Cardiac Troponin I C-Terminal Mutations (K178E and K179E) Cause Severe Heart Failure and Early Mortality in Transgenic Mice

The C-terminal region of cardiac troponin I (cTnI164-210) plays an important role in cardiac muscle contraction. Most genetic cardiomyopathies in human are associated with the mutations in cTnI C-terminus. Among them, K178E mutation was reported to cause restrictive cardiomyopathy (RCM) in human. Deletion of K177 is related to hypertrophic cardiomyopathy (HCM). Since the amino acids numbered 173-181 bind to actin, which increases the inhibitory effect of TnI, we hypothesize that K177 and K178 are both critical for normal cardiac function. We modeled the RCM mutation of lysine 178→glutamate (K178E) in human cTnI by cardiac specific expression of the mutated protein (cTnI179Glu in mouse sequence) in transgenic mice. In addition, we created cTnI178Glu transgenic mice expressing cTnI K178E as a comparison. The RCM cTnI179Glu transgenic mice showed a dramatic phenotype of a high rate of early death. Some survived TG mice were infertile. Interestingly, the mutation of cTnI K178E (cTnI K177E in human sequence) had a similar phenotype as shown in RCM cTnI179Glu mice. The replacement of the mutant cTnI K178E in cTnI178Glu mouse lines was about 20-40%. Bi-atrial enlargement was a dramatic sign observed in most of the cTnI178Glu TG mice, and was developed early at age of 2 weeks. Severe cardiac dysfunction and early death were observed in these TG mice as well. The data from transgenic mouse studies indicate that like RCM cTnI K179E mutation, the cTnI K178E mutation in mouse hearts can also cause severe cardiomyopathy with heart failure and early death, suggesting that cTnI C-terminus is critical in maintaining normal cardiac function.(Supported by NIH GM073621 and AHA09GRNT2400138)