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Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie.

ABSTRACT: Congenital disorders of glycosylation (CDG), formerly known as carbohydrate-deficient glycoprotein syndromes, lead to diseases with variable clinical pictures. We report the delineation of a novel type of CDG identified in 2 children presenting with severe developmental delay, seizures, and dysmorphic features. We detected hypoglycosylation on serum transferrin and cerebrospinal fluid beta-trace protein. Lipid-linked oligosaccharides in the endoplasmic reticulum of patient fibroblasts showed an accumulation of the dolichyl pyrophosphate Man(5)GlcNAc(2) structure, compatible with the reduced dolichol-phosphate-mannose synthase (DolP-Man synthase) activity detected in these patients. Accordingly, 2 mutant alleles of the DolP-Man synthase DPM1 gene, 1 with a 274C>G transversion, the other with a 628delC deletion, were detected in both siblings. Complementation analysis using DPM1-null murine Thy1-deficient cells confirmed the detrimental effect of both mutations on the enzymatic activity. Furthermore, mannose supplementation failed to improve the glycosylation status of DPM1-deficient fibroblast cells, thus precluding a possible therapeutic application of mannose in the patients. Because DPM1 deficiency, like other subtypes of CDG-I, impairs the assembly of N-glycans, this novel glycosylation defect was named CDG-Ie.

SUBMITTER: Imbach T

PROVIDER: S-EPMC377434 | biostudies-literature | 2000 Jan

REPOSITORIES: biostudies-literature

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Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie.

Imbach T T Schenk B B Schollen E E Burda P P Stutz A A Grunewald S S Bailie N M NM King M D MD Jaeken J J Matthijs G G Berger E G EG Aebi M M Hennet T T

The Journal of clinical investigation 20000101 2

Congenital disorders of glycosylation (CDG), formerly known as carbohydrate-deficient glycoprotein syndromes, lead to diseases with variable clinical pictures. We report the delineation of a novel type of CDG identified in 2 children presenting with severe developmental delay, seizures, and dysmorphic features. We detected hypoglycosylation on serum transferrin and cerebrospinal fluid beta-trace protein. Lipid-linked oligosaccharides in the endoplasmic reticulum of patient fibroblasts showed an ...[more]

PMID: 10642602

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Project description:N-glycans provide structural and functional stability to asparagine-linked (N-linked) glycoproteins, and add flexibility. Glycan biosynthesis is elaborative, multi-compartmental and involves many glycosyltransferases. Failure to assemble N-glycans leads to phenotypic changes developing infection, cancer, congenital disorders of glycosylation (CDGs) among others. Biosynthesis of N-glycans begins at the endoplasmic reticulum (ER) with the assembly of dolichol-linked tetra-decasaccharide (Glc3Man9GlcNAc2-PP-Dol) where dolichol phosphate mannose synthase (DPMS) plays a central role. DPMS is also essential for GPI anchor biosynthesis as well as for O- and C-mannosylation of proteins in yeast and in mammalian cells. DPMS has been purified from several sources and its gene has been cloned from 39 species (e.g., from protozoan parasite to human). It is an inverting GT-A folded enzyme and classified as GT2 by CAZy (carbohydrate active enZyme; http://www.cazy.org ). The sequence alignment detects the presence of a metal binding DAD signature in DPMS from all 39 species but finds cAMP-dependent protein phosphorylation motif (PKA motif) in only 38 species. DPMS also has hydrophobic region(s). Hydropathy analysis of amino acid sequences from bovine, human, S. crevisiae and A. thaliana DPMS show PKA motif is present between the hydrophobic domains. The location of PKA motif as well as the hydrophobic domain(s) in the DPMS sequence vary from species to species. For example, the domain(s) could be located at the center or more towards the C-terminus. Irrespective of their catalytic similarity, the DNA sequence, the amino acid identity, and the lack of a stretch of hydrophobic amino acid residues at the C-terminus, DPMS is still classified as Type I and Type II enzyme. Because of an apparent bio-sensing ability, extracellular signaling and microenvironment regulate DPMS catalytic activity. In this review, we highlight some important features and the molecular diversities of DPMS.

Project description:We report the case of a 2-year-old girl who was diagnosed with Mannose-6-phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) and provide a review of the relevant literature. The young girl presented with recurrent unexplained diarrhea, vomiting, hypoproteinemia, and elevated liver transaminases. Whole-exome sequencing revealed that the patient had compound heterozygous mutations in the MPI gene (NM_0024). An exon 4 (c.455G > T, p.R152l) mutation was inherited from the mother and an exon 7 (c.884G > A, p.R295H) mutation from the father. One week after the start of mannose treatment, the vomiting and diarrhea symptoms disappeared completely and did not show any side effects. We also provide a brief review of the relevant literature. Including the present case, a total of 52 patients from hospitals across 17 countries were diagnosed with MPI-CDG. Age at disease onset ranged from birth to 15 years, with an onset under 2 years in most patients (43/50). Overall, patients presented with at least one or more of the following symptoms: chronic diarrhea (41/46), vomiting (23/27), hepatomegaly (39/44), hepatic fibrosis (20/37), protein-losing enteropathy (30/36), elevated serum transaminases (24/34), hyperinsulinemic-hypoglycemia (24/34), hypoalbuminemia (33/38), prolonged coagulation (26/30), splenomegaly (13/21), non-pitting edema (14/20), failure to thrive (13/36), portal hypertension (4/9), epilepsy (2/17), thrombosis (12/14), and abnormally elevated leukocytes (5). None of the patients was reported to have an intellectual disability (0/28). The majority of patients (26/30) showed clinical symptoms, and laboratory results improved after oral mannose administration. Our findings suggest that MPI-CDG should be considered in children with unexplained recurrent digestive and endocrine systems involvement, and gene examination should be performed immediately to obtain a definite diagnosis in order to begin treatment in a timely manner.

Dataset Information

Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie.

Publications

Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie.

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