Protein-Specific Glycoprofiling for Patient Diagnostics

Lefeber, Dirk

doi:10.1373/clinchem.2015.248518

Cited by 9 publications

(3 citation statements)

References 13 publications

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“…SLC35A1 deficiency has been referred to as congenital disorder of N-linked glycosylation IIf (CDG-IIf), with the new nomenclature being SLC35A1-CDG [73]. Abnormal protein glycosylation is implicated in numerous genetic and acquired diseases ranging from diabetes, cancer, and inflammatory disease to neurodegenerative and neuromuscular disease [74]. Over 125 genetic disorders have been attributed to many glycosylation pathways [75], but a distinct difference should be made between the disorders of the pathways compared to direct mutations of the NST itself.…”

Section: Slc35a1: Cmp-sialic Acid Transporter (Cst)mentioning

confidence: 99%

Nucleotide Sugar Transporter SLC35 Family Structure and Function

Hadley

Litfin

Day

et al. 2019

Computational and Structural Biotechnology Journal

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The covalent attachment of sugars to growing glycan chains is heavily reliant on a specific family of solute transporters (SLC35), the nucleotide sugar transporters (NSTs) that connect the synthesis of activated sugars in the nucleus or cytosol, to glycosyltransferases that reside in the lumen of the endoplasmic reticulum (ER) and/or Golgi apparatus. This review provides a timely update on recent progress in the NST field, specifically we explore several NSTs of the SLC35 family whose substrate specificity and function have been poorly understood, but where recent significant progress has been made. This includes SLC35 A4, A5 and D3, as well as progress made towards understanding the association of SLC35A2 with SLC35A3 and how this relates to their potential regulation, and how the disruption to the dilysine motif in SLC35B4 causes mislocalisation, calling into question multisubstrate NSTs and their subcellular localisation and function. We also report on the recently described first crystal structure of an NST, the SLC35D2 homolog Vrg-4 from yeast. Using this crystal structure, we have generated a new model of SLC35A1, (CMP-sialic acid transporter, CST), with structural and mechanistic predictions based on all known CST-related data, and includes an overview of reported mutations that alter transport and/or substrate recognition (both de novo and site-directed). We also present a model of the CST-del177 isoform that potentially explains why the human CST isoform remains active while the hamster CST isoform is inactive, and we provide a possible alternate access mechanism that accounts for the CST being functional as either a monomer or a homodimer. Finally we provide an update on two NST crystal structures that were published subsequent to the submission and during review of this report.

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Section: Slc35a1: Cmp-sialic Acid Transporter (Cst)mentioning

confidence: 99%

Nucleotide Sugar Transporter SLC35 Family Structure and Function

Hadley

Litfin

Day

et al. 2019

Computational and Structural Biotechnology Journal

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“…A decade later, the emergence of advanced quadrupole time-of-flight (QTOF) detection in combination with nanoLC-ESI-MS enabled the development of high resolution intact transferrin glycoprofiling which in turn improved the CDG diagnostics (van Scherpenzeel et al 2015 ). Normal transferrin IEF profiles have been observed in some CDG-I and -II cases, such as ALG14-CDG, ALG11-CDG, MOGS-CDG, SLC35A3-CDG, and SLC35C1-CDG (Lefeber 2016 ; Al Teneiji et al 2017 ), as well as in some defects in sugar metabolism like GNE-CDG (Voermans et al 2010 ), NANS-CDG (Van Karnebeek et al 2016 ), PGM3-CDG (Stray-Pedersen et al 2014 ), and also in a tissue-specific and GA homeostasis defect of VPS13B-CDG/Cohen syndrome (Duplomb et al 2014 ).…”

Section: Application Of Clinical Glycomics For Cdg Diagnosticsmentioning

confidence: 99%

Clinical glycomics for the diagnosis of congenital disorders of glycosylation

Bakar

Lefeber

Scherpenzeel

2018

J of Inher Metab Disea

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Clinical glycomics comprises a spectrum of different analytical methodologies to analyze glycan structures, which provides insights into the mechanisms of glycosylation. Within clinical diagnostics, glycomics serves as a functional readout of genetic variants, and can form a basis for therapy development, as was described for PGM1-CDG. Integration of glycomics with genomics has resulted in the elucidation of previously unknown disorders of glycosylation, namely CCDC115-CDG, TMEM199-CDG, ATP6AP1-CDG, MAN1B1-CDG, and PGM1-CDG. This review provides an introduction into protein glycosylation and presents the different glycomics methodologies ranging from gel electrophoresis to mass spectrometry (MS) and from free glycans to intact glycoproteins. The role of glycomics in the diagnosis of congenital disorders of glycosylation (CDG) is presented, including a diagnostic flow chart and an overview of glycomics data of known CDG subtypes. The review ends with some future perspectives, showing upcoming technologies as system wide mapping of the N- and O-glycoproteome, intact glycoprotein profiling and analysis of sugar metabolism. These new advances will provide additional insights and opportunities to develop personalized therapy. This is especially true for inborn errors of metabolism, which are amenable to causal therapy, because interventions through supplementation therapy can directly target the pathogenesis at the molecular level.

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“…The blood plasma glycoproteome holds great potential for biomarker discovery since abnormal glycomes have been reported for numerous human diseases 2 . Evidence is emerging that protein-specific analysis of glycosylation changes will drastically increase the specificity of such biomarkers [3][4][5][6] . Proteome-wide analysis of protein glycosylation through liquid chromatography -tandem mass spectrometry (LC-MS/MS) analysis of glycopeptides, or glycoproteomics, has matured to such a state in recent years that clinical application is becoming reality to improve diagnostics and gain new insights into disease mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Plasma glycoproteomics delivers high-specificity disease biomarkers by detecting site-specific glycosylation abnormalities

Wessels

Kulkarni

Dael

et al. 2022

Preprint

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The human plasma glycoproteome holds enormous potential to identify personalized biomarkers to diagnose and understand disease. Recent advances in mass spectrometry and software development are opening novel avenues to mine the glycoproteome for protein- and site-specific glycosylation changes. Here, we describe a novel plasma N-glycoproteomics method for disease diagnosis and evaluated its clinical applicability by performing comparative glycoproteomics in blood plasma of 40 controls and a cohort of 74 patients with 13 different genetic diseases that directly impact the protein N-glycosylation pathway. The plasma glycoproteome yielded high-specificity biomarker signatures for each of the individual genetic defects. Bioinformatic analyses revealed site-specific glycosylation differences that could be explained by underlying glycobiology and in specific diseases by protein-intrinsic factors. Our work illustrates the strong potential of plasma glycoproteomics to significantly increase specificity of glycoprotein biomarkers with direct insights in site-specific glycosylation changes to better understand the mechanisms underlying human disease.

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Protein-Specific Glycoprofiling for Patient Diagnostics

Cited by 9 publications

References 13 publications

Nucleotide Sugar Transporter SLC35 Family Structure and Function

Nucleotide Sugar Transporter SLC35 Family Structure and Function

Clinical glycomics for the diagnosis of congenital disorders of glycosylation

Plasma glycoproteomics delivers high-specificity disease biomarkers by detecting site-specific glycosylation abnormalities

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