Synergistic use of glycomics and single‐molecule molecular inversion probes for <scp>identification</scp> of congenital disorders of glycosylation type‐1

Bakar, Nurulamin Abu; Ashikov, Angel; Brum, Jaime Moritz; Smeets, Roel; Kersten, Marjan; Huijben, Karin; Keng, Wee Teik; Carvalho, Daniel R.; Rizzo, Isabela M. P. O.; Mello, Walquiria Domingues; Heiner‐Fokkema, M. Rebecca; Gorman, Kathleen; Grünewald, Stéphanie; Michelakakis, Helen; Μωραιτου, Μαρινα; Diego, Martinelli; Scherpenzeel, Monique van; Janssen, Mirian C. H.; Boer, Lonneke de; Heuvel, Lambertus P. van den; Thiel, Christian; Lefeber, Dirk

doi:10.1002/jimd.12496

Cited by 11 publications

(12 citation statements)

References 26 publications

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“…Such a compensatory mechanism has been described in HL-60 leukemia cells which show increased expression of the glutamine transporter, the glycoprotein SLC1A5, after induction of hypoglycosylation by TM (44). Finally, another explanation is provided by recent evidence suggesting that CDG-I defects, including PMM2-CDG, do not merely result in hypoglycosylation but also in glycan structural changes, including an elevated expression of short high-mannose Nglycans (45,46). This could possibly contribute to the high lectin signal detected in some of the PMM2-CDG PBMCs.…”

Section: Discussionmentioning

confidence: 92%

Evaluation of Cell Models to Study Monocyte Functions in PMM2 Congenital Disorders of Glycosylation

et al. 2022

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Congenital disorders of glycosylation (CDG) are inherited metabolic diseases characterized by mutations in enzymes involved in different steps of protein glycosylation, leading to aberrant synthesis, attachment or processing of glycans. Recently, immunological dysfunctions in several CDG types have been increasingly documented. Despite these observations, detailed studies on immune cell dysfunction in PMM2-CDG and other CDG types are still scarce. Studying PMM2-CDG patient immune cells is challenging due to limited availability of patient material, which is a result of the low incidence of the disease and the often young age of the subjects. Dedicated immune cell models, mimicking PMM2-CDG, could circumvent many of these problems and facilitate research into the mechanisms of immune dysfunction. Here we provide initial observations about the immunophenotype and the phagocytic function of primary PMM2-CDG monocytes. Furthermore, we assessed the suitability of two different glycosylation-impaired human monocyte models: tunicamycin-treated THP-1 monocytes and PMM2 knockdown THP-1 monocytes induced by shRNAs. We found no significant differences in primary monocyte subpopulations of PMM2-CDG patients as compared to healthy individuals but we did observe anomalous surface glycosylation patterns in PMM2-CDG patient monocytes as determined using fluorescent lectin binding. We also looked at the capacity of monocytes to bind and internalize fungal particles and found a slightly increased uptake of C. albicans by PMM2-CDG monocytes as compared to healthy monocytes. Tunicamycin-treated THP-1 monocytes showed a highly decreased uptake of fungal particles, accompanied by a strong decrease in glycosylation levels and a high induction of ER stress. In contrast and despite a drastic reduction of the PMM2 enzyme activity, PMM2 knockdown THP-1 monocytes showed no changes in global surface glycosylation levels, levels of fungal particle uptake similar to control monocytes, and no ER stress induction. Collectively, these initial observations suggest that the absence of ER stress in PMM2 knockdown THP-1 cells make this model superior over tunicamycin-treated THP-1 cells and more comparable to primary PMM2-CDG monocytes. Further development and exploitation of CDG monocyte models will be essential for future in-depth studies to ultimately unravel the mechanisms of immune dysfunction in CDG.

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Section: Discussionmentioning

confidence: 92%

Evaluation of Cell Models to Study Monocyte Functions in PMM2 Congenital Disorders of Glycosylation

et al. 2022

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“…Chen et al, described a new MS-based approach for CDG diagnosis, RapiFluor MS, that paves the way to the integration of N -glycomics approaches for diagnosis of glycosylation disorders [ 74 ]. In a recent glycomics study, specific glycomarkers for congenital disorders of N-glycosylation (CDG type I) were identified, which could be potentially used for diagnosis and therapy recording [ 75 ].…”

Section: Resultsmentioning

confidence: 99%

Systematic Review: Drug Repositioning for Congenital Disorders of Glycosylation (CDG)

Brasil

Allocca

Magrinho

et al. 2022

IJMS

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Advances in research have boosted therapy development for congenital disorders of glycosylation (CDG), a group of rare genetic disorders affecting protein and lipid glycosylation and glycosylphosphatidylinositol anchor biosynthesis. The (re)use of known drugs for novel medical purposes, known as drug repositioning, is growing for both common and rare disorders. The latest innovation concerns the rational search for repositioned molecules which also benefits from artificial intelligence (AI). Compared to traditional methods, drug repositioning accelerates the overall drug discovery process while saving costs. This is particularly valuable for rare diseases. AI tools have proven their worth in diagnosis, in disease classification and characterization, and ultimately in therapy discovery in rare diseases. The availability of biomarkers and reliable disease models is critical for research and development of new drugs, especially for rare and heterogeneous diseases such as CDG. This work reviews the literature related to repositioned drugs for CDG, discovered by serendipity or through a systemic approach. Recent advances in biomarkers and disease models are also outlined as well as stakeholders’ views on AI for therapy discovery in CDG.

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“…Transcriptomics, proteomics, phenomics, metabolomics, lipidomics and methylomics are already routinely implemented as a part of the molecular diagnostic workflow in multiple centres worldwide. Other technologies and analyses such as epi‐transcriptomics, metagenomics, fluxomics, glycomics and other omics are yet to be evaluated for the purposes of disease‐gene prioritisation 151–155 . Currently, the main limitation of the wide application of these approaches is the cost.…”

Section: Discussionmentioning

confidence: 99%

“…Other technologies and analyses such as epi-transcriptomics, metagenomics, fluxomics, glycomics and other omics are yet to be evaluated for the purposes of disease-gene prioritisation. [151][152][153][154][155] Currently, the main limitation of the wide application of these approaches is the cost. However, falling costs, increasing democratisation and constantly growing evidence of the diagnostic power of multi-omics profiling pave the way for routine clinical implementation of these technologies.…”

Section: Discussionmentioning

confidence: 99%

Integrative omics approaches to advance rare disease diagnostics

Smirnov

Konstantinovskiy

Prokisch

2023

J of Inher Metab Disea

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Over the past decade high‐throughput DNA sequencing approaches, namely whole exome and whole genome sequencing became a standard procedure in Mendelian disease diagnostics. Implementation of these technologies greatly facilitated diagnostics and shifted the analysis paradigm from variant identification to prioritisation and evaluation. The diagnostic rates vary widely depending on the cohort size, heterogeneity, and disease and range from around 30% to 50% leaving the majority of patients undiagnosed. Advances in omics technologies and computational analysis provide an opportunity to increase these unfavourable rates by providing evidence for disease‐causing variant validation and prioritisation. This review aims to provide an overview of the current application of several omics technologies including RNA‐sequencing, proteomics, metabolomics and DNA‐methylation profiling for diagnostics of rare genetic diseases in general and inborn errors of metabolism in particular.This article is protected by copyright. All rights reserved.

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Synergistic use of glycomics and single‐molecule molecular inversion probes for identification of congenital disorders of glycosylation type‐1

Cited by 11 publications

References 26 publications

Evaluation of Cell Models to Study Monocyte Functions in PMM2 Congenital Disorders of Glycosylation

Evaluation of Cell Models to Study Monocyte Functions in PMM2 Congenital Disorders of Glycosylation

Systematic Review: Drug Repositioning for Congenital Disorders of Glycosylation (CDG)

Integrative omics approaches to advance rare disease diagnostics

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