Congenital disorders of glycosylation Jaeken, Jaak
Annals of the New York Academy of Sciences,
December 2010, Letnik:
1214, Številka:
1
Journal Article
Recenzirano
Congenital (genetic) disorders of glycosylation (CDG) are a rapidly growing disease family, with some 45 members reported since its first clinical description in 1980. Most of these are protein ...hypoglycosylation diseases, but recently three defects in lipid glycosylation have been identified. Most protein hypoglycosylation diseases are due to defects in the N‐glycosylation pathway (16 diseases). The remaining ones affect the O‐glycosylation pathway (8 diseases), both the N‐ and the O‐glycosylation pathways, or other pathways (17 diseases). CDG can affect nearly all organs and systems, but there is often an important neurological component. The first‐line screening for the N‐glycosylation diseases is serum transferrin isoelectrofocusing (IEF), and for the O‐glycosylation disorders apo CIII IEF. It has to be stressed that a normal test result does by no means exclude a CDG. In case of an abnormal result and as long as the basic defect has not been elucidated, the disease is labeled CDG‐x (CDG‐Ix when the transferrin IEF shows a type 1 pattern, and CDG‐IIx when it shows a type 2 pattern).
Nearly 70 inherited human glycosylation disorders span a breathtaking clinical spectrum, impacting nearly every organ system and launching a family-driven diagnostic odyssey. Advances in genetics, ...especially next generation sequencing, propelled discovery of many glycosylation disorders in single and multiple pathways. Interpretation of whole exome sequencing results, insights into pathological mechanisms, and possible therapies will hinge on biochemical analysis of patient-derived materials and animal models. Biochemical diagnostic markers and readouts offer a physiological context to confirm candidate genes. Recent discoveries suggest novel perspectives for textbook biochemistry and novel research opportunities. Basic science and patients are the immediate beneficiaries of this bidirectional collaboration.
Congenital disorders of glycosylation (CDG) are a rapidly expanding group of metabolic disorders that result from abnormal protein or lipid glycosylation. They are often difficult to clinically ...diagnose because they broadly affect many organs and functions and lack clinical uniformity. However, recent technological advances in next-generation sequencing have revealed a treasure trove of new genetic disorders, expanded the knowledge of known disorders, and showed a critical role in infectious diseases. More comprehensive genetic tools specifically tailored for mammalian cell-based models have revealed a critical role for glycosylation in pathogen–host interactions, while also identifying new CDG susceptibility genes. We highlight recent advancements that have resulted in a better understanding of human glycosylation disorders, perspectives for potential future therapies, and mysteries for which we continue to seek new insights and solutions.
Over 125 congenital disorders of glycosylation (CDG) are clinically diverse and cover all major glycosylation pathways.
Next-generation sequencing (NGS) enabled discovery of over 51 novel glycosylation disorders and identified de novo mutations in several disorders.
Complex genetic screening of human cells shows glycosylation is critical for many pathogens, especially viruses. Targeting glycosylation pathways could become a short-term treatment.
Simple monosaccharide therapies and novel chemical approaches offer treatments for several glycosylation disorders.
Congenital disorders of glycosylation: Still “hot” in 2020 Ondruskova, Nina; Cechova, Anna; Hansikova, Hana ...
Biochimica et biophysica acta. General subjects,
January 2021, 2021-01-00, 20210101, Letnik:
1865, Številka:
1
Journal Article
Recenzirano
Congenital disorders of glycosylation (CDG) are inherited metabolic diseases caused by defects in the genes important for the process of protein and lipid glycosylation. With the ever growing number ...of the known subtypes and discoveries regarding the disease mechanisms and therapy development, it remains a very active field of study.
This review brings an update on the CDG-related research since 2017, describing the novel gene defects, pathobiomechanisms, biomarkers and the patients' phenotypes. We also summarize the clinical guidelines for the most prevalent disorders and the current therapeutical options for the treatable CDG.
In the majority of the 23 new CDG, neurological involvement is associated with other organ disease. Increasingly, different aspects of cellular metabolism (e.g., autophagy) are found to be perturbed in multiple CDG.
This work highlights the recent trends in the CDG field and comprehensively overviews the up-to-date clinical recommendations.
•Over 20 novel CDG have been discovered in the last three years, making a total of 137.•A marked rise is seen in the number of GPI anchor synthesis defects.•A more or less effective therapy is now available for 12 CDG.•A glycosylation defect is often linked to (a) complex cellular perturbance(s).
The survey summarizes in its first part the current status of knowledge on the Congenital Disorders of Glycosylation (CDG) with regard to their phenotypic spectrum, diagnostic and therapeutic ...strategies, and pathophysiology. It documents the clinical and basic research activities, and efforts to involve patients and their families. In the second part, it tries to look into the future of CDG. More specific biomarkers are needed for fast CDG diagnosis and treatment monitoring. Whole genome sequencing will play an increasingly important role in the molecular diagnosis of unsolved CDG. Epigenetic defects are expected to join the rapidly expanding genetic and allelic heterogeneity of the CDG family. Novel treatments are urgently needed particularly for PMM2-CDG, the most prevalent CDG. Patient services such as apps should be developed e.g. to document the natural history and monitor treatment. Networking (EURO-CDG, the European Reference Networks (MetabERN)) is an efficient tool to disseminate knowledge and boost collaboration at all levels. The final goal is of course to improve the quality of life of the patients and their families.
Phosphomannomutase 2 (PMM2) converts mannose-6-phospahate to mannose-1-phosphate; the substrate for GDP-mannose, a building block of the glycosylation biosynthetic pathway. Pathogenic variants in the ...PMM2 gene have been shown to be associated with protein hypoglycosylation causing PMM2-congenital disorder of glycosylation (PMM2-CDG). While mannose supplementation improves glycosylation in vitro, but not in vivo, we hypothesized that liposomal delivery of mannose-1-phosphate could increase the stability and delivery of the activated sugar to enter the targeted compartments of cells. Thus, we studied the effect of liposome-encapsulated mannose-1-P (GLM101) on global protein glycosylation and on the cellular proteome in skin fibroblasts from individuals with PMM2-CDG, as well as in individuals with two N-glycosylation defects early in the pathway, namely ALG2-CDG and ALG11-CDG. We leveraged multiplexed proteomics and N-glycoproteomics in fibroblasts derived from different individuals with various pathogenic variants in PMM2, ALG2 and ALG11 genes. Proteomics data revealed a moderate but significant change in the abundance of some of the proteins in all CDG fibroblasts upon GLM101 treatment. On the other hand, N-glycoproteomics revealed the GLM101 treatment enhanced the expression levels of several high-mannose and complex/hybrid glycopeptides from numerous cellular proteins in individuals with defects in PMM2 and ALG2 genes. Both PMM2-CDG and ALG2-CDG exhibited several-fold increase in glycopeptides bearing Man6 and higher glycans and a decrease in Man5 and smaller glycan moieties, suggesting that GLM101 helps in the formation of mature glycoforms. These changes in protein glycosylation were observed in all individuals irrespective of their genetic variants. ALG11-CDG fibroblasts also showed increase in high mannose glycopeptides upon treatment; however, the improvement was not as dramatic as the other two CDG. Overall, our findings suggest that treatment with GLM101 overcomes the genetic block in the glycosylation pathway and can be used as a potential therapy for CDG with enzymatic defects in early steps in protein N-glycosylation.
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