LYCOPHORIN-A (GPA), GPB, GPC, and GPD G constitute a group of red blood cell (RBC) transmembrane proteins that, although perhaps not widely appreciated in clinical hematology, have been important players in the fields of membrane biochemistry and cellular biology for several decades. GPA was the first membrane protein to be sequenced1, 2 and has subsequently served as a model for topology of receptors and other transmembrane glycoproteins in both erythroid and nonerythroid cells. Initially, hematologic interest in the glycophorins was limited to blood bank serologists and the characterization of blood group antigens located on these sialoglycoproteins. However, with emerging data from functional studies, it is becoming apparent that certain glycophorins play important, but differing, roles in regulating RBC membrane mechanical properties and in maintaining RBC shape. Because several of these glycophorins are also expressed in various nonerythroid tissues, the functional importance of their interactions with the membrane skeleton may have a widespread biologic significance. The presence of glycophorins in the RBC membrane was initially detected by Fairbanks et aL3 The four varieties of glycophorin comprise approximately 2% of the total RBC membrane protein, with GPA as the major component present at 5 to 9 x lo5 copies per cell, while the less abundant GPB, GPC, and GPD are present at 0.8 to 3 x lo5, 0.5 to 1 X 105, and 0.2 x lo5 copies per cell, re~ pectively. 4-~ Because of their high sialic acid content, these molecules account for approximately 60% of the RBC’s negative surface charge. As such, they play a pivotal role in modulating RBC-RBC interactions, as well as RBC interactions with the vascular endothelium and other circulating blood cells. Over the past 2 decades, an unfortunate confusion was created in the glycophorin field by the appearance of four different nomenclatures (Table l). 3, 6, s-10 Fortunately for us, a consensus has recently been reached among the investigators in the field, who have agreed to designate the various glycophorins as GPA, GPB, GPC, and GPD.

Protein, cDNA and genomic sequence analysis have provided a detailed characterization of the primary structure of GPA, GPB, and GPC. 1, 2J1-1s The primary structure of GPD is currently under study, but immunochemical and biochemical data imply that this is a protein closely related to GPC. Although these four sialoglycoproteins share the “glycophorin” name, suggesting a common genetic origin, this is partially a misnomer, because recent molecular biologic studies have firmly established that three of these glycophorins constitute different gene produ~ ts.*~,~~,~~ GPA, GPB, and GPC are encoded by three different genes on two different chromosomes. GPC and GPD do, however, appear to be closely related, arising from the same gene through use of alternative translation initiation sites. 21, Z2 Recently, a novel GPE gene was isolated that might have evolved from GPA by homologous recombination at Alu