A case of fatal Type I congenital disorders of glycosylation (CDG I) associated with low dehydrodolichol diphosphate synthase (DHDDS) activity

Orphanet J Rare Dis. 2016 Jun 24;11(1):84. doi: 10.1186/s13023-016-0468-1.

S Sabry ¹ ² ³ ⁴, S Vuillaumier-Barrot ¹ ² ⁵, E Mintet ¹ ², M Fasseu ¹ ², V Valayannopoulos ⁶, D Héron ⁷ ⁸, N Dorison ⁸, C Mignot ⁷ ⁸ ⁹, N Seta ⁵ ¹⁰, I Chantret ¹ ², T Dupré ¹ ² ⁵, S E H Moore ¹¹ ¹²

Affiliations

1 INSERM U1149, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, Paris, France.
2 Université Denis Diderot, Paris 7, Paris, France.
3 Université Pierre et Marie Curie, Paris 6, Paris, France.
4 Biochemical Genetics Department, Human Genetics Division, National Research Center NRC, Cairo, Egypt.
5 AP-HP, Hôpital Bichat-Claude Bernard, Biochimie, Paris, France.
6 Département de Pédiatrie, AP-HP, Hôpital Necker-Enfants Malades, Paris, France.
7 Département de Génétique & Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital Pitié Salpétrière, Paris, France.
8 Groupe de Recherche Clinique « Déficience Intellectuelle et Autisme » UPMC, Paris, France.
9 Neuropédiatrie, Hôpital Trousseau, Paris, France.
10 Université Paris Descartes, Paris, France.
11 INSERM U1149, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, Paris, France. [email protected].
12 Université Denis Diderot, Paris 7, Paris, France. [email protected].

PMID: 27343064 DOI: 10.1186/s13023-016-0468-1

Abstract

Background: 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.

Results: 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.

Conclusions: 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.

Keywords

Dolichol linked oligosaccharide; Endoplasmic reticulum; Protein N-glycosylation; Retinitis pigmentosa.

Name
Email *

	Sorry, but the email address you supplied was invalid.