New insights into the Rh superfamily of genes and proteins in erythroid cells and nonerythroid tissues.

The past decade has seen extensive studies of the erythrocyte Rh30 polypeptides and Rh-associated glycoprotein, which specify the clinically important Rh blood group system. Here we consider recent advances on these and other Rh homologues in the context of gene organization, molecular evolution, tissue-specific expression, protein structure, and potential biological functions. The Rh family is now known to contain a large number of homologues that form a unique branch in the eucarya life domain. The ancient origin and broad distribution imply central roles for the various Rh proteins in maintaining normal cellular and organismal homeostatic conditions. Rh homologues occur in the form of multiple chromosomal loci in mice and humans, but as single-copy genes in unicellular organisms (e.g., green alga and slime mold). While primitive Rh genes vary largely in exon/intron design, the mammalian Rh homologues bear a similar genomic organization. Sequence comparisons have revealed the signatures and a consensus 12-transmembrane fold characteristic of the Rh family. Phylogenetic analysis has placed all Rh homologues as a related cluster that intercepts ammonium transporter (Amt) clusters, indicating an intimate evolutionary and structural relationship between the Rh and Amt families. The biochemical identification and epithelial expression of RhBG and RhCG orthologues in mammalian kidney, liver, skin, testis, and brain suggest that they serve as transporters likely participating in ammonia homeostasis. Further inquires into the structure, function, biosynthesis, and interaction of Rh proteins will shed new light on ammonia homeostasis in a wide range of human physiological and pathological states.