title: Guanosine diphosphate-mannose:GlcNAc2-PP-dolichol mannosyltransferase deficiency (congenital disorders of glycosylation type Ik): five new patients and seven novel mutations.
abstract: BACKGROUND
  In type I congenital disorders of glycosylation (CDG I), proteins necessary for the biosynthesis of the lipid-linked oligosaccharide (LLO) required for protein N-glycosylation are defective. A deficiency in guanosine diphosphate-mannose: GlcNAc(2)-PP-dolichol mannosyltransferase-1 (MT-1) causes CDG Ik (OMIM 608540), and only five patients, with severe multisystemic clinical presentations, have been described with this disease. Objective To characterise genetic, biochemical and clinical data in five new CDG Ik cases and compare these findings with those of the five previously described patients. Methods LLO biosynthesis was examined in skin biopsy fibroblasts, mannosyltransferases were assayed in microsomes prepared from these cells, and ALG1-encoding MT-1 was sequenced at the DNA and complementary DNA levels. Clinical data for the five new patients were collated.
  
  
  RESULTS
  Cells from five patients with non-typed CDG I revealed accumulations of GlcNAc(2)-PP-dolichol, the second intermediate in the biosynthesis of LLO. Assay of MT-1, -2 and -3, the first three mannosyltransferases required for extension of this intermediate, demonstrated only MT-1 to be deficient. DNA sequencing of ALG1 revealed nine different mutations, seven of which have not been previously reported. Clinical presentations are severe, with dysmorphias, CNS involvement and ocular disturbances being prevalent.
  
  
  CONCLUSIONS
  5 patients with CDG Ik are described, and their identification reveals that in France, this disease and CDG Ib (mannose phosphate isomerase deficiency: OMIM 602579) are the most frequently diagnosed CDG I after CDG Ia (phosphomannomutase 2 deficiency: OMIM 601785) and substantiate previous observations indicating that this disease presents at the severe end of the CDG I clinical spectrum.
authors.affiliation: Laboratoire Biochimie A, INSERM, 3ème étage de la tour, 46 rue Henri Huchard, 75018 Paris, France. thierry.dupre@bch.aphp.fr
authors.forename: T
authors.initials: T
authors.lastname: Dupré
authors.forename: S
authors.initials: S
authors.lastname: Vuillaumier-Barrot
authors.forename: I
authors.initials: I
authors.lastname: Chantret
authors.forename: H
authors.initials: H
authors.lastname: Sadou Yayé
authors.forename: H S
authors.initials: HS
authors.lastname: Yayé
authors.forename: C
authors.initials: C
authors.lastname: Le Bizec
authors.forename: A
authors.initials: A
authors.lastname: Afenjar
authors.forename: C
authors.initials: C
authors.lastname: Altuzarra
authors.forename: C
authors.initials: C
authors.lastname: Barnérias
authors.forename: L
authors.initials: L
authors.lastname: Burglen
authors.forename: P
authors.initials: P
authors.lastname: de Lonlay
authors.forename: F
authors.initials: F
authors.lastname: Feillet
authors.forename: S
authors.initials: S
authors.lastname: Napuri
authors.forename: N
authors.initials: N
authors.lastname: Seta
authors.forename: S E H
authors.initials: SE
authors.lastname: Moore
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D002675:Child, Preschool; D018981:Congenital Disorders of Glycosylation / Q000145:classification / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D008070:Lipopolysaccharides / Q000096:biosynthesis; D008297:Male; D008364:Mannosyltransferases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D009154:Mutation
chemical_list: D008070:Lipopolysaccharides; C023023:lipid-linked oligosaccharides; D008364:Mannosyltransferases; C035777:chitobiosyldiphosphodolichol beta-mannosyltransferase