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Gene Review

RHAG  -  Rh-associated glycoprotein

Homo sapiens

Synonyms: Ammonium transporter Rh type A, CD241, Erythrocyte membrane glycoprotein Rh50, Erythrocyte plasma membrane 50 kDa glycoprotein, RH2, ...
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Disease relevance of RHAG

  • The available information on the structure of RH50 facilitated search for candidate mutations underlying the Rh deficiency syndrome, an autosomal recessive disorder characterized by mild to moderate chronic hemolytic anemia and spherostomatocytosis [1].
  • Similarly, sera from patients with Graves' disease displayed significant reactivity with only one of five peptides, RH2 (residues 352-366), when compared with normal sera [2].

High impact information on RHAG

  • The Rh antigen is a multi-subunit complex composed of Rh polypeptides and associated glycoproteins (Rh50, CD47, LW and glycophorin B); these interact in the red cell membrane and are lacking or severely reduced in Rhnull cells [3].
  • We propose that mutant alleles of Rh50, which map to chromosome 6p11-21.1, are likely candidates for suppressors of the RH locus accounting for most cases of Rh-deficiency [3].
  • However, analysis of RHAG transcript, which encodes Rh50 glycoprotein, identified a single G-->T transversion in the initiation codon, causing a missense amino acid change (ATG[Met]-->ATT[Ile]) [4].
  • This point mutation also occurred in the genomic region spanning exon 1 of RHAG, and its genotypic status in the mother and two children was confirmed by analysis of single-strand conformation polymorphism [4].
  • Our findings point to incomplete penetrance of the Rhmod mutation, in the form of "leaky" translation, leading to some posttranslational defects affecting the structure, interaction, and processing of Rh50 glycoprotein [4].

Biological context of RHAG

  • Homology plot analysis using the 5' sequence of the mouse RHAG gene revealed four homologous stretches and multiple insertions of repetitive sequences among them; four LINE/L1 and four Alu in the human and as well as one LINE/L1 and one LTR/MaLR in the mouse gene [5].
  • These results suggest that the 5'-flanking sequence of RHAG gene is a preferable target sequence for retroviral transposition and that the enhancer was inserted in the same manner, resulting in the acquisition of erythroid dominant expression [5].
  • Organization of the human RH50A gene (RHAG) and evolution of base composition of the RH gene family [6].
  • Here, we show that the human RH50A gene (RHAG) is composed of 10 exons whose size and exon/intron junctions are well conserved compared to those of the RH genes [6].
  • A splicing mutation of the RHAG gene associated with the Rhnull phenotype [7].

Anatomical context of RHAG

  • Although the Rh50 glycoprotein is a critical co-expressing factor, one or more factors seem to be required to express RhD or RhC(c)E(e) antigens on the plasma membranes [8].
  • The Rh (Rhesus) protein family comprises Rh50 glycoprotein and Rh30 polypeptides, which form a complex essential for Rh antigen expression and erythrocyte membrane integrity [1].
  • HEL and K562 cells showed a transcription levels ratio of 1 to 9.9 for Rh50, and 12.3 to 1 for Rh [9].
  • Northern blot analysis of leukemic cell lines showed that expression of RH50 gene is restricted to cells with erythroid features [9].
  • Co-expression studies of Rh50 and RhD or cE gene in non-erythroid cells, 293, and expression studies of Rh50 in another erythroid cell, HEL, did not show any Rh antigens on the transduced cells, despite the Northern blot study showing both transcripts in the cells [10].

Associations of RHAG with chemical compounds

  • 5. RhAG also conferred resistance to methylamine (MA), a toxic analog of ammonium, and expression in wild-type cells revealed that resistance was correlated with efflux of MA [11].
  • Heterologous expression of the RH-2 gene in Chinese hamster ovary cells led to the appearance of high affinity binding sites for 5-HT (Kd = 2.6 nM, Bmax = 2.9 pmol/mg of membrane protein), and the receptor expressed in Chinese hamster ovary cells was coupled to inhibition of adenylyl cyclase [12].
  • Examples of the 5-HT1D-like pharmacology displayed by RH-2 include high affinity for the 5-HT1D-selective compound sumatriptan (Ki = 9.4 nM) and for the alpha 2-adrenergic receptor antagonist rauwolscine (Ki = 47 nM) [12].
  • The anti-neoplastic properties of an Selenium compound were studied in vitro on several tumor cell lines: Breast (MCF-7, MCF-10, SKBR-3, BCAP37), Lung (RH2), Prostate (LNCap and PC-3), Colon (T84, Caco-2), Small Intestine (HCF8), and Liver (HepG2) [13].
  • Addition of chemotherapeutic agents either Taxol or Doxorubicin with Selenium caused further inhibition of MCF-7, SKBR-3, RH2, HCF8, and HepG2 cells [13].

Other interactions of RHAG

  • The duplication event leading to RH50 and RH30 genes was estimated to have occurred between 250 and 346 million years ago [14].
  • In two of these genes, MEP1A and RHAG, we identified two novel polymorphisms associated with the disease haplotype [15].
  • The expression of its antigens is controlled by a two-component genetic system consisting of RH and RHAG loci, which encode Rh30 polypeptides and Rh50 glycoprotein, respectively [16].
  • In one patient with the Rhnull disease of regulator type, a shortened Rh50 transcript lacking the sequence of exon 7 was detected, while no abnormality was found in transcripts encoding Rh30 polypeptides and Rh-related CD47 glycoprotein [1].
  • The core promoter of RH50 gene was located within 68bp length from the translation start position, which included an inverse GATA motif, although obvious motifs for Sp1 or erythroid Krüppel-like factor were lacking [9].

Analytical, diagnostic and therapeutic context of RHAG


  1. The human Rh50 glycoprotein gene. Structural organization and associated splicing defect resulting in Rh(null) disease. Huang, C.H. J. Biol. Chem. (1998) [Pubmed]
  2. Prokaryotic expression of the thyrotropin receptor and identification of an immunogenic region of the protein using synthetic peptides. Takai, O., Desai, R.K., Seetharamaiah, G.S., Jones, C.A., Allaway, G.P., Akamizu, T., Kohn, L.D., Prabhakar, B.S. Biochem. Biophys. Res. Commun. (1991) [Pubmed]
  3. Candidate gene acting as a suppressor of the RH locus in most cases of Rh-deficiency. Cherif-Zahar, B., Raynal, V., Gane, P., Mattei, M.G., Bailly, P., Gibbs, B., Colin, Y., Cartron, J.P. Nat. Genet. (1996) [Pubmed]
  4. Rhmod syndrome: a family study of the translation-initiator mutation in the Rh50 glycoprotein gene. Huang, C., Cheng, G.J., Reid, M.E., Chen, Y. Am. J. Hum. Genet. (1999) [Pubmed]
  5. Cloning and characterization of erythroid-specific DNase I-hypersensitive site in human rhesus-associated glycoprotein gene. Iwamoto, S., Suganuma, H., Kamesaki, T., Omi, T., Okuda, H., Kajii, E. J. Biol. Chem. (2000) [Pubmed]
  6. Organization of the human RH50A gene (RHAG) and evolution of base composition of the RH gene family. Matassi, G., Chérif-Zahar, B., Raynal, V., Rouger, P., Cartron, J.P. Genomics (1998) [Pubmed]
  7. A splicing mutation of the RHAG gene associated with the Rhnull phenotype. Kawano, M., Iwamoto, S., Okuda, H., Fukuda, S., Hasegawa, N., Kajii, E. Ann. Hum. Genet. (1998) [Pubmed]
  8. Advance in the Rh blood group system. Kajii, E. Nippon Hoigaku Zasshi (1998) [Pubmed]
  9. Identification of 5' flanking sequence of RH50 gene and the core region for erythroid-specific expression. Iwamoto, S., Omi, T., Yamasaki, M., Okuda, H., Kawano, M., Kajii, E. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  10. Expression analysis of human Rhesus blood group antigens by gene transduction into erythroid and non-erythroid cells. Iwamoto, S., Yamasaki, M., Kawano, M., Okuda, H., Omi, T., Takahashi, J., Tani, Y., Omine, M., Kajii, E. Int. J. Hematol. (1998) [Pubmed]
  11. Mechanism of genetic complementation of ammonium transport in yeast by human erythrocyte Rh-associated glycoprotein. Westhoff, C.M., Siegel, D.L., Burd, C.G., Foskett, J.K. J. Biol. Chem. (2004) [Pubmed]
  12. Cloning and pharmacological characterization of a novel human 5-hydroxytryptamine1D receptor subtype. Veldman, S.A., Bienkowski, M.J. Mol. Pharmacol. (1992) [Pubmed]
  13. Effect of selenium in combination with Adriamycin or Taxol on several different cancer cells. Vadgama, J.V., Wu, Y., Shen, D., Hsia, S., Block, J. Anticancer Res. (2000) [Pubmed]
  14. The members of the RH gene family (RH50 and RH30) followed different evolutionary pathways. Matassi, G., Chérif-Zahar, B., Pesole, G., Raynal, V., Cartron, J.P. J. Mol. Evol. (1999) [Pubmed]
  15. Exclusion of the juvenile myoclonic epilepsy gene EFHC1 as the cause of migraine on chromosome 6, but association to two rare polymorphisms in MEP1A and RHAG. Norberg, A., Forsgren, L., Holmberg, D., Holmberg, M. Neurosci. Lett. (2006) [Pubmed]
  16. Molecular biology and genetics of the Rh blood group system. Huang, C.H., Liu, P.Z., Cheng, J.G. Semin. Hematol. (2000) [Pubmed]
  17. Surface expression of Rh-associated glycoprotein (RhAG) in nonerythroid COS-1 cells. Suyama, K., Li, H., Zhu, A. Blood (2000) [Pubmed]
  18. Absence of CD47 in protein 4.2-deficient hereditary spherocytosis in man: an interaction between the Rh complex and the band 3 complex. Bruce, L.J., Ghosh, S., King, M.J., Layton, D.M., Mawby, W.J., Stewart, G.W., Oldenborg, P.A., Delaunay, J., Tanner, M.J. Blood (2002) [Pubmed]
  19. Isolation of cDNA clones for a 50 kDa glycoprotein of the human erythrocyte membrane associated with Rh (rhesus) blood-group antigen expression. Ridgwell, K., Spurr, N.K., Laguda, B., MacGeoch, C., Avent, N.D., Tanner, M.J. Biochem. J. (1992) [Pubmed]
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