Restrictive cardiomyopathy (RCM) is a rare disorder characterized by impaired ventricular filling with decreased diastolic volume. We are reporting the functional effects of the first cardiac
troponin T (CTnT) mutation linked to infantile RCM resulting from a de novo deletion mutation of
glutamic acid 96. The mutation was introduced into adult and fetal
isoforms of human cardiac
TnT (HCTnT3-DeltaE96 and HCTnT1-DeltaE106, respectively) and studied with either cardiac
troponin I (CTnI) or slow skeletal
troponin I (SSTnI). Skinned cardiac fiber measurements showed a large leftward shift in the Ca(2+) sensitivity of force development with no differences in the maximal force. HCTnT1-DeltaE106 showed a significant increase in the activation of
actomyosin ATPase with either CTnI or SSTnI, whereas HCTnT3-DeltaE96 was only able to increase the
ATPase activity with CTnI. Both mutants showed an impaired ability to inhibit the
ATPase activity. The capacity of the CTnI.CTnC and SSTnI.CTnC complexes to fully relax the fibers after
TnT displacement was also compromised. Experiments performed using fetal
troponin isoforms showed a less severe impact compared with the adult
isoforms, which is consistent with the cardioprotective role of SSTnI and the rapid onset of RCM after birth following the
isoform switch. These data indicate that
troponin mutations related to RCM may have specific functional phenotypes, including large leftward shifts in the Ca(2+) sensitivity and impaired abilities to inhibit
ATPase and to relax skinned fibers. All of this would account for and contribute to the severe diastolic dysfunction seen in RCM.