Molecular basis of glycophorin C variants and their associated blood group antigens

Abstract

The normal and variant forms of GPC and GPD molecules carry antigens of the Gerbich blood group system. This blood group system comprises three high-incidence antigens (Ge2, Ge3 and Ge4) and four low-incidence antigens (Wb, Lsa, Dha and Ana). Erythrocytes of the Ge and Yus phenotypes lack normal GPC and GPD molecules but express variant molecules (denoted GPC.Ge, GPC.Yus, respectively) that functionally substitute for normal GPC and GPD in the membrane. Leach phenotype cells lack GPC and GPD molecules and are elliptocytic in shape with a membrane that is less deformable than that of normal cells. The Lsa antigen is expressed on higher molecular-weight variants of GPC (GPC.Lsa) and GPD (GPD.Lsa). Wb, Dha and Ana antigens arise from point mutations in the GYPC gene and are expressed on GPC.Wb, GPC.Dha and GPD.Ana, respectively. The structure of each of the variant GPC and GPD molecules and the location of the Gerbich blood group system antigens is discussed. The GYPC gene, located on chromosome 2q14-q21, is 13.5 kb long and comprises four exons. Exons 1, 2 and most of exon 3 encode the N-terminal extracellular domain while the remainder of exon 3 and exon 4 encode transmembrane and cytoplasmic domains of GPC. Exons 2 and 3 are highly homologous, with less than 5% nucleotide divergence. The molecular basis of generation of variation GPC and GPD molecules, and the structure of the GYPC gene from different Leach phenotype individuals, is discussed.

Polymorphism in the Plasmodium falciparum erythrocyte-binding ligand JESEBL/EBA-181 alters its receptor specificity

“…On human erythrocytes carrying the Gerbich-negative blood group antigen, glycophorin C is missing part of its peptide backbone. In addition, it contains an abnormal N-linked glycan (44). It is possible that the N-linked glycan on glycophorin C is the receptor for BAEBL, because a point mutation in BAEBL is unlikely to recognize an unrelated protein.…”

Other Blood Group Antigens and Antibodies

“…135 The gene, located at chromosome 2q14-q21, consists of four exons. The two glycoproteins are products of the GYPC gene.…”

“…135 Except in Papua New Guinea, Gerbich-negative RBCs are seldom found. Of the four low-incidence antigens, three (Wb, An a , Dh a ) are the result of an amino acid substitution, and one (Ls a ) is created by a novel amino acid sequence derived from a duplication of exon 3 and encoded by nucleotides at the exon 3 to exon 3 junction.…”

“…Of the four low-incidence antigens, three (Wb, An a , Dh a ) are the result of an amino acid substitution, and one (Ls a ) is created by a novel amino acid sequence derived from a duplication of exon 3 and encoded by nucleotides at the exon 3 to exon 3 junction. 135 The Leach phenotype has been restricted to people of Northern European extraction. The three Gerbich-negative phenotypes are as follows: Ge:−2,3,4 (the Yus phenotype), Ge:−2,−3,4 (the Gerbich phenotype), and Ge:−2,−3,−4 (the Leach phenotype).…”

Characterization of a Plasmodium falciparum erythrocyte-binding protein paralogous to EBA-175

“…There are three mutations of the glycophorin C͞D gene that lack high-incidence antigens (25). Leach erythrocytes are null for these proteins; Gerbich and Yus erythrocytes contain exon 3 and 2 deletions, respectively, that lead to a shortened glycophorin C and missing glycophorin D. Both Gerbich and Yus cells have abnormal N-linked glycosylation of the truncated form of glycophorin C (24).…”