Rhag, the Rhesus-associated glycoprotein, is crucial for maintaining the structure and stability of erythrocytes and is essential for the assembly of the Rh protein complex in the erythrocyte membrane and the expression of Rh antigens [2,3]. It may also be involved in gas transport processes, specifically in NH₃ conductance in erythrocytes [1]. Genetic models, such as gene knockout mouse models, have been valuable in studying its functions.

Mice with inactivated Rhag genes (Rhag-/-) have a total absence of Rhag and Rh proteins. Preliminary analysis of these KO mice indicates that Rhag plays a significant role in the presence and likely the function of Rh proteins in red cells [4]. In human studies, single missense mutations in the Rhag -encoding gene can lead to spherocytosis and deficiencies in Rh complex formation, and a novel missense mutation was found to selectively disrupt RhD antigen expression [2]. A nonsense variant in RHAG underlies the Nordic Rhnull phenotype, characterized by the absence of all Rh antigens on erythrocytes [5].

In conclusion, Rhag is essential for erythrocyte structure, Rh antigen expression, and may contribute to gas transport in erythrocytes. Studies using Rhag KO mouse models and human genetic variants have provided insights into its role in maintaining normal erythrocyte function and have implications for understanding rare blood phenotypes such as the Rhnull phenotype.

References:

1. Ripoche, P, Goossens, D, Devuyst, O, Verkman, A S, Cartron, J-P. 2006. Role of RhAG and AQP1 in NH3 and CO2 gas transport in red cell ghosts: a stopped-flow analysis. In Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine, 13, 117-22. doi:. https://pubmed.ncbi.nlm.nih.gov/16574458/

2. Mu, S, Cui, Y, Wang, W, Zhu, O, Zhu, D. 2018. A RHAG point mutation selectively disrupts Rh antigen expression. In Transfusion medicine (Oxford, England), 29, 121-127. doi:10.1111/tme.12519. https://pubmed.ncbi.nlm.nih.gov/29508504/

3. Avent, N D, Reid, M E. . The Rh blood group system: a review. In Blood, 95, 375-87. doi:. https://pubmed.ncbi.nlm.nih.gov/10627438/

4. Goossens, D, Bony, V, Gane, P, Colin, Y, Cartron, J-P. 2006. Generation of mice with inactivated Rh or Rhag genes. In Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine, 13, 164-6. doi:. https://pubmed.ncbi.nlm.nih.gov/16581281/

5. Hellberg, Åsa, Arsenovic, Mirjana Grujic, Sørvoll, Ingvild Hausberg, Olsson, Martin L, Storry, Jill R. 2023. A novel nonsense variant in RHAG underlies a Nordic Rhnull phenotype. In Vox sanguinis, 118, 690-694. doi:10.1111/vox.13478. https://pubmed.ncbi.nlm.nih.gov/37265146/