A new insight into PMM2 mutations in the French population.

Congenital disorder of Glycosylation type Ia is an autosomal recessive disorder, characterized by a central nervous system dysfunction and multiorgan failure associated with defective N-glycosylation and phosphomannomutase (PMM) deficiency related to mutations in the PMM2 gene (mRNA U85773.1, gene ID 5373). More than 75 different mutations have been previously described. In our study, 38 different mutations were found in 52 French families with CDG-Ia. Eleven mutations had not been previously published in CDG-Ia patients: eight missense and three splice mutations. We studied the PMM activity of eight novel recombinant mutant proteins in an E. coli expression system, comparing them with the wild type protein, c.422 G>A (R141H), and c.415 G>A (E139K) mutant proteins. We also studied the previously described c.590 C>A (E197A) found on the same allele as c.394 A>T (I132F). All mutant proteins studied except E197A had decreased activity and/or were thermolabile, and were pathogenic mutations. Haplotype studies revealed a founder effect for E139K mutation, only described in France and found in seven CDG-Ia families (7.6%). In contrast, at least two different haplotypes were observed for the R141H mutation in France, studied in 23 families. The R141H seems to be a combination of the "old" R141H mutation found all over Europe and a second "French" R141H, and could be substantially older than E139K.