Functional significance of PMM2 mutations in mildly affected patients with congenital 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 PMM2. Methods: Analysis of the PMM2 cDNA and gene revealed the mutations affecting the glycosylation efficiency. Results: The patients have 30% to 50% normal PMM activity in fibroblasts due to different mutations in PMM2, and we studied the effect of each mutation on the PMM activity in a Saccharomyces cerevisiae expression system. Conclusions: Each patient carried a severe mutation that decreased the PMM activity to less than 10% as well as a relatively mild mutation. A new mutation, deletion of base 24, changed the reading frame. The C9Y, C241S, and L32R mutations showed 27% to 45% activity when expressed in the eukaryotic expression system, and the more severe D148N was shown to be thermolabile.