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P1PK Blood Group System

Globoside
Gene locus - A4GALT and B3GALNT1
Alleles

Introduction

The P-related system is characterized by three antigens whose epitopes are lipid-linked straight-chain carbohydrate units. Combinations of these antigens, and an interplay of their presence or absence, results in five phenotypes that define this system. The three antigens are: Pk antigen - Gal-alpha1,4-Gal-beta1,4-Glc-beta1-ceramide, also known as globotriosylceramide (Gb3Cer) or CD77; P antigen - GalNAc-beta1,3-Gal-alpha1,4-Gal-beta1,4-Glc-beta1-ceramide, also known as globoside (Gb4Cer); and, P1 antigen - Gal-alpha1,4-Gal-beta1,4-GlcNAc-beta1,3-Gal-beta1,4-Glc beta1 ceramide (see the figure below). P2 indicates the absence of P1 antigen, and p indicates the absence of Pk, P, and P1 and signifies a null phenotype. Two glycosyltransferases seem to be responsible for the synthesis of the three antigens. The locus for the P antigen is B3GALNT1 and recent evidence (Thuresson et al., Blood, 2011, 117:678-687) suggests that the locus for both Pk and P1 antigens is A4GALT1.

image

Pk and P belong to the globoside series and P1 belongs to the paragloboside (neolacto) series. They are synthesized by the sequential action of glycosyltransferases, the first step being the glucosylation of ceramide, followed by addition of beta galactose (Gal) to result in lactosylceramide (LacCer), a common precursor of the three antigens. After this, their biosynthetic pathways diverge. Pk results from the addition of alpha Gal by the action of alpha4-GalT1; Pk is the substrate for beta3-GalNAcT1, which adds N-acetylgalactosamine (GalNAc), resulting in the P antigen. Thus, Pk and P bear a precursor-product relationship specified by the presence or absence beta3-GalNAcT1. Galactosylgloboside is created following addition of a galactose in a alpha1-4 linkage to the P antigen. Recent studies suggest that the resulting terminal disaccharide specifies the NOR antigens responsible for NOR polyagglutination syndrome and that this addition occurs through the action of an alpha1,4Gal transferase of altered specificity, encoded by an allele of A4GALT gene which bears a change at nucleotide 631C>G (see list of alleles). The same galtransferase may also be responsible for synthesis of the P1 antigen.(Suchanowska et al.J.Biol.Chem.2012 45 38220-38230)

NOR antigen: - Gal-alpha1,4-GalNAc-beta1,3-Gal-alpha1,4-Gal-beta1,4-Glc-beta1-ceramide,

Adddition of sialic acid in an alpha2 linkage to galactosylgloboside produces LKE antigen; however, the gene responsible for this step has not been identified as yet.

It has been proposed (see references above) that the A4GALT gene, that encodes the alpha1,4-galactosyltransferase, is a single gene,that consists of four exons whose expression can vary. One exon, named exon 2a, is an alternative exon, an intronic sequence spliced to exon 1. Transcripts of three different alleles of A4GALT gene, specify the three phenotypes, either Pk and P1, Pk, or P (absence of P1) and a polymorphic site in exon 2a defines the presence or absence of the P1 antigen. B3GALNT1 gene was first reported in 1998 to be a member of the beta1,3-galactosyltransferase gene family and given the name B3GALT3. It was later shown to possess UDP-N-acetylgalactosamine:globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase or globoside synthase activity, but, in many instances, the gene name has not been changed to B3GALNT1, according to the suggestion from Okajima et al., J Biol Chem, 2000, 275(51):40498-503. Here the designation B3GALNT1 is used.

The genes

The single A4GALT gene resides on chromosome 22q13.2 and encodes a type II membrane glycosyltransferase of 360 amino acids. As noted above, recent studies suggest the presence of three alleles and indicate a complex gene organization with three constitutive exons and an alternative exon2a, that derives its sequence from the 5' end of intron 1. The entire coding sequence of the enzyme is encoded by exon 3, and a polymorphic site in exon 2a is the basis for P1/P2 polymorphism in the population. The sequence of exon 2a contains a potential ORF that may encode a regulatory peptide for level of expression of A4GALT and its activity in synthesis of P1.

Function of proteins

Pk glycolipid is the CD77 antigen, a B cell differentiation antigen. P antigen is a possible initiator of signal transduction through API and CREB associated with cell adhesion.

Tissue distribution

Antigens of the P1PK system exist on membranes of erythrocytes and other blood cells, endothelial cells, fibroblasts, smooth muscle cells of digestive tract and urogenital tissues, interstitial cells of mature placenta, tumor cells, and malignant cell lines. The P antigen is found in the lipopolysaccharides of certain bacteria.

Disease association

Antigens of P1PK system act as receptors, and participate in adhesion of pathogenic bacteria such as pyelonephritogenic and uroepithelial E. coli, strains of Streptococcus suis, and Pseudomonas aeruginosa. They also act as ligands for verotoxins from Shigella dysentereiae and enterohaemorrhagic E. coli. They may act as a fusion cofactor in the entry of the HIV virus. Cytotoxic IgM and IgG3 antibodies directed against P and/or Pk antigens are associated with a higher than normal rate of spontaneous miscarriages.

About the alleles

Genes in the A4GALT1 and B3GALNT1 families encode glycosyltransferases that participate in the last steps of the biosynthesis of Pk, P1 and P antigens respectively. Studies of the genes in individuals lacking these antigens led to the identification of genes that encode the respective enzymes and identified mutations that result in inactive enzyme. Thus, individuals with the rare but clinically significant erythrocyte phenotype p lack the capability to synthesize the Pk antigen; those that lack the capability to synthesize the P antigen show the rare but clinically significant P1k and P2k phenotypes. In the list of alleles, reference for alleles of A4GALT is the sequence with GenBank acc. no. AJ245581; for B3GALNT1, it is AB050855.

Other database IDs and links

NCBI genes
8706 for B3GALNT1
53947 for A4GALT
Uniprot ID
O75752 for B3GALNT1
Q9NPC4 for A4GALT
Genbank proteins
NP_003772 for B3GALNT1
NP_059132 for A4GALT
Gene nomenclature database ID
918 for B3GALNT1
18149 for A4GALT
Genbank nucleic acids
NM_003781 for B3GALNT1
NM_033167 for B3GALNT1
NM_033168 for B3GALNT1
NM_033169 for B3GALNT1
NM_017436 for A4GALT
NCBI homologenes for homologs and orthologs
32457 for B3GALNT1
9690 for A4GALT
NCBI dbSNP for single nucleotide polymorphisms
8706 for B3GALNT1
53947 for A4GALT
OMIM ID - at Online Mendelian Inheritance in Man
603094 for B3GALNT1
607922 for A4GALT

Literature

Marcus DM, Immunol Ser, 43:701, 1989; Bailly P and Bouhors J-P, Blood Cell Biochem, 6:299, 1995; Steffensen et al., J Biol Chem 275: 16723, 2000; Okajima et al., J Biol Chem, 275:40498, 2000; Kojima et al., J Biol Chem 275:15152, 2000; Keusch JJ et al., J Biol Chem, 275:25315, 2000; Furukawa et al., J Biol Chem 275:37752, 2000; Hellberg et al., J Biol Chem, 277:29455, 2002; Hellberg et al., Transfusion 43:899, 2003; Thuresson et al., Blood, 117:678-687, 2011.

New PubMed entries with the terms P1PK and blood from the last 30 days.
NCBI Book Sections with the terms P1PK and blood.

Contributors

Martin L. Olsson, MD, PhD, and Asa Hellberg, MSc, Department of Transfusion Medicine, Institute of Laboratory Medicine and Blood Centre, University Hospital, Se 22185, Lund, Sweden

Contributors for specific alleles are listed with the alleles.

Links


Updated 2014-03-24 19:29:32.977
 
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