Glycobiology Advance Access originally published online on May 18, 2009
Glycobiology 2009 19(8):910-917; doi:10.1093/glycob/cwp067
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Quality control of glycoproteins bearing truncated glycans in an ALG9-defective (CDG-IL) patient
3 Laboratory for Molecular Diagnosis, Center for Human Genetics, University of Leuven, B-3000 Leuven, Belgium
4 Unité de Glycobiologie Structurale et Fonctionnelle UMR/CNRS 8576, IFR147, Université des Sciences et Technologies de Lille, F-59655 Villeneuve d’Ascq, France
5 Center for Metabolic Disease, Department of Pediatrics, University of Leuven, B-3000 Leuven, Belgium
6 Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, OX1 3QU Oxford, UK
1 To whom correspondence should be addressed: Tel: +33-(0)32043-4430; Fax: +33-(0)32043-6555; e-mail: Francois.Foulquier{at}univ-lille1.fr
Received on November 28, 2008; revised on April 9, 2009; accepted on May 10, 2009
We describe an ALG9-defective (congenital disorders of glycosylation type IL) patient who is homozygous for the p.Y286C (c.860A>G) mutation. This patient presented with psychomotor retardation, axial hypotonia, epilepsy, failure to thrive, inverted nipples, hepatomegaly, and pericardial effusion. Due to the ALG9 deficiency, the cells of this patient accumulated the lipid-linked oligosaccharides Man6GlcNAc2-PP-dolichol and Man8GlcNAc2-PP-dolichol. It is known that the oligosaccharide structure has a profound effect on protein glycosylation. Therefore, we investigated the influence of these truncated oligosaccharide structures on the protein transfer efficiency, the quality control of newly synthesized glycoproteins, and the eventual degradation of the truncated glycoproteins formed in this patient. We demonstrated that lipid-linked Man6GlcNAc2 and Man8GlcNAc2 are transferred onto proteins with the same efficiency. In addition, glycoproteins bearing these Man6GlcNAc2 and Man8GlcNAc2 structures efficiently entered in the glucosylation/deglucosylation cycle of the quality control system to assist in protein folding. We also showed that in comparison with control cells, patient's cells degraded misfolded glycoproteins at an increasing rate. The Man8GlcNAc2 isomer C on the patient's glycoproteins was found to promote the degradation of misfolded glycoproteins.
Key words: congenital disorders of glycosylation / ER / quality control / N-glycosylation
2 These authors contributed equally to this work.