Reduced heparan sulfate accumulation in enterocytes contributes to protein-losing enteropathy in a congenital disorder of glycosylation

intestinal biopsy in a boy with gastroenteritis-induced protein-losing ente ropathy (PLE) showed loss of heparan sulfate (HS) and syndecan-1 core prote in from the basolateral surface of the enterocytes, which improved after PL E subsided. Isoelectric focusing analysis of serum transferrin indicated a congenital disorder of glycosylation (CDG) and subsequent analysis showed t hree point mutations in the ALG6 gene encoding an alpha1,3-glucosyltransfer ase needed. for the addition of the first glucose to the dolichol-linked ol igosaccharide. The maternal mutation, C998T, causing an A333V substitution, has been shown to cause CDG-Ic, whereas the two paternal mutations, TS91C (Y131H) and C924A (S308R) have not previously been reported. The mutations were tested for their ability to rescue faulty N-linked glycosylation of ca rboxypeptidase Y in an ALG6-deficient Saccharomyces cerevisiae strain. Norm al human ALG6 rescues glycosylation and A333V partially rescues, whereas th e combined paternal mutations (Y131H and S308R) are ineffective. Underglyco sylation resulting from each of these mutations is much more severe in rapi dly dividing yeast, Similarly, incomplete protein glycosylation in the pati ent is most severe in rapidly dividing enterocytes during gastroenteritis-i nduced stress. Incomplete N-linked glycosylation of an HS core protein and/ or other biosynthetic enzymes may explain the selective localized loss of H S and PLE.