title: A case of fatal Type I congenital disorders of glycosylation (CDG I) associated with low dehydrodolichol diphosphate synthase (DHDDS) activity.
abstract: Type I congenital disorders of glycosylation (CDG-I) are mostly complex multisystemic diseases associated with hypoglycosylated serum glycoproteins. A subgroup harbour mutations in genes necessary for the biosynthesis of the dolichol-linked oligosaccharide (DLO) precursor that is essential for protein N-glycosylation. Here, our objective was to identify the molecular origins of disease in such a CDG-Ix patient presenting with axial hypotonia, peripheral hypertonia, enlarged liver, micropenis, cryptorchidism and sensorineural deafness associated with hypo glycosylated serum glycoproteins.
  
  
  
  Targeted sequencing of DNA revealed a splice site mutation in intron 5 and a non-sense mutation in exon 4 of the dehydrodolichol diphosphate synthase gene (DHDDS). Skin biopsy fibroblasts derived from the patient revealed ~20 % residual DHDDS mRNA, ~35 % residual DHDDS activity, reduced dolichol-phosphate, truncated DLO and N-glycans, and an increased ratio of [2-(3)H]mannose labeled glycoprotein to [2-(3)H]mannose labeled DLO. Predicted truncated DHDDS transcripts did not complement rer2-deficient yeast. SiRNA-mediated down-regulation of DHDDS in human hepatocellular carcinoma HepG2 cells largely mirrored the biochemical phenotype of cells from the patient. The patient also harboured the homozygous ALG6(F304S) variant, which does not cause CDG but has been reported to be more frequent in PMM2-CDG patients with severe/fatal disease than in those with moderate presentations. WES did not reveal other strong candidate causal genes.
  
  
  
  We describe a patient presenting with severe multisystem disease associated with DHDDS deficiency. As retinitis pigmentosa is the only clinical sign in previously reported cases, this report broadens the spectrum of phenotypes associated with this condition.
authors.affiliation: INSERM U1149, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, Paris, France.|Université Denis Diderot, Paris 7, Paris, France.|Université Pierre et Marie Curie, Paris 6, Paris, France.|Biochemical Genetics Department, Human Genetics Division, National Research Center NRC, Cairo, Egypt.
authors.forename: S
authors.initials: S
authors.lastname: Sabry
authors.affiliation: INSERM U1149, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, Paris, France.|Université Denis Diderot, Paris 7, Paris, France.|AP-HP, Hôpital Bichat-Claude Bernard, Biochimie, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Vuillaumier-Barrot
authors.affiliation: INSERM U1149, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, Paris, France.|Université Denis Diderot, Paris 7, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Mintet
authors.affiliation: INSERM U1149, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, Paris, France.|Université Denis Diderot, Paris 7, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Fasseu
authors.affiliation: Département de Pédiatrie, AP-HP, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Valayannopoulos
authors.affiliation: Département de Génétique & Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital Pitié Salpétrière, Paris, France.|Groupe de Recherche Clinique « Déficience Intellectuelle et Autisme » UPMC, Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Héron
authors.affiliation: Groupe de Recherche Clinique « Déficience Intellectuelle et Autisme » UPMC, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Dorison
authors.affiliation: Département de Génétique & Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital Pitié Salpétrière, Paris, France.|Groupe de Recherche Clinique « Déficience Intellectuelle et Autisme » UPMC, Paris, France.|Neuropédiatrie, Hôpital Trousseau, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Mignot
authors.affiliation: AP-HP, Hôpital Bichat-Claude Bernard, Biochimie, Paris, France.|Université Paris Descartes, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Seta
authors.affiliation: INSERM U1149, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, Paris, France.|Université Denis Diderot, Paris 7, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Chantret
authors.affiliation: INSERM U1149, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, Paris, France.|Université Denis Diderot, Paris 7, Paris, France.|AP-HP, Hôpital Bichat-Claude Bernard, Biochimie, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Dupré
authors.affiliation: INSERM U1149, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, Paris, France. stuart.moore@inserm.fr.|Université Denis Diderot, Paris 7, Paris, France. stuart.moore@inserm.fr.
authors.forename: S E H
authors.initials: SE
authors.lastname: Moore
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D002855:Chromatography, Thin Layer; D018981:Congenital Disorders of Glycosylation / Q000097:blood / Q000201:enzymology* / Q000378:metabolism; D004286:Dolichols / Q000031:analogs & derivatives / Q000378:metabolism; D005091:Exons / Q000235:genetics; D006023:Glycoproteins / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D006031:Glycosylation; D056945:Hep G2 Cells; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D009844:Oligosaccharides / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012867:Skin / Q000378:metabolism
chemical_list: D004286:Dolichols; D006023:Glycoproteins; D009844:Oligosaccharides; D011134:Polysaccharides; D034741:RNA, Small Interfering; C079181:dehydrodolichol; D019883:Alkyl and Aryl Transferases; C051389:dehydrodolichyl diphosphate synthetase
keywords: Dolichol linked oligosaccharide; Endoplasmic reticulum; Protein N-glycosylation; Retinitis pigmentosa