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Missense mutations in the C-terminal portion of the B4GALNT2-encoded glycosyltransferase underlying the Sd(a−) phenotype

Stenfelt, Linn LU orcid ; Hellberg, Åsa LU ; Möller, Mattias LU orcid ; Thornton, Nicole ; Larson, Göran and Olsson, Martin L. LU orcid (2019) In Biochemistry and Biophysics Reports 19.
Abstract

Sda is a high-frequency carbohydrate histo-blood group antigen, GalNAcβ1-4(NeuAcα2-3)Galβ, implicated in pathogen invasion, cancer, xenotransplantation and transfusion medicine. Complete lack of this glycan epitope results in the Sd(a−) phenotype observed in 4% of individuals who may produce anti-Sda. A candidate gene (B4GALNT2), encoding a Sda-synthesizing β-1,4-N-acetylgalactosaminyltransferase (β4GalNAc-T2), was cloned in 2003 but the genetic basis of human Sda deficiency was never elucidated. Experimental and bioinformatic approaches were used to identify and characterize B4GALNT2 variants in nine Sd(a−) individuals. Homozygosity for rs7224888:T > C dominated the cohort (n = 6) and... (More)

Sda is a high-frequency carbohydrate histo-blood group antigen, GalNAcβ1-4(NeuAcα2-3)Galβ, implicated in pathogen invasion, cancer, xenotransplantation and transfusion medicine. Complete lack of this glycan epitope results in the Sd(a−) phenotype observed in 4% of individuals who may produce anti-Sda. A candidate gene (B4GALNT2), encoding a Sda-synthesizing β-1,4-N-acetylgalactosaminyltransferase (β4GalNAc-T2), was cloned in 2003 but the genetic basis of human Sda deficiency was never elucidated. Experimental and bioinformatic approaches were used to identify and characterize B4GALNT2 variants in nine Sd(a−) individuals. Homozygosity for rs7224888:T > C dominated the cohort (n = 6) and causes p.Cys466Arg, which targets a highly conserved residue located in the enzymatically active domain and is judged deleterious to β4GalNAc-T2. Its allele frequency was 0.10–0.12 in different cohorts. A Sd(a−) compound heterozygote combined rs7224888:T > C with a splice-site mutation, rs72835417:G > A, predicted to alter splicing and occurred at a frequency of 0.11–0.12. Another compound heterozygote had two rare nonsynonymous variants, rs148441237:A > G (p.Gln436Arg) and rs61743617:C > T (p.Arg523Trp), in trans. One sample displayed no differences compared to Sd(a+). When investigating linkage disequilibrium between B4GALNT2 variants, we noted a 32-kb block spanning intron 9 to the intergenic region downstream of B4GALNT2. This block includes RP11-708H21.4, a long non-coding RNA recently reported to promote tumorigenesis and poor prognosis in colon cancer. The expression patterns of B4GALNT2 and RP11-708H21.4 correlated extremely well in >1000 cancer cell lines. In summary, we identified a connection between variants of the cancer-associated B4GALNT2 gene and Sda, thereby establishing a new blood group system and opening up for the possibility to predict Sd(a+) and Sd(a‒) phenotypes by genotyping.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
B4GALNT2, Glycosyltransferase, Red blood cell, Sd(a‒) phenotype, Sd histo-blood group antigen
in
Biochemistry and Biophysics Reports
volume
19
article number
100659
publisher
Elsevier
external identifiers
  • scopus:85068995469
  • pmid:31367682
ISSN
2405-5808
DOI
10.1016/j.bbrep.2019.100659
project
Elucidation of the genetic basis of carbohydrate histo-blood group systems
language
English
LU publication?
yes
id
5a8dca32-7a54-47d5-a8b6-11789a151e23
date added to LUP
2019-07-23 09:16:27
date last changed
2025-10-14 09:44:54
@article{5a8dca32-7a54-47d5-a8b6-11789a151e23,
  abstract     = {{<p>Sd<sup>a</sup> is a high-frequency carbohydrate histo-blood group antigen, GalNAcβ1-4(NeuAcα2-3)Galβ, implicated in pathogen invasion, cancer, xenotransplantation and transfusion medicine. Complete lack of this glycan epitope results in the Sd(a−) phenotype observed in 4% of individuals who may produce anti-Sd<sup>a</sup>. A candidate gene (B4GALNT2), encoding a Sd<sup>a</sup>-synthesizing β-1,4-N-acetylgalactosaminyltransferase (β4GalNAc-T2), was cloned in 2003 but the genetic basis of human Sd<sup>a</sup> deficiency was never elucidated. Experimental and bioinformatic approaches were used to identify and characterize B4GALNT2 variants in nine Sd(a−) individuals. Homozygosity for rs7224888:T &gt; C dominated the cohort (n = 6) and causes p.Cys466Arg, which targets a highly conserved residue located in the enzymatically active domain and is judged deleterious to β4GalNAc-T2. Its allele frequency was 0.10–0.12 in different cohorts. A Sd(a−) compound heterozygote combined rs7224888:T &gt; C with a splice-site mutation, rs72835417:G &gt; A, predicted to alter splicing and occurred at a frequency of 0.11–0.12. Another compound heterozygote had two rare nonsynonymous variants, rs148441237:A &gt; G (p.Gln436Arg) and rs61743617:C &gt; T (p.Arg523Trp), in trans. One sample displayed no differences compared to Sd(a+). When investigating linkage disequilibrium between B4GALNT2 variants, we noted a 32-kb block spanning intron 9 to the intergenic region downstream of B4GALNT2. This block includes RP11-708H21.4, a long non-coding RNA recently reported to promote tumorigenesis and poor prognosis in colon cancer. The expression patterns of B4GALNT2 and RP11-708H21.4 correlated extremely well in &gt;1000 cancer cell lines. In summary, we identified a connection between variants of the cancer-associated B4GALNT2 gene and Sd<sup>a</sup>, thereby establishing a new blood group system and opening up for the possibility to predict Sd(a+) and Sd(a‒) phenotypes by genotyping.</p>}},
  author       = {{Stenfelt, Linn and Hellberg, Åsa and Möller, Mattias and Thornton, Nicole and Larson, Göran and Olsson, Martin L.}},
  issn         = {{2405-5808}},
  keywords     = {{B4GALNT2; Glycosyltransferase; Red blood cell; Sd(a‒) phenotype; Sd histo-blood group antigen}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Biochemistry and Biophysics Reports}},
  title        = {{Missense mutations in the C-terminal portion of the B4GALNT2-encoded glycosyltransferase underlying the Sd(a−) phenotype}},
  url          = {{http://dx.doi.org/10.1016/j.bbrep.2019.100659}},
  doi          = {{10.1016/j.bbrep.2019.100659}},
  volume       = {{19}},
  year         = {{2019}},
}