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

SUMMARY. 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, Ls^a, Dh^a and An^a). 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 Ls^a antigen is expressed on higher molecular-weight variants of GPC (GPC.Ls^a) and GPD (GPD.L3^a). Wb, Dh^a and An^a antigens arise from point mutations in the GYPC gene and are expressed on GPC.Wb, GPC.Dh^a and GPD.An^a, 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.