Functional significance of PMM2 mutations in mildly affected patients withcongenital disorders of glycosylation Ia

Purpose: Congenital disorders of glycosylation (CDG) result from mutations in N-glycan biosynthesis. Mutations in phosphomannomutase (PMM2) cause CDG- la. Here, we report four clinically mild patients and their mutations in PM M2. Methods: Analysis of the PMM2 cDNA and gene revealed the mutations affe cting the glycosylation efficiency. Results: The patients have 30% to 50% n ormal PMM activity in fibroblasts due to different mutations in PMM2, and w e studied the effect of each mutation on the PMM activity in a Saccharomyce s cerevisiae expression system. Conclusions: Each patient carried a severe mutation that decreased the PMM activity to less than 10% as well as a rela tively mild mutation. A new mutation, deletion of base 24, changed the read ing frame. The C9Y, C241S, and L32R mutations showed 27% to 45% activity wh en expressed in the eukaryotic expression system, and the more severe D148N was shown to be thermolabile.