title: A new intronic mutation in the DPM1 gene is associated with a milder form of CDG Ie in two French siblings.
abstract: Congenital disorders of glycosylation (CDG) type I (CDG I) are rare autosomal recessive diseases caused by deficiencies in the assembly of the dolichol-linked oligosaccharide (DLO) that is required for N-glycoprotein biosynthesis. CDG Ie is due to a defect in the synthesis of dolichyl-phosphoryl-mannose (Dol-P-Man), which is needed for DLO biosynthesis as well as for other glycosylation pathways. Human Dol-P-Man synthase is a heterotrimeric complex composed of DPM1p, DPM2p, and DPM3p, with DPM1p being the catalytic subunit. Here, we report two new CDG Ie patients who present milder symptoms than the five other CDG Ie patients described to date. The clinical pictures of the patients MS and his sister MT are dominated by major ataxia, with no notable hepatic involvement. MS cells accumulate the immature DLO species Dol-PP-GlcNAc2Man5 and possess only residual Dol-P-Man synthase activity. One homozygous intronic mutation, g.IVS4-5T>A, was found in the DPM1 gene, leading to exon skipping and transcription of a shortened transcript. Moreover, DPM1 expression was reduced by more than 90% in MS cells, in a nonsense-mediated mRNA decay (NMD)-independent manner. Full analysis of the DPM2 and DPM3 genes revealed a decrease in DPM2 expression and normal expression of DPM3. This description emphasizes the large spectrum of symptoms characterizing CDG I patients.
authors.affiliation: INSERM U 504, Villejuif 94807, France. Julia.G.J.Dancourt@Dartmouth.edu
authors.forename: Julia
authors.initials: J
authors.lastname: Dancourt
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vuillaumier-Barrot
authors.forename: Helene Ogier
authors.initials: HO
authors.lastname: de Baulny
authors.forename: Ignacio
authors.initials: I
authors.lastname: Sfaello
authors.forename: Anne
authors.initials: A
authors.lastname: Barnier
authors.forename: Christianne
authors.initials: C
authors.lastname: le Bizec
authors.forename: Thierry
authors.initials: T
authors.lastname: Dupre
authors.forename: Genevieve
authors.initials: G
authors.lastname: Durand
authors.forename: Nathalie
authors.initials: N
authors.lastname: Seta
authors.forename: Stuart E H
authors.initials: SE
authors.lastname: Moore
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D015153:Blotting, Western; D002675:Child, Preschool; D018981:Congenital Disorders of Glycosylation / Q000175:diagnosis / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D006031:Glycosylation; D006801:Humans; D007438:Introns; D008297:Male; D008364:Mannosyltransferases / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D035781:Siblings
chemical_list: D017931:DNA Primers; D008364:Mannosyltransferases; C022755:dolichyl-phosphate beta-D-mannosyltransferase