congenital disorders of glycosylation
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2022 ◽  
Author(s):  
Zoé Durin ◽  
Johanne Dubail ◽  
Aurore Layotte ◽  
Dominique Legrand ◽  
Valérie Cormier-Daire ◽  
...  

2021 ◽  
Author(s):  
Giovanna L. Gallo ◽  
Ayelen Valko ◽  
Nathalia Herrera Aguilar ◽  
Ariel D. Weisz ◽  
Cecilia D'Alessio

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.


Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3275
Author(s):  
Zinia D’Souza ◽  
Farhana Taher Sumya ◽  
Amrita Khakurel ◽  
Vladimir Lupashin

The Golgi is the central organelle of the secretory pathway and it houses the majority of the glycosylation machinery, which includes glycosylation enzymes and sugar transporters. Correct compartmentalization of the glycosylation machinery is achieved by retrograde vesicular trafficking as the secretory cargo moves forward by cisternal maturation. The vesicular trafficking machinery which includes vesicular coats, small GTPases, tethers and SNAREs, play a major role in coordinating the Golgi trafficking thereby achieving Golgi homeostasis. Glycosylation is a template-independent process, so its fidelity heavily relies on appropriate localization of the glycosylation machinery and Golgi homeostasis. Mutations in the glycosylation enzymes, sugar transporters, Golgi ion channels and several vesicle tethering factors cause congenital disorders of glycosylation (CDG) which encompass a group of multisystem disorders with varying severities. Here, we focus on the Golgi vesicle tethering and fusion machinery, namely, multisubunit tethering complexes and SNAREs and their role in Golgi trafficking and glycosylation. This review is a comprehensive summary of all the identified CDG causing mutations of the Golgi trafficking machinery in humans.


2021 ◽  
Author(s):  
Hannes E Bülow ◽  
Maisha Rahman ◽  
Nelson J. Ramirez-Suarez ◽  
Carlos A Diaz-Balzac

N-glycans are molecularly diverse sugars borne by over 70% of proteins transiting the secretory pathway and have been implicated in protein folding, stability, and localization. Mutations in genes important for N-glycosylation result in congenital disorders of glycosylation that are often associated with intellectual disability. Here, we show that structurally distinct N-glycans regulate the activity of an extracellular protein complex involved in patterning of somatosensory dendrites in Caenorhabditis elegans. Specifically, aman-2/Golgi alpha-mannosidase II, a conserved key enzyme in the biosynthesis of specific N-glycans regulates the activity of the Menorin adhesion complex without obviously affecting protein stability and localization of its components. AMAN-2 functions cell-autonomously to ensure decoration of the neuronal transmembrane receptor DMA-1/LRR-TM with high-mannose/hybrid N-glycans. Moreover, distinct types of N-glycans on specific N-glycosylation sites regulate the DMA-1/LRR-TM receptor, which together with three other extracellular proteins forms the Menorin adhesion complex. In summary, specific N-glycan structures regulate dendrite patterning by coordinating the activity of an extracellular adhesion complex suggesting that the molecular diversity of N-glycans can contribute to developmental specificity in the nervous system.


2021 ◽  
Vol 12 ◽  
Author(s):  
Julien H. Park ◽  
Thorsten Marquardt

Despite advances in the identification and diagnosis of congenital disorders of glycosylation (CDG), treatment options remain limited and are often constrained to symptomatic management of disease manifestations. However, recent years have seen significant advances in treatment and novel therapies aimed both at the causative defect and secondary disease manifestations have been transferred from bench to bedside. In this review, we aim to give a detailed overview of the available therapies and rising concepts to treat these ultra-rare diseases.


2021 ◽  
Vol 9 ◽  
Author(s):  
Patryk Lipiński ◽  
Anna Tylki-Szymańska

Congenital disorders of glycosylation (CDG) are a group of clinically heterogeneous disorders characterized by defects in the synthesis of glycans and their attachment to proteins and lipids. This manuscript aims to provide a classification of the clinical presentation, diagnostic methods, and treatment of CDG based on the literature review and our own experience (referral center in Poland). A diagnostic algorithm for CDG was also proposed. Isoelectric focusing (IEF) of serum transferrin (Tf) is still the method of choice for diagnosing N-glycosylation disorders associated with sialic acid deficiency. Nowadays, high-performance liquid chromatography, capillary zone electrophoresis, and mass spectrometry techniques are used, although they are not routinely available. Since next-generation sequencing became more widely available, an improvement in diagnostics has been observed, with more patients and novel CDG subtypes being reported. Early and accurate diagnosis of CDG is crucial for timely implementation of appropriate therapies and improving clinical outcomes. However, causative treatment is available only for few CDG types.


Author(s):  
Andreas Hüllen ◽  
Kristina Falkenstein ◽  
Corina Weigel ◽  
Hidde Huidekoper ◽  
Nora Naumann‐Bartsch ◽  
...  

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