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We have identified the PMM2 genotypes of 22 unrelated Danish patients with carbohydrate-deficient glycoprotein syndrome type 1A: R141H/F119L (18), R141H/C192G (1), F119L/F119L (1), F119L/G117R (1) and D223E/T237R (1). The lack of patients homozygous for R141H is statistically highly significant, but unexplained. In order to investigate the effect of PMM2 mutations on phosphomannomutase (PMM2) activity, PMM2-cDNA was cloned into a pET3a vector. Following introduction of mutations into PMM2-cDNA by site-specific mutagenesis, wild type and mutant PMM2-cDNA were expressed in E. coli Bl21(DE3) cells, and the activity of PMM2 was determined by an enzymatic assay using mannose 1-phosphate as substrate. Recombinant R141H, G117R, and T237R PMM2 had no detectable catalytic activity, and the F119L PMM2 had 25% of the activity of the wild type. The activity of the C192G and D223E PMM2 was in the normal range, but the affinity for their substrate was lower, and the proteins were more sensitive to increased temperatures. Each patient has at least one mutation which retains residual PMM2 activity. Our results support the hypotheses that a genotype conveying residual PMM2 catalytic activity is required for survival, and that homozygosity for R141H impairs PMM2 to a degree incompatible with life.

Carbohydrate-deficient glycoprotein syndrome type 1A: expression and characterisation of wild type and mutant PMM2 in E. coli