A novel fission yeast platform to model N-glycosylation and the bases of congenital disorders of glycosylation Type I

2021 ◽  
Author(s):  
Giovanna L. Gallo ◽  
Ayelen Valko ◽  
Nathalia Herrera Aguilar ◽  
Ariel D. Weisz ◽  
Cecilia D'Alessio
Keyword(s):  
Substrate Specificity ◽  
Schizosaccharomyces Pombe ◽  
Fission Yeast ◽  
Transfer Efficiency ◽  
Congenital Disorders ◽  
Type I ◽  
Congenital Disorders Of Glycosylation ◽  
Mutant Strains ◽  
Molecular Bases ◽  
Single Subunit

Congenital Disorders of Glycosylation Type I (CDG-I) are inherited human diseases caused by deficiencies in lipid-linked oligosaccharide (LLO) synthesis or the glycan transfer to proteins during N-glycosylation. We constructed a platform of 16 Schizosaccharomyces pombe mutant strains that synthesize all possible theoretical combinations of LLOs containing three to zero Glc and nine to five Man. The occurrence of unexpected LLOs suggested the requirement of specific Man residues for glucosyltransferases activities. We then quantified protein hypoglycosylation in each strain and found that in S. pombe the presence of Glc in the LLO is more relevant to the transfer efficiency than the amount of Man residues. Surprisingly, a decrease in the number of Man in glycans somehow improved the glycan transfer. The most severe hypoglycosylation was produced in cells completely lacking Glc and having a high number of Man. This deficiency could be reverted by expressing a single subunit OST with a broad range of substrate specificity. Our work shows the usefulness of this new S. pombe set of mutants as a platform to model the molecular bases of human CDG-I diseases.

scholarly journals A mutation in mannose‐phosphate‐dolichol utilization defect 1 reveals clinical symptoms of congenital disorders of glycosylation type I and dystroglycanopathy

JIMD Reports ◽  
2019 ◽  
Vol 50 (1) ◽  
pp. 31-39
Author(s):  
Walinka Tol ◽  
Angel Ashikov ◽  
Eckhard Korsch ◽  
Nurulamin Abu Bakar ◽  
Michèl A. Willemsen ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Congenital Disorders ◽  
Type I ◽  
Congenital Disorders Of Glycosylation

Elevation of plasma aspartylglucosaminidase is a useful marker for the congenital disorders of glycosylation type I (CDG I)

2005 ◽  
Vol 28 (6) ◽  
pp. 1197-1198 ◽  
Author(s):  
M. Jackson ◽  
P. Clayton ◽  
S. Grunewald ◽  
G. Keir ◽  
K. Mills ◽  
...  
Keyword(s):  
Congenital Disorders ◽  
Type I ◽  
Congenital Disorders Of Glycosylation

scholarly journals Congenital disorders of glycosylation type I leads to altered processing of N-linked glycans, as well as underglycosylation

2001 ◽  
Vol 359 (2) ◽  
pp. 249 ◽  
Author(s):  
Philippa MILLS ◽  
Kevin MILLS ◽  
Peter CLAYTON ◽  
Andrew JOHNSON ◽  
David WHITEHOUSE ◽  
...  
Keyword(s):  
Congenital Disorders ◽  
Type I ◽  
Congenital Disorders Of Glycosylation

scholarly journals Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing

2012 ◽  
Vol 21 (19) ◽  
pp. 4151-4161 ◽  
Author(s):  
Sharita Timal ◽  
Alexander Hoischen ◽  
Ludwig Lehle ◽  
Maciej Adamowicz ◽  
Karin Huijben ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Gene Identification ◽  
Congenital Disorders ◽  
Type I ◽  
Congenital Disorders Of Glycosylation ◽  
Whole Exome

scholarly journals Clinical, biochemical and molecular phenotype of congenital disorders of glycosylation: long-term follow-up

2020 ◽  
Author(s):  
Anna Bogdańska ◽  
Patryk Lipiński ◽  
Paulina Szymańska-Rożek ◽  
Aleksandra Jezela-Stanek ◽  
Dariusz Rokicki ◽  
...  
Keyword(s):  
Failure To Thrive ◽  
Congenital Disorders ◽  
Type I ◽  
Congenital Disorders Of Glycosylation ◽  
Diagnostic Features ◽  
Strong Negative Correlation ◽  
Single Centre Study ◽  
Long Term Follow Up

Abstract Background: Congenital disorders of glycosylation (CDG) result from defects in the synthesis of glycans and the attachment of glycans to proteins and lipids. Our study aimed to describe the clinical, biochemical and molecular findings of CDG patients, and to present the long-term follow-up. Material and methods: A single-centre study (1995-2019 years) of patients with congenital disorders of N-glycosylation and combined N- and O-hypoglycosylation, diagnosed based on the serum transferrin (Tf) and apolipoprotein C-III (apoC-III) isoforms analysis, and confirmed molecularly, was performed. Results: Among 32 patients included into the study, 24 had type I Tf isoform profile, in 12 of them deficient PMM2 activity was detected. Three patients were diagnosed with ALG13-CDG; serum Tf isoform profile was normal in one of them, in one other was indicative for type I. Four patients had type II Tf isoform profile. The phenotypic and genotypic spectrum of 32 patients with CDG during long-term (in some cases over 20 years) observation was characterised and several measurements of serum Tf isoforms taken. Statistical analysis revealed strong negative correlation between Asialo-Tf and Tetrasialo-Tf, as well as between Disialo-Tf and Tetrasialo-Tf. Positive correlation was shown between Tetrasialo-Tf and Penasialo-Tf. Within type I CDG, no difference in % Tf isoforms was revealed between PMM2-CDG and non-PMM2-CDG patients. However, these two groups differed significantly in the such diagnostic features as: cerebellar ataxia, failure to thrive, hypothyroidism, pericardial effusion, cardiomyopathy, inverted nipples, prolonged INR. The effect of treatment with mannose in 2 patients with MPI-CDG were assesed and we found that % of Asialo-Tf, Monosialo-Tf, and Disialo-Tf was significanty lowered, whereas Tetrasialo- Tf and Pentasialo-Tf rose, coming closer or falling into the reference range. Conclusions: The novel finding was an abnormal Tf IEF pattern in two ALG13-CDG patients and normal in one ALG1-CDG patient. Clinical manifestation of presented CDG patients was similar to that reported in the literature. Mannose supplementation in MPI-CDG patients, as well as galactose supplementation in PGM-CDG patient improved patients’ clinical picture and Tf isoform profiles.

scholarly journals A Novel N-Tetrasaccharide in Patients with Congenital Disorders of Glycosylation, Including Asparagine-Linked Glycosylation Protein 1, Phosphomannomutase 2, and Mannose Phosphate Isomerase Deficiencies

2016 ◽  
Vol 62 (1) ◽  
pp. 208-217 ◽  
Author(s):  
Wenyue Zhang ◽  
Philip M James ◽  
Bobby G Ng ◽  
Xueli Li ◽  
Baoyun Xia ◽  
...  
Keyword(s):  
Diagnostic Marker ◽  
Alternative Pathway ◽  
Biological Significance ◽  
Congenital Disorders ◽  
Type I ◽  
Congenital Disorders Of Glycosylation ◽  
Cell Lysate ◽  
Cultured Skin ◽  
Phosphomannomutase 2

Abstract BACKGROUND Primary deficiencies in mannosylation of N-glycans are seen in a majority of patients with congenital disorders of glycosylation (CDG). We report the discovery of a series of novel N-glycans in sera, plasma, and cultured skin fibroblasts from patients with CDG having deficient mannosylation. METHOD We used LC-MS/MS and MALDI-TOF-MS analysis to identify and quantify a novel N-linked tetrasaccharide linked to the protein core, an N-tetrasaccharide (Neu5Acα2,6Galβ1,4-GlcNAcβ1,4GlcNAc) in plasma, serum glycoproteins, and a fibroblast lysate from patients with CDG caused by ALG1 [ALG1 (asparagine-linked glycosylation protein 1), chitobiosyldiphosphodolichol β-mannosyltransferase], PMM2 (phosphomannomutase 2), and MPI (mannose phosphate isomerase). RESULTS Glycoproteins in sera, plasma, or cell lysate from ALG1-CDG, PMM2-CDG, and MPI-CDG patients had substantially more N-tetrasaccharide than unaffected controls. We observed a >80% decline in relative concentrations of the N-tetrasaccharide in MPI-CDG plasma after mannose therapy in 1 patient and in ALG1-CDG fibroblasts in vitro supplemented with mannose. CONCLUSIONS This novel N-tetrasaccharide could serve as a diagnostic marker of ALG1-, PMM2-, or MPI-CDG for screening of these 3 common CDG subtypes that comprise >70% of CDG type I patients. Its quantification by LC-MS/MS may be useful for monitoring therapeutic efficacy of mannose. The discovery of these small N-glycans also indicates the presence of an alternative pathway in N-glycosylation not recognized previously, but its biological significance remains to be studied.

Congenital disorders of glycosylation type I leads to altered processing of N-linked glycans, as well as underglycosylation

2001 ◽  
Vol 359 (2) ◽  
pp. 249-254 ◽  
Author(s):  
Philippa MILLS ◽  
Kevin MILLS ◽  
Peter CLAYTON ◽  
Andrew JOHNSON ◽  
David WHITEHOUSE ◽  
...  
Keyword(s):  
Congenital Disorders ◽  
Type I ◽  
Congenital Disorders Of Glycosylation ◽  
Normal Controls

The N-linked glycans on transferrin and α1-antitrypsin from patients with congenital disorders of glycosylation type I have increased fucosylation and branching relative to normal controls. The elevated levels of monofucosylated biantennary glycans are probably due to increased α-(1 → 6) fucosylation. The presence of bi- and trifucosylated triantennary and tetra-antennary glycans indicated that peripheral α-(1 → 3), as well as core α-(1 → 6), fucosylation is increased. Altered processing was observed on both the fully and underglycosylated glycoforms.

Sign in / Sign up

Export Citation Format

Share Document