A frequent mild mutation in ALG6 may exacerbate the clinical severity of patients with congenital disorder of glycosylation Ia (CDG-Ia) caused by phosphomannomutase deficiency

Single nucleotide polymorphisms occur throughout the human genome. A gene that causes one of the congenital disorders of glycosylation (CDG) has a mutation (911T→C) that changes a phenylalanine to serine at position 304 (F304S) of the α1,3 glucosyl transferase. We show that this change reduces the ability of the gene product to rescue defective glycosylation of an alg6-deficient strain of Saccharomyces cerevisiae during rapid growth. This finding suggested that the mutation might affect glycosylation in humans. We therefore compared the frequency of this variant in 301 controls and in 101 CDG patients who carry known mutations in other genes involved in CDG, i.e. PMM2 (CDG-Ia; 91 patients) and MPI (CDG-Ib; 10 patients). The variant allele frequency is identical in both CDG patients (0.30) and controls (0.28). Importantly, the F304S genotype frequency in 55 CDG-Ia patients classified as mild/moderate (n = 28), or severe (n = 27) was significantly higher in severely affected patients (0.41) than in mild/moderately affected patients (0.21). Mortality (n = 9) was higher when F304S was present (n = 6). Severely affected patients with the PMM2 mutations F119L/R141H (n = 22) carry the F304S mutation more often (0.36) than mildly affected patients (0.18, n = 11) with this mutation. Clinical severity of mildly affected sibs with the same PMM2 mutations did not correlate with F304S genotype. Thus, the presence of the F304S allele may exacerbate the clinical outcome, especially in severely affected CDG patients. We speculate that this type of variant may be implicated in other multi-factorial disorders that involve N-glycosylation.