LUTHERAN ANTIGENS, CD44-RELATED ANTIGENS, AND LUTHERAN REGULATORY GENES

The Lutheran (Lu) blood group antigens are a family of human erythrocy te antigens which reside on two closely related erythrocyte integral m embrane proteins. Sixteen Lutheran or so-called para-Lutheran antigens have thus far been described, and human antisera to many of them have been shown to immunoblot two proteins, of 78 and 85 kDa. Lu cDNA enco des an integral membrane protein of 597 amino acids that is a member o f the Ig superfamily. Lu proteins comprise five Ig superfamily domains , along with a single transmembrane domain and a cytoplasmic domain of about 60 amino acids. The two proteins seen in biochemical studies of red cell membranes appear to be derived from 2 mRNA species that diff er only in their 3' ends, suggesting that they arise from alternate sp licing of a single preRNA. Three genetic backgrounds for the Lu(a-b-) [Lu null] phenotype have been described. A recessive Lu null phenotype is rarely observed as a result of homozygosity for two amorphic LU al leles. However, the most common Lu(a-b-) phenotype appears to be cause d by an independently segregating, dominant gene, designated In (Lu), which inhibits expression of all Lutheran antigens to nearly undetecta ble levels. This gene also affects the expression of other cell surfac e proteins and blood group antigens that are genetically unlinked to t he Lutheran locus, including CD44 and MER2. CD44, a member of the cart ilage Link family of proteins, bears the In and AnWj blood group antig ens. A widely distributed protein CD44 is expressed at normal levels o n all tissues except erythrocytes in the presence of the In (Lu) gene. A second Lutheran regulatory gene, XS2, is responsible for the third Lu(a-b-) phenotype, which exhibits an X-linked inheritance pattern. Th e XS2 gene down-regulates but does not abolish expression of LU genes and does not affect expression of CD44.