C O N T E N T SSee AlsoDescriptionDiego antigens are carried on the erythroid band 3 protein (anion exchanger 1, AE1), product of a single gene, SLC4A1 (solute carrier family 4, anion exchanger, member 1). It is the major integral membrane protein of the erythrocyte. Erythroid band 3 protein is a member of a family of three anion exchangers AE1, AE2 and AE3 expressed in a variety of tissues. They share a high degree of homology in the membrane domain, both AE2 and AE3 having a much longer amino- terminal cytoplasmic domains than AE1. Band 3 consists of two structurally and functionally largely independent domains: the amino-terminal cytoplasmic domain links the membrane to the underlying spectrin-actin based skeleton using ankyrin and protein 4.1 as the bridging proteins; the carboxy-terminal membrane domain mediates the exchange of chloride and bicarbonate anions across the plasma membrane. Structural models predict that the membrane domain consists of 12 to 14 transmembrane helices connected by ecto- and endoplasmic loops. The longest, fourth loop, is N-glycosylated and its single lactosamine-rich glycan chain carries over half of the red cell ABO blood group epitopes. The absence of Band 3 in mice erythrocytes results in severe spherocytosis and hemolysis but the skeleton assembly is not disrupted and levels of major skeletal components such as spectrin or protein 4.1 are normal; however Glycophorin A is absent and proteins of the Rh family are reduced; red blood cell differentiation proceeds normally. (Peters et al., Cell 86, 917, 1996; Hassoun H. et al., Blood 91, 2146, 1998; Bruce et al., Blood 101, 4180, 2003). Recently the crystal structure of the Band 3 cytoplasmic domain was solved at 2.6 A resolution. The binding sites for ankyrin, Protein 4.1 and several other peripheral proteins were localized. Consequences of some mutations are evaluated (Zhang et al., Blood 96, 2925, 2000). Function of proteinsMain function: 1) the amino-terminal cytoplasmic domain - links the membrane to the underlying spectrin-based membrane skeleton and interacts with several glycolytic enzymes, hemoglobin and hemichromes; 2) the carboxy-terminal membrane domain - mediates the exchange of chloride and bicarbonate anions across the plasma membrane and contributes to the stability of the lipid bilayer via interactions with adjacent phospholipid molecules. Additional functions: 1) in congenital dyserythropoietic anemia (CDA) a typical finding is the absence of Band 3 glycosylation. Currently it is not clear whether or not this plays a role in pathogenesis of CDA. 2) Band 3 has been implicated in the formation of so-called senescent antigens in aging erythrocytes. This antigen appears to be recognized by the reticuloendothelial system and the aged red cell is removed from circulation. The exact molecular structure of the senescent antigen has not been elucidated. 3) Band 3 plays a role in attachment of malarial parasites to the surface of red cells and in adhesion of parasitized cells to the vascular endothelium. Also, it appears to participate in adhesion of sickle erythrocytes to vessel walls. Interactions of the cytoplasmic domain with glycolytic enzymes plays a role in regulation of intracellular metabolism. Thus band 3 plays a role in control of cell flexibility and shape, ion transport, regulation of carbohydrate metabolism and cell life span. Tissue distributionThe erythroid SLCA1 gene is expressed in red cells and its product, Band 3, is the most abundant integral protein of the red cell membrane with over 1 million copies per red cell. It is also expressed in the kidney. Some reports, so far unconfirmed, suggested expression in bones and inner ear. The expression of AE2 and AE3 has a much wider distribution. Disease associationNone with alleles encoding variants of the Diego blood group antigen, but products of the other alleles have been implicated in pathogenesis of Southern Asian (Melanesian) ovalocytosis (Band3 SAO), congenital acanthocytosis (Band3 HT), distal renal tubular acidosis (Band3 dRTA) and hereditary spherocytosis (all others). About the allelesExcept for the allele SLC4A1-Memphis, large differences exist in the incidence of expression of different alleles among the world populations. For example, the DIa blood group antigen, associated with the expression of the SLC4A1-DIa allele has never been found in individuals of presumed unmixed European origin, except for one American of Polish origin, one Irish Australian and one Czech blood donor; yet, this allele is characterisitic of Mongoloids. Gene frequency is as high as 40% among South American Indians, but frequencies vary widely, and the gene is absent from a few tribes. The gene also shows high frequencies among Central American Indians, but moderate ones among North American Indians, and it is absent among the Eskimos. In Eastern Asia the frequencis are 1-5%, but in Korea and Tibet, 7% and 8% respectively. In the list of alleles, the alleles shown belong to two types: 1) alleles (denoted by a name), whose products show some structural abnormality, usually associated with spherocytosis or changes in gel behavior or labeling with DIDS; those alleles are often associated with a disease state; and 2) alleles (denoted by the blood group phenotype they exhibit) whose products exibit a variant serological behavior. The latter usually are single mutations and many are clustered in the segment encoding loop 3. The sequence of SLC4A1-DIb (the "wild type" gene; acc. no. M27819) is taken as reference; the cDNA and translation changes are numbered from the codon for the initiator Met. DiscussionWhile Africans, or Negroids, have a considerable number of blood group marker genes peculiar to themselves, east Asians, or Mongoloids, have only one known one, the Diego or Dia gene. The allelic Dib gene is, even in Mongoloid populations, the commoner of the two. The Dia gene is interesting as being possessed in common by east Asians and American Indians, and this is one of the indicators of the Asian origin of the latter.(1) LinksAttribution
References1. Mourant, AE. Blood Relations, Blood Groups and Anthropology. Oxford University Press, Oxford, UK 1983. |
