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J. Biol. Chem., Vol. 278, Issue 11, 9962-9971, March 14, 2003

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A Deficiency in Dolichyl-P-glucose:Glc₁Man₉GlcNAc₂-PP-dolichyl 3-Glucosyltransferase Defines a New Subtype of Congenital Disorders of Glycosylation^*

Isabelle Chantret^§, Julia Dancourt, Thierry Dupré^§¶, Christophe Delenda, Stéphanie Bucher, Sandrine Vuillaumier-Barrot^§¶, Hélène Ogier de Baulny^§**, Céline Peletan^**, Olivier Danos, Nathalie Seta^§¶, Geneviève Durand^§¶, Rafael Oriol^§, Patrice Codogno^§, and Stuart E. H. Moore^§

From the  Unité de Glycobiologie et Signalisation Cellulaire, INSERM, U504, Bâtiment INSERM, 16 Avenue Paul Vaillant-Couturier, 94807 Villejuif, ^¶ Biochimie A, Hôpital Bichat, and  Généthon III, CNRS, URA 1923 1 Bis Rue de l'Internationale, 91002 Evry Cedex, and ^** Hôpital Robert Debré, Assistance Publique Hôpitaux de Paris, 75004 Paris, France

The underlying causes of type I congenital disorders of glycosylation (CDG I) have been shown to be mutations in genes encoding proteins involved in the biosynthesis of the dolichyl-linked oligosaccharide (Glc₃Man₉GlcNAc₂-PP-dolichyl) that is required for protein glycosylation. Here we describe a CDG I patient displaying gastrointestinal problems but no central nervous system deficits. Fibroblasts from this patient accumulate mainly Man₉GlcNAc₂-PP-dolichyl, but in the presence of castanospermine, an endoplasmic reticulum glucosidase inhibitor Glc₁Man₉GlcNAc₂-PP-dolichyl predominates, suggesting inefficient addition of the second glucose residue onto lipid-linked oligosaccharide. Northern blot analysis revealed the cells from the patient to possess only 10-20% normal amounts of mRNA encoding the enzyme, dolichyl-P-glucose:Glc₁Man₉GlcNAc₂-PP-dolichyl 3-glucosyltransferase (hALG8p), which catalyzes this reaction. Sequencing of hALG8 genomic DNA revealed exon 4 to contain a base deletion in one allele and a base insertion in the other. Both mutations give rise to premature stop codons predicted to generate severely truncated proteins, but because the translation inhibitor emetine was shown to stabilize the hALG8 mRNA from the patient to normal levels, it is likely that both transcripts undergo nonsense-mediated mRNA decay. As the cells from the patient were successfully complemented with wild type hALG8 cDNA, we conclude that these mutations are the underlying cause of this new CDG I subtype that we propose be called CDG Ih.

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