Abstract
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. As a result, individuals with Rhnull suffer chronic haemolytic anaemia known as the Rh-deficiency syndrome. Most frequently, Rhnull, phenotypes are caused by homozygosity of an autosomal suppressor gene unlinked to the RH locus (Rhnull regulator or Rhmod types). We have analysed the genes and transcripts encoding Rh, CD47 and Rh50 proteins in five such unrelated Rhnull cases. In all patients, we identified alteration of Rh50 — frameshift, nucleotide mutations, or failure of amplification — which correlated with Rhnull phenotype. 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.
Similar content being viewed by others
References
Agre, R. & Cartron, J.P. Molecular biology of the Rh antigens. Blood. 78, 551–563 (1991).
Cartron, J.R. & Agre, P. Rh blood group antigens: protein and gene structure. Semin. Haemal. 30, 193–208 (1993).
Race, R.R. & Sanger, R., The Rh blood Groups. In Blood Groups in Man, 6th edn. 78–260 (Blackwell, Oxford, 1975).
Tippett, R. Regulator genes affecting red cell antigens. Transfusion Medicine Rev. 4, 56–68 (1990).
Ishimori, T. & Hasekura, H.A. Japanese with no detectable Rh blood group antigens due to silent Rh alleles or deleted chromosomes. Transfusion. 7, 84–87 (1967).
Nash, R. & Shojania, A.H. Hematological aspect of Rh deficiency syndrome: a case report and review of the literature. Am. J. Hematol. 24, 267–275 (1987).
Lauf, P.K. & Joiner, C.H. Increased potassium transport and ouabain binding in human Rh-null red blood cells. Blood. 48, 457–468 (1976).
Ballas, S. et al. Red cell membranes and cation deficiency in Rh-null syndrome. Blood. 63, 1046–1055 (1984).
Kuypers, F. et al. Rh-null human erythrocytes have an abnormal membrane phospholipid organization. Biochem. J. 221, 931–934 (1984).
Anstee, D.J. & Tanner, M.J.A. Biochemical aspects of the blood group Rh (rhesus) antigens. In Baillère's Clinical Haematology, Red Cell Membrane and Red Cell Antigens,Vol . 6, 401–422 (BaillièreTindall, London, 1993).
Cartron, J.p. Defining the Rh blood group antigens. Blood Rev. 8, 199–212 (1994).
Avent, N.D. et al. Monoclonal antibodies that recognize different membrane proteins that are deficient in Rhnull human erythrocytes. Biochem. J. 251, 499–505 (1988).
Mawby, W.J., Holmes, C.H., Anstee, D.J., Spring, F. & Tanner, M.J.A. Isolation and characterization of CD47 glycoprotein: a multispanning membrane protein which is the same as integrin-associated protein (IAP) and the ovarian tumor marker OA3. Biochem. J. 304, 525–530 (1994).
Campbell, I.G., Freemont, P.S., Foulkes, W. & Trowsdale, J. An ovarian tumor marker with homology to vaccinia virus contains an IgV-like region and multiple transmembrane domains. Cancer Res. 52, 5416–5420 (1992).
Lindberg, F.R. et al. Rh-related antigen CD47 is the signal transducer integrin-associated protein. J. Biol. Chem. 269, 1567–1570 (1994).
Schwartz, M.A., Brown, E.J. & Fazeli, B. A 50 kDa integrin-associated protein is required for integrin-regulated calcium entry in endothelilal cells. J. Biol. Chem. 268, 19931–19934 (1993).
Ridgwell, K., Spurr, N.K., Laguda, B., Macgeoch, C., Avent, N.D. & Tanner, M.J.A. Isolation of cDNA clones for a 50 kDa glycoprotein of the human erythrocyte membrane associated with Rh (Rhesus) blood group antigen expression. Biochem. J. 287, 223–228 (1992).
Eyers, S.A.C., Ridgwell, K., Mawby, W.J. & Tanner, M.J.A. Topology and organization of human Rh (Rhesus) blood group related polypeptides. J. Biol. Chem. 269, 6417–6423 (1994).
Cherif-Zahar, B. et al. Structure and expression of the RH locus in the Rh-deficiency syndrome. Blood. 82, 656–662 (1993).
Carritt, B., Blunt, T., Avent, N.D., Daniels, G. & Steers, F. Rhnull phenotypes are not due to a gross deletion and can occur on different genetic backgrounds. Ann. Hum. Genet. 57, 273–279 (1993).
Alloisio, N. et al. Evidence that red blood cell protein p55 may participate in the skeleton-membrane linkage that involves protein 4.1 and glycophorin C. Blood. 82, 1323–1327 (1993).
Triglia, T., Peterson, M.G. & Kemp, D.J. A procedure for in vitro amplification of DMA segments that lie outside the boundaries of known sequences.Nucl. Acids Res. 16, 8186 (1988).
Cherif-Zahar, B., Mattel, M.G., Le Van Kim, C., Cartron, J.R. & Colin, Y. Localization of the human Rh blood group gene structure to chromosome region 1p34. 3-p36.1 by in situ hybridization. Hum. Genet. 86, 398–400 (1991).
Gardner, B., Anstee, D.J., Mawby, W.J., Tanner, M.J.A. & von dem Borne, A.E.G . Kr. The abundance and organization of polypeptides associated with antigens of the Rh blood group system. Transfusion Med. 1, 77–85 (1991).
Poss, M.T., Swanson, J.L., Telen, M.J., Lasky, L.C. & Vallera, D.A. Monoclonal antibody recognizing a unique Rh-related specificity. Vox. Sang. 64, 231–239 (1993).
Deen, P.M.T., Croes, H. ., van Aubel, R.A.M.H., Ginsel, L.A., & van Os, C.H. . Water channels encoded by mutant aquaporin-2 genes in nephrogenic diabetes insipidus are impaired in their cellular routing. J. Clin. Invest. 95, 2291–2296 (1995).
Hermand, P. et al. Immunochemical characterization of Rhesus proteins with antibodies raised against synthetic peptides. Blood. 82, 669–676 (1993).
Mollison, P.L., Engelfriet, C.R. & Contreras, M., Transfusion in Clinical Medicine, 9th edn., 204–245 (Blackwell, London, 1993).
Tournamille, C., Le Van Kim, C., Gane, R., Cartron, J.R. & Colin, Y. Molecular basis and PCR-DNA typing of the FyrVFy5 blood group polymorphism. Hum. Genet. 95, 407–410 (1995).
Izraeli, S., Pfleiderer, C. & Lion, T. Detection of gene expression by PCR amplification of RNA derived from frozen heparinized whole blood. Nucl. Acids Res. 19, 6051 (1991).
Sanger, F., Nicklen, S. & Coulson, A.R. DNA sequencing with chain-terminating inhibitors. Proc. Natl. Acad. Sci. USA. 74, 5463–5467 (1977).
Mattel, M.G., Phillip, N., Passage, E., Moisan, J.R., Mandel, J.L. & Mattei, J.F. DNA probe localization at 18p11.3 band by in situ hybridization and identification of a small supernumerary chromosome. Hum. Genet. 69, 268–271 (1985).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Cherif-Zahar, B., Raynal, V., Gane, P. et al. Candidate gene acting as a suppressor of the RH locus in most cases of Rh-deficiency. Nat Genet 12, 168–173 (1996). https://doi.org/10.1038/ng0296-168
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0296-168
- Springer Nature America, Inc.
This article is cited by
-
The molecular genetics of blood group polymorphism
Human Genetics (2009)
-
Expression of the human erythroid Rh glycoprotein (RhAG) enhances both NH3 and NH4+ transport in HeLa cells
Pflügers Archiv - European Journal of Physiology (2005)
-
The human Rhesus-associated RhAG protein and a kidney homologue promote ammonium transport in yeast
Nature Genetics (2000)