Human Molecular Genetics, 2002, Vol. 11, No. 5 599-604
© 2002 Oxford University Press
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
The Burnham Institute, Glycobiology Program, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA, 1Department of Clinical Genetics, University Hospital Rigshospitalet, Copenhagen, Denmark, 2Center for Human Genetics, University of Leuven, Leuven, Belgium and 3Center for Metabolic Medicine, Great Ormond Street Hospital for Sick Children, Great Ormond Street, London WC1N 3JH, UK
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 
1,3 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.
+ To whom correspondence should be addressed. Tel: +1 858 646 3142; Fax: +1 858 713 6281; Email: hudson@burnham.org Present address: Vibeke Westphal, Novo Nordisk, Novo Allé 6As.068, DK-2880 Bagsvaerd, Denmark