IgG glycosylation analysis

Hühn, Carolin; Selman, Maurice H. J.; Ruhaak, L. Renee; Deelder, André M.; Wuhrer, Manfred

doi:10.1002/pmic.200800715

Cited by 280 publications

(248 citation statements)

References 210 publications

(546 reference statements)

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“…The biological activity of IgG is regulated by the N-glycans attached to the highly variable Fc domain. 15 Changes in core fucose and sialic acid content of IgG can lead to very substantial functional changes as seen in the antibody-dependent cellular cytotoxicity activity or conversely, may confer anti-inflammatory properties. 16 It is established that before and after initiation of treatment, galactosaemia patients exhibit defects in both assembly and processing of N-glycans.…”

Section: Introductionmentioning

confidence: 99%

Classical galactosaemia: novel insights in IgG N-glycosylation and N-glycan biosynthesis

et al. 2016

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Classical galactosaemia (OMIM #230400), a rare disorder of carbohydrate metabolism, is caused by a deficient activity of galactose-1-phosphate uridyltransferase (EC 2.7.7.12). The pathophysiology of the long-term complications, mainly cognitive, neurological and female fertility problems remains poorly understood. The lack of validated biomarkers to determine prognosis, monitor disease progression and responses to new therapies, pose a huge challenge. We report the detailed analysis of an automated robotic hydrophilic interaction ultra-performance liquid chromatography N-glycan analytical method of high glycan peak resolution applied to serum IgG. This has revealed specific N-glycan processing defects observed in 40 adult galactosaemia patients (adults and adolescents), in comparison with 81 matched healthy controls. We have identified a significant increase in core fucosylated neutral glycans (Po0.0001) and a significant decrease in core fucosylated (Po0.001), non-fucosylated (Po0.0001) bisected glycans and, of specific note, decreased N-linked mannose-5 glycans (Po0.0001), in galactosaemia patients. We also report the abnormal expression of a number of related relevant N-glycan biosynthesis genes in peripheral blood mononuclear cells from 32 adult galactosaemia patients. We have noted significant dysregulation of two key N-glycan biosynthesis genes: ALG9 upregulated (Po0.001) and MGAT1 downregulated (Po0.01) in galactosaemia patients, which may contribute to its ongoing pathophysiology. Our data suggest that the use of IgG N-glycosylation analysis with matched N-glycan biosynthesis gene profiles may provide useful biomarkers for monitoring response to therapy and interventions. They also indicate potential gene modifying steps in this N-glycan biosynthesis pathway, of relevance to galactosaemia and related N-glycan biosynthesis disorders.

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Section: Introductionmentioning

confidence: 99%

Classical galactosaemia: novel insights in IgG N-glycosylation and N-glycan biosynthesis

et al. 2016

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“…1 Each heavy chain in the Fc region carries a single covalently attached biantennary N-glycan at the highly conserved asparagine 297. 2 Fc glycans are essential structural components of the IgG molecule and minor changes in glycan composition can significantly alter the conformation of the Fc region changing the interaction with receptor proteins and thus modulating the effector functions of IgG. 3,4 The lack of core fucose enhances the IgG1 binding to activating Fc receptor FcγRIIIa leading to increased antibody-dependent cellular cytotoxicity (ADCC) and destruction of target cells.…”

Section: ■ Introductionmentioning

confidence: 99%

High-Throughput IgG Fc N-Glycosylation Profiling by Mass Spectrometry of Glycopeptides

et al. 2013

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Age and sex dependence of subclass specific immunoglobulin G (IgG) Fc N-glycosylation was evaluated for 1709 individuals from two isolated human populations. IgGs were obtained from plasma by affinity purification using 96-well protein G monolithic plates and digested with trypsin. Fc Nglycopeptides were purified and analyzed by negative-mode MALDI-TOF-MS with 4-chloro-α-cyanocinnamic acid (Cl-CCA) matrix. Age-associated glycosylation changes were more pronounced in younger individuals (<57 years) than in older individuals (>57 years) and in females than in males. Galactosylation and sialylation decreased with increasing age and showed significant sex dependence. Interestingly, the most prominent drop in the levels of galactosylated and sialylated glycoforms in females was observed around the age of 45 to 60 years when females usually enter menopause. The incidence of bisecting N-acetylglucosamine increased in younger individuals and reached a plateau at older age. Furthermore, we compared the results to the total IgG N-glycosylation of the same populations recently analyzed by hydrophilic interaction liquid chromatography (HILIC). Significant differences were observed in the levels of galactosylation, bisecting N-acetylglucosamine and particularly sialylation, which were shown to be higher in HILIC analysis. Age and sex association of glycosylation features was, to a large extent, comparable between MALDI-TOF-MS and HILIC IgG glycosylation profiling.

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“…Disregulation of glycosylation is associated with a wide range of diseases, including cancer, diabetes, and cardiovascular, congenital, immunological, and infectious disorders (18 -20), but because of experimental difficulties in analyzing complex glycan structures, the knowledge about glycan structure and function is still lagging behind the knowledge about other macromolecules (21). However, recent technological advances have allowed reliable, high-throughput quantification of N-glycans (22)(23)(24), which now permit large scale studies aimed at understanding of the role of protein glycosylation in complex diseases.…”

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confidence: 99%

Human Plasma Glycome in Attention-Deficit Hyperactivity Disorder and Autism Spectrum Disorders

Pivac

Knežević

Gornik

et al. 2011

Molecular & Cellular Proteomics

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Over a half of all proteins are glycosylated, and their proper glycosylation is essential for normal function. Unfortunately, because of structural complexity of nonlinear branched glycans and the absence of genetic template for their synthesis, the knowledge about glycans is lagging significantly behind the knowledge about proteins or DNA. Using a recently developed quantitative high throughput glycan analysis method we quantified components of the plasma N-glycome in 99 children with attention-deficit hyperactivity disorder (ADHD), 81 child and 5 adults with autism spectrum disorder, and a total of 340 matching healthy controls. No changes in plasma glycome were found to associate with autism spectrum disorder, but several highly significant associations were observed with ADHD. Further structural analysis of plasma glycans revealed that ADHD is associated with increased antennary fucosylation of biantennary glycans and decreased levels of some complex glycans with three or four antennas. The design of this study prevented any functional conclusions about the observed associations, but specific differences in glycosylation appears to be strongly associated with ADHD and warrants further studies in this direction. Molecular & Cellular Proteomics 10: 10.1074/mcp.M110.004200, 1-7, 2011. Attention-deficit hyperactivity disorder (ADHD)1 and autism spectrum disorders (ASDs) are both highly heritable multifactorial and clinically heterogeneous childhood-onset neurodevelopmental disorders (1, 2). The hallmarks of ADHD are severe inattention, hyperactivity, and impulsivity whereas the characteristic symptoms of ASD include impaired communication and social interaction skills as well as repetitive and restricted behavior and interests (3). Several pieces of evidence point toward some shared heritability and thus genetic factors contributing to the occurrence of both ADHD an ASD (4). Children with ADHD and ASD frequently share symptoms of impaired communication skills, impaired social interactions (4), and develop difficulties in familial, educational, and academic functioning (5, 6). The abnormal functioning of the dopaminergic and serotonergic systems (5, 7-9), among other neurotransmitters, were repeatedly found in ADHD and ASD, and therefore the candidate genes common for both disorders are the dopaminergic transporter gene, dopaminergic receptor type 3 and type 4 genes, serotonin transporter gene, and genes for catechol-o-methyl-transferase and monoamine oxidase type A (4), although genome-wide association studies did not confirm with certainty all these candidates (10). A shared genetic basis is further suggested by the higher frequency of ADHD and ASD traits in children with a defined genetic diagnosis such as 22q11 deletion syndrome, XXYY syndrome, and microdeletions or duplications in the chromosome 15q13.2-q13.3 region (11,12). However, the molecular agents related to various biological processes and interactions between different risk factors responsible for development of ADHD and ASD remain elusive (6).Prote...

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IgG glycosylation analysis

Cited by 280 publications

References 210 publications

Classical galactosaemia: novel insights in IgG N-glycosylation and N-glycan biosynthesis

Classical galactosaemia: novel insights in IgG N-glycosylation and N-glycan biosynthesis

High-Throughput IgG Fc N-Glycosylation Profiling by Mass Spectrometry of Glycopeptides

Human Plasma Glycome in Attention-Deficit Hyperactivity Disorder and Autism Spectrum Disorders

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