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Glycoproteomic and Phenotypic Elucidation of B4GALNT2 Expression Variants in the SID Histo-Blood Group System

Stenfelt, Linn LU orcid ; Nilsson, Jonas ; Hellberg, Åsa LU ; Liew, Yew Wah ; Morrison, Jenny ; Larson, Göran and Olsson, Martin L. LU orcid (2022) In International Journal of Molecular Sciences 23(7).
Abstract

The Sda histo-blood group antigen (GalNAcβ1-4(NeuAcα2-3)Galβ-R) is implicated in various infections and constitutes a potential biomarker for colon cancer. Sd(a−) individuals (2–4% of Europeans) may produce anti-Sda, which can lead to incompatible blood transfusions, especially if donors with the high-expressing Sd(a++)/Cad phenotype are involved. We previously reported the association of B4GALNT2 mutations with Sd(a−), which established the SID blood-group system. The present study provides causal proof underpinning this correlation. Sd(a−) HEK293 cells were trans-fected with different B4GALNT2 constructs and evaluated by immunostaining and glycoproteomics. The predominant SIDnull candidate allele with... (More)

The Sda histo-blood group antigen (GalNAcβ1-4(NeuAcα2-3)Galβ-R) is implicated in various infections and constitutes a potential biomarker for colon cancer. Sd(a−) individuals (2–4% of Europeans) may produce anti-Sda, which can lead to incompatible blood transfusions, especially if donors with the high-expressing Sd(a++)/Cad phenotype are involved. We previously reported the association of B4GALNT2 mutations with Sd(a−), which established the SID blood-group system. The present study provides causal proof underpinning this correlation. Sd(a−) HEK293 cells were trans-fected with different B4GALNT2 constructs and evaluated by immunostaining and glycoproteomics. The predominant SIDnull candidate allele with rs7224888:T>C (p.Cys406Arg) abolished Sda synthesis, while this antigen was detectable as N-or O-glycans on glycoproteins following transfection of wildtype B4GALNT2. Surprisingly, two rare missense variants, rs148441237:A>G and rs61743617:C>T, found in a Sd(a−) compound heterozygote, gave results similar to wildtype. To elucidate on whether Sd(a++)/Cad also depends on B4GALNT2 alterations, this gene was sequenced in five individuals. No Cad-specific changes were identified, but a detailed erythroid Cad glycoprotein profile was obtained, especially for glycophorin-A (GLPA) O-glycosylation, equilibrative nucleoside transporter 1 (S29A1) O-glycosylation, and band 3 anion transport protein (B3AT) N-glycosylation. In conclusion, the p.Cys406Arg β4GalNAc-T2 variant causes Sda-deficiency in humans, while the enigmatic Cad phenotype remains unresolved, albeit further characterized.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
carbohydrate biosynthesis, erythrocyte, flow cytometry, gene expression, glycobiology, glycopeptide, glycoprotein, glycosyltransferase, mass spectrometry (MS), SID blood group system
in
International Journal of Molecular Sciences
volume
23
issue
7
article number
3936
publisher
MDPI AG
external identifiers
  • scopus:85127387083
  • pmid:35409292
ISSN
1661-6596
DOI
10.3390/ijms23073936
language
English
LU publication?
yes
id
02c2d704-75f9-4460-bbeb-b0a538a14d21
date added to LUP
2022-05-20 14:15:27
date last changed
2024-06-13 12:31:44
@article{02c2d704-75f9-4460-bbeb-b0a538a14d21,
  abstract     = {{<p>The Sd<sup>a</sup> histo-blood group antigen (GalNAcβ1-4(NeuAcα2-3)Galβ-R) is implicated in various infections and constitutes a potential biomarker for colon cancer. Sd(a−) individuals (2–4% of Europeans) may produce anti-Sd<sup>a</sup>, which can lead to incompatible blood transfusions, especially if donors with the high-expressing Sd(a++)/Cad phenotype are involved. We previously reported the association of B4GALNT2 mutations with Sd(a−), which established the SID blood-group system. The present study provides causal proof underpinning this correlation. Sd(a−) HEK293 cells were trans-fected with different B4GALNT2 constructs and evaluated by immunostaining and glycoproteomics. The predominant SID<sup>null</sup> candidate allele with rs7224888:T&gt;C (p.Cys406Arg) abolished Sd<sup>a</sup> synthesis, while this antigen was detectable as N-or O-glycans on glycoproteins following transfection of wildtype B4GALNT2. Surprisingly, two rare missense variants, rs148441237:A&gt;G and rs61743617:C&gt;T, found in a Sd(a−) compound heterozygote, gave results similar to wildtype. To elucidate on whether Sd(a++)/Cad also depends on B4GALNT2 alterations, this gene was sequenced in five individuals. No Cad-specific changes were identified, but a detailed erythroid Cad glycoprotein profile was obtained, especially for glycophorin-A (GLPA) O-glycosylation, equilibrative nucleoside transporter 1 (S29A1) O-glycosylation, and band 3 anion transport protein (B3AT) N-glycosylation. In conclusion, the p.Cys406Arg β4GalNAc-T2 variant causes Sd<sup>a</sup>-deficiency in humans, while the enigmatic Cad phenotype remains unresolved, albeit further characterized.</p>}},
  author       = {{Stenfelt, Linn and Nilsson, Jonas and Hellberg, Åsa and Liew, Yew Wah and Morrison, Jenny and Larson, Göran and Olsson, Martin L.}},
  issn         = {{1661-6596}},
  keywords     = {{carbohydrate biosynthesis; erythrocyte; flow cytometry; gene expression; glycobiology; glycopeptide; glycoprotein; glycosyltransferase; mass spectrometry (MS); SID blood group system}},
  language     = {{eng}},
  number       = {{7}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Glycoproteomic and Phenotypic Elucidation of B4GALNT2 Expression Variants in the SID Histo-Blood Group System}},
  url          = {{http://dx.doi.org/10.3390/ijms23073936}},
  doi          = {{10.3390/ijms23073936}},
  volume       = {{23}},
  year         = {{2022}},
}