Lutheran antigens, CD44-related antigens, and Lutheran regulatory genes

The Lutheran (Lu) blood group antigens are a family of human erythrocyte antigens which reside on two closely-related erythrocyte integral membrane 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 encodes an integral membrane protein of 597 amino acids that is a member of 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 differ only in their 3' ends, suggesting that they arise from alternate splicing 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 alleles. However, the most common Lu(a-b-) phenotype appears to be caused by an independently segregating, dominant gene, designated In (Lu), which inhibits expression of all Lutheran antigens to nearly undetectable levels. This gene also affects the expression of other cell surface proteins and blood group antigens that are genetically unlinked to the Lutheran locus, including CD44 and MER2. CD44, a member of the cartilage link family of proteins, bears the In and AnWj blood group antigens. A widely distributed protein CD44 is expressed at normal levels on 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. The XS2 gene down-regulates but does not abolish expression of LU genes and does not affect expression of CD44.