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Disruption of a GATA1-binding motif upstream of XG/PBDX abolishes Xga expression and resolves the Xg blood group system

Möller, Mattias LU ; Lee, Yan Quan LU ; Vidovic, Karina LU ; Kjellström, Sven LU ; Björkman, Linda LU ; Storry, Jill R. LU and Olsson, Martin L. LU (2018) In Blood 132(3). p.334-338
Abstract

The Xga blood group is differentially expressed on erythrocytes from men and women. The underlying gene, PBDX, was identified in 1994, but the molecular background for Xga expression remains undefined. This gene, now designated XG, partly resides in pseudoautosomal region 1 and encodes a protein of unknown function from the X chromosome. By comparing calculated Xga allele frequencies in different populations with 2612 genetic variants in the XG region, rs311103 showed the strongest correlation to the expected distribution. The same single-nucleotide polymorphism (SNP) had the most significant impact on XG transcript levels in whole blood (P 5 2.0 3 10222). The minor allele, rs311103C, disrupts... (More)

The Xga blood group is differentially expressed on erythrocytes from men and women. The underlying gene, PBDX, was identified in 1994, but the molecular background for Xga expression remains undefined. This gene, now designated XG, partly resides in pseudoautosomal region 1 and encodes a protein of unknown function from the X chromosome. By comparing calculated Xga allele frequencies in different populations with 2612 genetic variants in the XG region, rs311103 showed the strongest correlation to the expected distribution. The same single-nucleotide polymorphism (SNP) had the most significant impact on XG transcript levels in whole blood (P 5 2.0 3 10222). The minor allele, rs311103C, disrupts a GATA-binding motif 3.7 kb upstream of the transcription start point. This silences erythroid XG messenger RNA expression and causes the Xg(a2) phenotype, a finding corroborated by SNP genotyping in 158 blood donors. Binding of GATA1 to biotinylated oligonucleotide probes with rs311103G but not rs311103C was observed by electrophoretic mobility shift assay and proven by mass spectrometry. Finally, a luciferase reporter assay indicated this GATA motif to be active for rs311103G but not rs311103C in HEL cells. By using an integrated bioinformatic and molecular biological approach, we elucidated the underlying genetic basis for the last unresolved blood group system and made Xga genotyping possible.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
132
issue
3
pages
5 pages
publisher
American Society of Hematology
external identifiers
  • scopus:85050133445
ISSN
0006-4971
DOI
10.1182/blood-2018-03-842542
language
English
LU publication?
yes
id
17f6396c-7c20-4ae8-9717-945a84f216d1
date added to LUP
2018-08-21 11:12:58
date last changed
2019-10-15 06:43:43
@article{17f6396c-7c20-4ae8-9717-945a84f216d1,
  abstract     = {<p>The Xg<sup>a</sup> blood group is differentially expressed on erythrocytes from men and women. The underlying gene, PBDX, was identified in 1994, but the molecular background for Xg<sup>a</sup> expression remains undefined. This gene, now designated XG, partly resides in pseudoautosomal region 1 and encodes a protein of unknown function from the X chromosome. By comparing calculated Xg<sup>a</sup> allele frequencies in different populations with 2612 genetic variants in the XG region, rs311103 showed the strongest correlation to the expected distribution. The same single-nucleotide polymorphism (SNP) had the most significant impact on XG transcript levels in whole blood (P 5 2.0 3 102<sup>22</sup>). The minor allele, rs311103C, disrupts a GATA-binding motif 3.7 kb upstream of the transcription start point. This silences erythroid XG messenger RNA expression and causes the Xg(a2) phenotype, a finding corroborated by SNP genotyping in 158 blood donors. Binding of GATA1 to biotinylated oligonucleotide probes with rs311103G but not rs311103C was observed by electrophoretic mobility shift assay and proven by mass spectrometry. Finally, a luciferase reporter assay indicated this GATA motif to be active for rs311103G but not rs311103C in HEL cells. By using an integrated bioinformatic and molecular biological approach, we elucidated the underlying genetic basis for the last unresolved blood group system and made Xg<sup>a</sup> genotyping possible.</p>},
  author       = {Möller, Mattias and Lee, Yan Quan and Vidovic, Karina and Kjellström, Sven and Björkman, Linda and Storry, Jill R. and Olsson, Martin L.},
  issn         = {0006-4971},
  language     = {eng},
  month        = {07},
  number       = {3},
  pages        = {334--338},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Disruption of a GATA1-binding motif upstream of<i> XG</i>/<i>PBDX</i> abolishes Xg<sup>a</sup> expression and resolves the Xg blood group system},
  url          = {http://dx.doi.org/10.1182/blood-2018-03-842542},
  volume       = {132},
  year         = {2018},
}