Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency

Triosephosphate isomerase (TPI) deficiency (TPI Df) is an untreatable glycolytic enzymopathy that results in hemolytic anemia, progressive muscular impairment and irreversible brain damage. Although there is a ‘common’ mutation (TPI(E105D)), other pathogenic mutations have been described. We identified patients who were compound heterozygous for a newly described mutation, TPI(Q181P), and the common TPI(E105D) mutation. Intriguingly, these patients lacked neuropathy or cognitive impairment. We then initiated biochemical and structural studies of TPI(Q181P). Surprisingly, we found that purified TPI(Q181P) protein had markedly impaired catalytic properties whereas crystallographic studies demonstrated that the TPI(Q181P) mutation resulted in a highly disordered catalytic lid. We propose that genetic complementation occurs between the two alleles, one with little activity (TPI(Q181P)) and one with low stability (TPI(E105D)). Consistent with this, TPI(Q181P/E105D) fibroblasts exhibit a significant reduction in the TPI protein. These data suggest that impaired stability, and not catalytic activity, is a better predictor of TPI Df severity. Lastly, we tested two recently discovered chemical modulators of mutant TPI stability, itavastatin and resveratrol, and observed a significant increase in TPI in TPI(Q181P/E105D) patient cells.