A functional platform for the selection of pathogenic variants of PMM2 amenable to rescue via the use of pharmacological chaperones

Hum Mutat. 2022 Oct;43(10):1430-1442. doi: 10.1002/humu.24431. Epub 2022 Jul 16.


Different strategies are being investigated for treating PMM2-CDG, the most common congenital disorder of glycosylation. The use of pharmacochaperones (PCs) is one of the most promising. The present work characterizes the expression, stability, and enzymatic properties of 15 previously described clinical variants of the PMM2 protein, four novel variants, the Pmm2 mouse variant p.Phe115Leu, and its p.Phe119Leu human counterpart, with the aim of extending the potential use of pharmacochaperoning treatment. PMM2 variants were purified as stable homodimers, except for p.Asp65Gly, p.Ile120Thr, and p.Thr237Lys (no expression detected), p.Thr226Ser and p.Val231Met (aggregates), and p.Glu93Ala, p.Phe119Leu, and p.Phe115Leu (partial dissociated). Enzyme activity analyses identified severe variants and milder ones. Pure dimeric mutant proteins showed a reduction in thermal stability except for p.Asn216Asp. The thermal stability of all the unstable mutants was recovered in the presence of the PC compound VIII. This study adds to the list of destabilizing human variants amenable to rescue by small chemical compounds that increase the stability/activity of PMM2. The proposed platform can be reliably used for assessing the disease-causing effects of PMM2 missense variants, for assessing the correlation between genotype and phenotype, for confirming new clinical defects, and for identifying destabilizing mutations amenable to rescue by PCs.

Keywords: PCs; PMM2; PMM2-CDG; conformational disease; destabilizing; hypomorphic variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Congenital Disorders of Glycosylation* / genetics
  • Glycosylation
  • Humans
  • Mice
  • Mutation
  • Phenotype
  • Phosphotransferases (Phosphomutases)* / genetics


  • Phosphotransferases (Phosphomutases)
  • Pmm2 protein, mouse
  • phosphomannomutase 2, human