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

Ashwini Maratha; Henning Stockmann; Karen Coss; M. Estela Rubio-Gozalbo; Ina Knerr; Maria Fitzgibbon; Terri P. McVeigh; Patricia Foley; Catherine Moss; Hugh Owen Colhoun; Britt Van Erven; Kelly Stephens; Peter Doran; Pauline Rudd; Eileen Treacy

doi:10.1038/ejhg.2015.254

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

Ashwini Maratha, Henning Stockmann, Karen Coss, M. Estela Rubio-Gozalbo, Ina Knerr, Maria Fitzgibbon, Terri P. McVeigh, Patricia Foley, Catherine Moss, Hugh Owen Colhoun, Britt Van Erven, Kelly Stephens, Peter Doran, Pauline Rudd, Eileen Treacy^*

^*Corresponding author for this work

Infectious Diseases

Research output: Contribution to journal › Article › peer-review

40 Citations (Scopus)

Abstract

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 (P<0.0001) and a significant decrease in core fucosylated (P<0.001), non-fucosylated (P<0.0001) bisected glycans and, of specific note, decreased N-linked mannose-5 glycans (P<0.0001), 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 (P<0.001) and MGAT1 downregulated (P<0.01) 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.

Original language	English
Pages (from-to)	976-984
Number of pages	9
Journal	European journal of human genetics : EJHG
Volume	24
Issue number	7
DOIs	https://doi.org/10.1038/ejhg.2015.254
Publication status	Published - 1 Jul 2016

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Maratha, A., Stockmann, H., Coss, K., Estela Rubio-Gozalbo, M., Knerr, I., Fitzgibbon, M., McVeigh, T. P., Foley, P., Moss, C., Colhoun, H. O., Van Erven, B., Stephens, K., Doran, P., Rudd, P., & Treacy, E. (2016). Classical galactosaemia: Novel insights in IgG N-glycosylation and N-glycan biosynthesis. European journal of human genetics : EJHG, 24(7), 976-984. https://doi.org/10.1038/ejhg.2015.254

@article{6f5c837263be4cea8457f78e8342bd4f,

title = "Classical galactosaemia: Novel insights in IgG N-glycosylation and N-glycan biosynthesis",

abstract = "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 (P<0.0001) and a significant decrease in core fucosylated (P<0.001), non-fucosylated (P<0.0001) bisected glycans and, of specific note, decreased N-linked mannose-5 glycans (P<0.0001), 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 (P<0.001) and MGAT1 downregulated (P<0.01) 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.",

author = "Ashwini Maratha and Henning Stockmann and Karen Coss and {Estela Rubio-Gozalbo}, M. and Ina Knerr and Maria Fitzgibbon and McVeigh, {Terri P.} and Patricia Foley and Catherine Moss and Colhoun, {Hugh Owen} and {Van Erven}, Britt and Kelly Stephens and Peter Doran and Pauline Rudd and Eileen Treacy",

year = "2016",

month = jul,

day = "1",

doi = "10.1038/ejhg.2015.254",

language = "English",

volume = "24",

pages = "976--984",

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Maratha, A, Stockmann, H, Coss, K, Estela Rubio-Gozalbo, M, Knerr, I, Fitzgibbon, M, McVeigh, TP, Foley, P, Moss, C, Colhoun, HO, Van Erven, B, Stephens, K, Doran, P, Rudd, P & Treacy, E 2016, 'Classical galactosaemia: Novel insights in IgG N-glycosylation and N-glycan biosynthesis', European journal of human genetics : EJHG, vol. 24, no. 7, pp. 976-984. https://doi.org/10.1038/ejhg.2015.254

TY - JOUR

T1 - Classical galactosaemia

T2 - Novel insights in IgG N-glycosylation and N-glycan biosynthesis

AU - Maratha, Ashwini

AU - Stockmann, Henning

AU - Coss, Karen

AU - Estela Rubio-Gozalbo, M.

AU - Knerr, Ina

AU - Fitzgibbon, Maria

AU - McVeigh, Terri P.

AU - Foley, Patricia

AU - Moss, Catherine

AU - Colhoun, Hugh Owen

AU - Van Erven, Britt

AU - Stephens, Kelly

AU - Doran, Peter

AU - Rudd, Pauline

AU - Treacy, Eileen

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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 (P<0.0001) and a significant decrease in core fucosylated (P<0.001), non-fucosylated (P<0.0001) bisected glycans and, of specific note, decreased N-linked mannose-5 glycans (P<0.0001), 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 (P<0.001) and MGAT1 downregulated (P<0.01) 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.

AB - 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 (P<0.0001) and a significant decrease in core fucosylated (P<0.001), non-fucosylated (P<0.0001) bisected glycans and, of specific note, decreased N-linked mannose-5 glycans (P<0.0001), 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 (P<0.001) and MGAT1 downregulated (P<0.01) 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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DO - 10.1038/ejhg.2015.254

M3 - Article

AN - SCOPUS:84953304865

SN - 1018-4813

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JO - European journal of human genetics : EJHG

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

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