Advanced

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

Stenfelt, Linn LU ; Hellberg, Åsa LU ; Möller, Mattias LU ; Thornton, Nicole; Larson, Göran and Olsson, Martin L. LU (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.

(Less)
Please use this url to cite or link to this publication:
author
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
publisher
Elsevier
external identifiers
  • scopus:85068995469
DOI
10.1016/j.bbrep.2019.100659
language
English
LU publication?
yes
id
5a8dca32-7a54-47d5-a8b6-11789a151e23
date added to LUP
2019-07-23 09:16:27
date last changed
2019-08-28 04:57:12
@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>},
  articleno    = {100659},
  author       = {Stenfelt, Linn and Hellberg, Åsa and Möller, Mattias and Thornton, Nicole and Larson, Göran and Olsson, Martin L.},
  keyword      = {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},
  volume       = {19},
  year         = {2019},
}