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MPDU1 mutations underlie a novel human congenital disorder of glycosylation, designated type If
Barbara Schenk, … , Thierry Hennet, Markus Aebi
Barbara Schenk, … , Thierry Hennet, Markus Aebi
Published December 1, 2001
Citation Information: J Clin Invest. 2001;108(11):1687-1695. https://doi.org/10.1172/JCI13419.
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Article

MPDU1 mutations underlie a novel human congenital disorder of glycosylation, designated type If

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Abstract

Deficiencies in the pathway of N-glycan biosynthesis lead to severe multisystem diseases, known as congenital disorders of glycosylation (CDG). The clinical appearance of CDG is variable, and different types can be distinguished according to the gene that is altered. In this report, we describe the molecular basis of a novel type of the disease in three unrelated patients diagnosed with CDG-I. Serum transferrin was hypoglycosylated and patients’ fibroblasts accumulated incomplete lipid-linked oligosaccharide precursors for N-linked protein glycosylation. Transfer of incomplete oligosaccharides to protein was detected. Sequence analysis of the Lec35/MPDU1 gene, known to be involved in the use of dolichylphosphomannose and dolichylphosphoglucose, revealed mutations in all three patients. Retroviral-based expression of the normal Lec35 cDNA in primary fibroblasts of patients restored normal lipid-linked oligosaccharide biosynthesis. We concluded that mutations in the Lec35/MPDU1 gene cause CDG. This novel type was termed CDG-If.

Authors

Barbara Schenk, Timo Imbach, Christian G. Frank, Claudia E. Grubenmann, Gerald V. Raymond, Haggit Hurvitz, Annick Raas-Rotschild, Anthony S. Luder, Jaak Jaeken, Eric G. Berger, Gert Matthijs, Thierry Hennet, Markus Aebi

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Figure 1

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(a) Isoelectric focusing of serum transferrin. Data from two different e...
(a) Isoelectric focusing of serum transferrin. Data from two different experiments are shown. The number of negative charges (sialic acid residues) is given at the left. Transferrin from healthy control individuals (lanes 1 and 5), from CDG-1a patients (lanes 2 and 7), from patient L (lane 3), patient A (lane 4), and patient S (lane 6) was analyzed. (b–d) Analysis of LLOs in CDG patients, control subjects, and yeast cells. Metabolically labeled LLOs were isolated from wild-type yeast cells (standard), ALG3-deficient yeast cells overexpressing the ALG6 locus (Δalg3 + pALG6), and fibroblasts derived from patient S (b), patient A (c), and patient L (d). [3H]oligosaccharides were released by mild acid hydrolysis and analyzed by HPLC. Elution was monitored by a radiodetector. The elution positions of Glc3Man9GlcNAc2 (G3M9), Man9GlcNAc2 (M9), Man8GlcNAc2 (M8), Man5GlcNAc2 (M5), and Glc3Man5GlcNAc2 (G3M5) are indicated.

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