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Identification of a novel A4GALT exon reveals the genetic basis of the P1/P2 histo-blood groups.

Thuresson, Britt LU ; Westman, Julia LU and Olsson, Martin L LU (2011) In Blood 117(2). p.678-687
Abstract
The A4GALT locus encodes a glycosyltransferase that synthesizes the terminal Galα1-4Gal of the P(k)(Gb3/CD77) glycosphingolipid, important in transfusion medicine, obstetrics and pathogen susceptibility. Critical nucleotide changes in A4GALT not only abolish P(k) formation but also another Galα1-4Gal-defined antigen, P1, which belongs to the only blood group system for which the responsible locus remains undefined. Since known A4GALT polymorphisms do not explain the P1-P(k)+ phenotype, P(2), we set out to elucidate the genetic basis of P(1)/P(2). Despite marked differences (P(1)>P(2)) in A4GALT transcript levels in blood, luciferase experiments showed no difference between P(1)/P(2)-related promoter sequences. Investigation of... (More)
The A4GALT locus encodes a glycosyltransferase that synthesizes the terminal Galα1-4Gal of the P(k)(Gb3/CD77) glycosphingolipid, important in transfusion medicine, obstetrics and pathogen susceptibility. Critical nucleotide changes in A4GALT not only abolish P(k) formation but also another Galα1-4Gal-defined antigen, P1, which belongs to the only blood group system for which the responsible locus remains undefined. Since known A4GALT polymorphisms do not explain the P1-P(k)+ phenotype, P(2), we set out to elucidate the genetic basis of P(1)/P(2). Despite marked differences (P(1)>P(2)) in A4GALT transcript levels in blood, luciferase experiments showed no difference between P(1)/P(2)-related promoter sequences. Investigation of A4GALT-mRNA in cultured human bone marrow cells revealed novel transcripts containing only the non-coding exon 1 and a sequence (here termed exon 2a) from intron 1. These 5'-capped transcripts include poly-A tails and 3 polymorphic sites, one of which was P(1)/P(2)-specific among >200 donors and opens a short reading frame in P(2) alleles. We exploited these data to devise the first genotyping assays to predict P1 status. P(1)/P(2) genotypes correlated with both transcript levels and P1/P(k) expression on red cells. Thus, P(1) zygosity partially explains the well-known interindividual variation in P1 strength. Future investigations need to focus on regulatory mechanisms underlying P1 synthesis. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
117
issue
2
pages
678 - 687
publisher
American Society of Hematology
external identifiers
  • wos:000286178700039
  • pmid:20971946
  • scopus:78751555877
ISSN
1528-0020
DOI
10.1182/blood-2010-08-301333
language
English
LU publication?
yes
id
19f6ba2e-125c-4696-bbf5-f91d93a768cd (old id 1710811)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20971946?dopt=Abstract
date added to LUP
2010-11-05 13:55:04
date last changed
2017-10-09 09:42:01
@article{19f6ba2e-125c-4696-bbf5-f91d93a768cd,
  abstract     = {The A4GALT locus encodes a glycosyltransferase that synthesizes the terminal Galα1-4Gal of the P(k)(Gb3/CD77) glycosphingolipid, important in transfusion medicine, obstetrics and pathogen susceptibility. Critical nucleotide changes in A4GALT not only abolish P(k) formation but also another Galα1-4Gal-defined antigen, P1, which belongs to the only blood group system for which the responsible locus remains undefined. Since known A4GALT polymorphisms do not explain the P1-P(k)+ phenotype, P(2), we set out to elucidate the genetic basis of P(1)/P(2). Despite marked differences (P(1)>P(2)) in A4GALT transcript levels in blood, luciferase experiments showed no difference between P(1)/P(2)-related promoter sequences. Investigation of A4GALT-mRNA in cultured human bone marrow cells revealed novel transcripts containing only the non-coding exon 1 and a sequence (here termed exon 2a) from intron 1. These 5'-capped transcripts include poly-A tails and 3 polymorphic sites, one of which was P(1)/P(2)-specific among >200 donors and opens a short reading frame in P(2) alleles. We exploited these data to devise the first genotyping assays to predict P1 status. P(1)/P(2) genotypes correlated with both transcript levels and P1/P(k) expression on red cells. Thus, P(1) zygosity partially explains the well-known interindividual variation in P1 strength. Future investigations need to focus on regulatory mechanisms underlying P1 synthesis.},
  author       = {Thuresson, Britt and Westman, Julia and Olsson, Martin L},
  issn         = {1528-0020},
  language     = {eng},
  number       = {2},
  pages        = {678--687},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Identification of a novel A4GALT exon reveals the genetic basis of the P1/P2 histo-blood groups.},
  url          = {http://dx.doi.org/10.1182/blood-2010-08-301333},
  volume       = {117},
  year         = {2011},
}