title: RFT1 deficiency in three novel CDG patients.
abstract: The medical significance of N-glycosylation is underlined by a group of inherited human disorders called Congenital Disorders of Glycosylation (CDG). One key step in the biosynthesis of the Glc(3)Man(9)GlcNAc(2)-PP-dolichol precursor, essential for N-glycosylation, is the translocation of Man(5)GlcNAc(2)-PP-dolichol across the endoplasmic reticulum membrane. This step is facilitated by the RFT1 protein. Recently, the first RFT1-deficient CDG (RFT1-CDG) patient was identified and presented a severe N-glycosylation disorder. In the present study, we describe three novel CDG patients with an RFT1 deficiency. The first patient was homozygous for the earlier reported RFT1 missense mutation (c.199C>T; p.R67C), whereas the two other patients were homozygous for the missense mutation c.454A>G (p.K152E) and c.892G>A (p.E298 K), respectively. The pathogenic character of the novel mutations was illustrated by the accumulation of Man(5)GlcNAc(2)-PP-dolichol and by reduced recombinant DNase 1 secretion. Both the glycosylation pattern and recombinant DNase 1 secretion could be normalized by expression of normal RFT1 cDNA in the patients' fibroblasts. The clinical phenotype of these patients comprised typical CDG symptoms in addition to sensorineural deafness, rarely reported in CDG patients. The identification of additional RFT1-deficient patients allowed to delineate the main clinical picture of RFT1-CDG and confirmed the crucial role of RFT1 in Man(5)GlcNAc(2)-PP-dolichol translocation.
authors.affiliation: Laboratory for Molecular Diagnosis, Center for Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: Wendy
authors.initials: W
authors.lastname: Vleugels
authors.forename: Micha A
authors.initials: MA
authors.lastname: Haeuptle
authors.forename: Bobby G
authors.initials: BG
authors.lastname: Ng
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Michalski
authors.forename: Roberta
authors.initials: R
authors.lastname: Battini
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.forename: Mark D
authors.initials: MD
authors.lastname: Ludman
authors.forename: Jaak
authors.initials: J
authors.lastname: Jaeken
authors.forename: François
authors.initials: F
authors.lastname: Foulquier
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.forename: Thierry
authors.initials: T
authors.lastname: Hennet
mesh_terms: D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005816:Genetic Complementation Test; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D010641:Phenotype
chemical_list: D008562:Membrane Glycoproteins; C486729:RFT1 protein, human
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