHC TnT mutations include increased unloaded sliding speed, increased or decreased Ca(2+) affinity, impairment of folding or sarcomeric integrity, and decreased force. Enhancement as well as impairment of contractile protein function is observed, suggesting that TnT, including the troponin tail region, modulates the regulation of cardiac contraction.
Tobacman
L S
LS
Department of Internal Medicine, The University of Iowa, Iowa City, Iowa 52242, USA. larrytobacman@uiowa.edu
Lin
D
D
Butters
C
C
Landis
C
C
Back
N
N
Pavlov
D
D
Homsher
E
E
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002417:Cattle; D003001:Cloning, Molecular; D018076:DNA, Complementary; D008969:Molecular Sequence Data; D009154:Mutation; D020107:Troponin T / Q000235:genetics / Q000378:metabolism*
D018076:DNA, Complementary; D020107:Troponin T