RHAG

RHAG, or Rh-associated glycoprotein, is a human gene that encodes a transmembrane glycoprotein essential for the surface expression of Rh blood group antigens on red blood cells. The RHAG protein interacts with the classical Rh antigens encoded by RHD and RHCE, forming a multimeric Rh complex that stabilizes RhD and RhCE at the erythrocyte membrane. Without functional RHAG, red cells may display reduced or absent Rh antigens even when RHD and RHCE genes are present.

Mutations or deletions in RHAG can give rise to Rh-deficiency phenotypes, including the Rhnull phenotype, in which all Rh antigens are absent from the red cell surface. Such phenotypes are often associated with membrane abnormalities and, in some cases, hemolytic anemia. These conditions illustrate that RHAG function is necessary for normal Rh antigen expression, independent of the alleles at the RHD or RHCE loci.

Expression and function: RHAG is predominantly expressed in erythroid cells and encodes a glycoprotein with a single transmembrane domain. The precise role of the Rh protein complex, including RHAG, is not fully resolved; Rh proteins are thought to participate in transport processes such as ammonium transport and in maintaining red cell membrane integrity. The exact contribution of RHAG to these functions remains an area of ongoing research.

Clinical relevance: Knowledge of RHAG helps explain certain serologic Rh antigen expression variants and informs blood typing and transfusion decisions when Rh antigen expression does not align with RHD/RHCE genotypes.

See also: Rh blood group system.