Glycobiology Advance Access published online on May 18, 2009
Glycobiology, doi:10.1093/glycob/cwp067
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Quality control of glycoproteins bearing truncated glycans in an ALG9 defective (CDG-IL) patient
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1 Laboratory for Molecular Diagnosis, Center for Human Genetics, University of Leuven, B-3000 Leuven, Belgium
2 Unité de Glycobiologie Structurale et Fonctionnelle UMR/CNRS 8576, IFR147, Université des Sciences et Technologies de Lille, F-59655 Villeneuve d’Ascq, France
3 Center for Metabolic Disease, Department of Pediatrics, University of Leuven, B-3000 Leuven, Belgium
4 Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, OX1 3QU Oxford, UK
* To whom correspondence should be addressed: Tel: +33 (0)32043 4430; Fax: +33 (0)32043 6555; Email: Francois.Foulquier{at}univ-lille1.fr
Received on November 28, 2008; 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 to control cells, patient's cells degraded misfolded glycoproteins at an increasing rate. In comparison to Man6GlcNAc2, the Man8GlcNAc2 isomer C on the patient's glycoproteins was found to promote the degradation of misfolded glycoproteins.
Key words: Congenital Disorders of Glycosylation / N-glycosylation / ER quality control
These authors contributed equally to this work.