Restrictive Cardiomyopathy 3
In a 12-month-old girl with restrictive cardiomyopathy (RCM3; 612422), Peddy et al. (2006) identified a 3-bp deletion (285delGGA) in exon 9 the TNNT2 gene, resulting in the deletion of glutamic acid at codon 96 (glu96del) in a highly conserved segment of the main tropomyosin-binding region in the N-terminal half of troponin T. The deletion was not found in either parent, who had normal echocardiograms at ages 28 and 34 years, respectively. The girl also carried a known MYBPC3 (600958) polymorphism, V896M, which was also found in her unaffected father; the authors suggested that the V896M variant may have acted as a modifier, exacerbating the phenotypic expression of the TNNT2 mutation and causing an unusually early onset of RMC.
Variant Function
Pinto et al. (2008) analyzed the effects of the 3-bp TNNT2 deletion in both the adult and fetal human cardiac TNNT2 isoforms, in order to evaluate the disease progression after birth when the isoform switch occurs. Both mutant isoforms showed a large increase in Ca(2+) sensitivity compared to their respective wildtypes, but there was no significant change in force recovery in any of the experiments. Both mutants showed an impaired ability to inhibit actomyosin ATPase activity, and the capacity of troponin complexes to fully relax fibers after troponin T displacement was also compromised. Experiments with fetal troponin isoforms showed a less severe impact compared with adult isoforms, consistent with a cardioprotective role for slow skeletal isoforms and with the rapid onset of RCM after birth following the isoform switch.
