Classic galactosemia is a rare
genetic disease of the
galactose metabolism, resulting from deficient activity of
galactose-1-phosphate uridylyltransferase (GALT). The current standard of care is lifelong
dietary restriction of
galactose, which however fails to prevent the development of long-term complications. Structural-functional studies demonstrated that the most prevalent GALT mutations give rise to
proteins with increased propensity to aggregate in
solution.
Arginine is a known stabilizer of aggregation-prone
proteins, having already shown a beneficial effect in other inherited metabolic disorders.Herein we developed a prokaryotic model of
galactose sensitivity that allows evaluating in a cellular context the mutations' impact on GALT function, as well as the potential effect of
arginine in functionally rescuing clinically relevant variants.This study revealed that some hGALT variants, previously described to exhibit no detectable activity in vitro, actually present residual activity when determined in vivo. Furthermore, it revealed that
arginine presents a mutation-specific beneficial effect, particularly on the prevalent p.Q188R and p.K285N variants, which led us to hypothesize that it might constitute a promising therapeutic agent in
classic galactosemia.