Seminars in Hematology
Volume 44, Issue 1 , Pages 42-50 , January 2007

The Structure and Function of the Rh Antigen Complex

  • Connie M. Westhoff

      Affiliations

    • Corresponding Author InformationAddress correspondence to Connie M. Westhoff, SBB, PhD, American Red Cross, 700 Spring Garden, Philadelphia, PA 19123.

References 

  1. Levine P, Burnham L, Katzin WM, Vogel P. The role of isoimmunization in the pathogenesis of erythroblastosis fetalis. Am J Obstet Gynecol. 1941;42:925–937
  2. Mollison PL, Hughes-Jones NC, Lindsay M, Wessely J. Suppression of primary RH immunization by passively-administered antibody (Experiments in volunteers). Vox Sang. 1969;16:421–439
  3. Freda V, Gorman J, Pollack W. Rh factor: Prevention of isoimmunization and clinical trials in mothers. Science. 1966;151:828–830
  4. Ballas S, Clark MR, Mohandas N, Colfer HF, Caswell MS, Bergen MO, et al. Red cell membranes and cation deficiency in Rhnull syndrome. Blood. 1984;63:1046–1055
  5. Bruce LJ, Ghosh S, King MJ, et al. Absence of CD47 in protein 4.2-deficient hereditary spherocytosis in man: an interaction between the Rh complex and the band 3 complex. Blood. 2002;100:1878–1885
  6. Dahl KN, Parthasarathy R, Westhoff CM, Layton DM, Discher DE. Protein 4.2 is critical to CD47-membrane skeleton attachment in human red cells. Blood. 2004;103:1131–1136
  7. Nicolas V, Le Van Kim C, Gane P, et al. Rh-RhAG/ankyrin-R, a new interaction site between the membrane bilayer and the red cell skeleton, is impaired by Rh(null)-associated mutation. J Biol Chem. 2003;278:25526–25533
  8. Marini AM, Matassi G, Raynal V, Andre B, Cartron JP, Cherif-Zahar B. The human Rhesus-associated RhAG protein and a kidney homologue promote ammonium transport in yeast. Nat Genet. 2000;26:341–344
  9. Westhoff CM, Ferreri-Jacobia M, Mak D-OD, Foskett JK. Identification of the erythrocyte Rh blood group glycoprotein as a mammalian ammonium transporter. J Biol Chem. 2002;277:12499–12502
  10. Khademi S, O’Connell J, Remis J, Robles-Colmenares Y, Miercke LJ, Stroud RM. Mechanism of ammonia transport by Amt/MEP/Rh: Structure of AmtB at 1.35 A. Science. 2004;305:1587–1594
  11. Conroy MJ, Bullough PA, Merrick M, Avent ND. Modelling the human rhesus proteins: Implications for structure and function. Br J Haematol. 2005;131:543–551
  12. Liu Z, Chen Y, Mo R, et al. Characterization of human RhCG and mouse Rhcg as novel nonerythroid Rh glycoprotein homologues predominantly expressed in kidney and testis. J Biol Chem. 2000;275:25641–25651
  13. Liu Z, Peng J, Mo R, Hui CC, Huang CH. Rh type B glycoprotein is a new member of the Rh superfamily and a putative ammonia transporter in mammals. J Biol Chem. 2001;276:1424–1433
  14. Weiner ID, Verlander JW. Renal and hepatic expression of the ammonium transporter proteins, Rh B glycoprotein and Rh C glycoprotein. Acta Physiol Scand. 2003;179:331–338
  15. Weiner ID, Miller RT, Verlander JW. Localization of the ammonium transporters, Rh B glycoprotein and Rh C glycoprotein, in the mouse liver. Gastroenterology. 2003;124:1432–1440
  16. Cherif-Zahar B, Mattei MG, Le Van Kim C, Bailly P, Cartron J-P, Colin Y. Localization of the human Rh blood group gene structure to chromosome 1p34.3-1p36.1 region by in situ hybridization. Hum Genet. 1991;86:398–400
  17. Arce MA, Thompson ES, Wagner S, Coyne KE, Ferdman BA, Lublin DM. Molecular cloning of RhD cDNA derived from a gene present in RhD-positive, but not RhD-negative individuals. Blood. 1993;82:651–655
  18. Simsek S, de Jong CAM, Cuijpers HTM, et al. Sequence analysis of cDNA derived from reticulocyte mRNAs coding for Rh polypeptides and demonstration of E/e and C/c polymorphism. Vox Sang. 1994;67:203–209
  19. Cherif-Zahar B, Bloy C, Le Van Kim C, et al. Molecular cloning and protein structure of a human blood group Rh polypeptide. Proc Natl Acad Sci U S A. 1990;87:6243–6247
  20. Wagner FF, Flegel WA. RHD gene deletion occurred in the Rhesus box. Blood. 2000;95:3662–3668
  21. Race RR, Sanger R. Blood Groups in Man. (ed 6). Oxford, England: Blackwell; 1975;
  22. Colin Y, Cherif-Zahar B, Le Van Kim C, Raynal V, Van Huffel V, Cartron JP. Genetic basis of the RhD-positive and RhD-negative blood group polymorphism as determined by Southern analysis. Blood. 1991;78:2747–2752
  23. Singleton BK, Green CA, Avent ND, et al. The presence of an RHD pseudogene containing a 37 base pair duplication and a nonsense mutation in Africans with the Rh D- negative blood group phenotype. Blood. 2000;95:12–18
  24. Chiu RW, Murphy MF, Fidler C, Zee BC, Wainscoat JS, Lo YM. Determination of RhD zygosity: Comparison of a double amplification refractory mutation system approach and a multiplex real-time quantitative PCR approach. Clin Chem. 2001;47:667–672
  25. Lo YM, Hjelm NM, Fidler C, et al. Prenatal diagnosis of fetal RhD status by molecular analysis of maternal plasma. N Engl J Med. 1998;339:1734–1738
  26. Rijnders RJ, Van Der Luijt RB, Peters ED, et al. Earliest gestational age for fetal sexing in cell-free maternal plasma. Prenat Diagn. 2003;23:1042–1044
  27. Bianchi DW, Avent ND, Costa JM, van der Schoot CE. Noninvasive prenatal diagnosis of fetal Rhesus D: Ready for prime(r) time. Obstet Gynecol. 2005;106:841–844
  28. Daniels G. Human Blood Groups. (ed 2). Cambridge, MA: Blackwell Science; 2002;
  29. Wagner FF, Gassner C, Muller TH, Schonitzer D, Schunter F, Flegel WA. Molecular basis of weak D phenotypes. Blood. 1999;93:385–393
  30. Blumenfeld OO, Patnaik SK. Allelic genes of blood group antigens: a source of human mutations and cSNPs documented in the Blood Group Antigen Gene Mutation Database. Hum Mutat. 2004;23:8–16
  31. Wagner FF, Flegel WA: The Rhesus Site. http://www.uni- ulm.de/∼fwagner/RH/RB/weakD.htm
  32. Shao CP, Maas JH, Su YQ, Kohler M, Legler TJ. Molecular background of Rh D- positive, D-negative, D(el) and weak D phenotypes in Chinese. Vox Sang. 2002;83:156–161
  33. Sun CF, Chou CS, Lai NC, Wang WT. RHD gene polymorphisms among RhD- negative Chinese in Taiwan. Vox Sang. 1998;75:52–57
  34. Beck ML, Harding J. Incidence of D category VI among Du donors in the USA. Transfusion. 1991;31(suppl):25
  35. Lacey PA, Caskey CR, Werner DJ, Moulds JJ. Fatal hemolytic disease of a newborn due to anti-D in an Rh-positive Du variant mother. Transfusion. 1993;23:91–94
  36. Krumpel B. Are weak D RBCs really immunogenic?. Transfusion. 2006;46:1061–1066
  37. Garratty G. Do we need to be more concerned about weak D antigens?. Transfusion. 2005;45:1547–1551
  38. Flegel WA. Homing in on D antigen immunogenicity. Transfusion. 2005;45:466–468
  39. Wagner T, Kormoczi GF, Buchta C, et al. Anti-D immunization by DEL red blood cells. Transfusion. 2005;45:520–526
  40. Yasuda H, Ohto H, Sakuma S, Ishikawa Y. Secondary anti-D immunization by Del red blood cells. Transfusion. 2005;45:1581–1584
  41. Westhoff CM. Review: The Rh blood group D antigen…dominant, diverse, and difficult. Immunohematol. 2005;21:155–163
  42. Wagner FF, Ladewig B, Flegel WA. The RHCE allele ceRT: D epitope 6 expression does not require D-specific amino acids. Transfusion. 2003;43:1248–1254
  43. Chen Q, Hustinx H, Flegel WA. The RHCE allele ceSL: The second example for D antigen expression without D-specific amino acids. Transfusion. 2006;46:766–772
  44. Beckers EA, Porcelijn L, Ligthart P, et al. The RoHar antigenic complex is associated with a limited number of D epitopes and alloanti-D production: A study of three unrelated persons and their families. Transfusion. 1996;36:104–108
  45. Daniels GL, Faas BH, Green CA, et al. The VS and V blood group polymorphisms in Africans: A serologic and molecular analysis. Transfusion. 1998;38:951–958
  46. Adams RJ, Brambilla DJ, Granger S, et al. Stroke and conversion to high risk in children screened with transcranial Doppler ultrasound during the STOP study. Blood. 2004;103:3689–3694
  47. Lee MT, Piomelli S, Granger S, et al. Stroke Prevention Trial in Sickle Cell Anemia (STOP): Extended follow-up and final results. Blood. 2006;109:847–852
  48. Vichinsky E, Fischer R, Fung E. A randomized, controlled phase II trial in sickle cell disease patients with chronic iron overload demonstrates that once-daily oral iron chelator deferasirox (Exjade, ICL670) is well tolerated and reduces iron burden. Blood. 2005;106:95a;(abstr)
  49. Ness PM. To match or not to match: The question for chronically transfused patients with sickle cell anemia. Transfusion. 1994;34:558–560
  50. Wayne AS, Kevy SV, Nathan DG. Transfusion management of sickle cell disease. Blood. 1993;81:1109–1123
  51. 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. 1996;12:168–173
  52. Huang C-H. Molecular insights into the Rh protein family and associated antigens. Curr Opin Hematol. 1997;4:94–103
  53. Marini A-M, Urrestarazu A, Beauwens R, Andre B. The Rh (Rhesus) blood group polypeptides are related to NH4+ transporters. TIBS. 1997;22:460–461
  54. Westhoff CM, Siegel DL, Burd CG, Foskett JK. Mechanism of genetic complementation of ammonium transport in yeast by human erythrocyte Rh-associated glycoprotein. J Biol Chem. 2004;279:17443–17448
  55. Mak DO, Dang B, Weiner ID, Foskett JK, Westhoff CM. Characterization of ammonia transport by the kidney Rh glycoproteins RhBG and RhCG. Am J Physiol Renal Physiol. 2006;290:F297–F305
  56. Ludewig U. Electroneutral ammonium transport by basolateral rhesus B glycoprotein. J Physiol. 2004;559:751–759
  57. Ripoche P, Bertrand O, Gane P, Birkenmeier C, Colin Y, Cartron JP. Human Rhesus-associated glycoprotein mediates facilitated transport of NH(3) into red blood cells. Proc Natl Acad Sci U S A. 2004;101:17222–17227
  58. Zheng L, Kostrewa D, Berneche S, Winkler FK, Li XD. The mechanism of ammonia transport based on the crystal structure of AmtB of Escherichia coli. Proc Natl Acad Sci U S A. 2004;101:17090–17095
  59. Verlander JW, Miller RT, Frank AE, Royaux IE, Kim YH, Weiner ID. Localization of the ammonium transporter proteins RhBG and RhCG in mouse kidney. Am J Physiol. 2003;284:F323–F337
  60. Handlogten ME, Hong SP, Westhoff CM, Weiner ID. Basolateral ammonium transport by the mouse inner medullary collecting duct, mIMCD-3, cell. Am J Physiol Renal Physiol. 2004;287:F628–F638
  61. Handlogten ME, Hong SP, Westhoff CM, Weiner ID. Apical ammonia transport by the mouse inner medullary collecting duct cell (mIMCD-3). Am J Physiol Renal Physiol. 2005;289:F347–F358
  62. Westhoff CM, Wylie DE. Transport characteristics of mammalian Rh and Rh glycoproteins expressed in heterologous systems. Transfus Clin Biol. 2006;13:132–138
  63. Matassi G, Cherif-Zahar B, Pesole G, Raynal V, Cartron JP. The members of the RH gene family (RH50 and RH30) followed different evolutionary pathways. J Mol Evol. 1999;48:151–159
  64. Kitano T, Sumiyama K, Shiroishi T, Saitou N. Conserved evolution of the Rh50 gene compared to its homologous Rh blood group gene. Biochem Biophy Res Commun. 1998;249:78–85
  65. Sturgeon P. Hematological observations on the anemia associated with blood type Rhnull. Blood. 1970;36:310–320
  66. Huang CH, Liu PZ, Chen JG. Molecular biology and genetics of the Rh blood group system. Semin Hematol. 2000;37:150–165
  67. Avent ND, Reid ME. The Rh blood group system: A review. Blood. 2000;95:375–387
  68. Bruce LJ, Beckmann R, Ribeiro ML, et al. A band 3-based macrocomplex of integral and peripheral proteins in the RBC membrane. Blood. 2003;101:4180–4188
  69. Dahl KN, Westhoff CM, Discher DE. Fractional attachment of CD47 (IAP) to the erythrocyte cytoskeleton and visual colocalization with Rh protein complexes. Blood. 2003;101:1194–1199
  70. Kosenko E, Kaminsky YG, Felipo V, Minana MD, Grisolia S. Chronic hyperammonemia prevents changes in brain energy and ammonia metabolites induced by acute ammonium intoxication. Biochim Biophys Acta. 1993;1180:321–326
  71. Huizenga JR, Tangerman A, Gips CH. Determination of ammonia in biological fluids. Ann Clin Biochem. 1994;31:529–543
  72. Reid ME, Lomas-Francis C. The Blood Group Antigen Facts Book. (ed 2). San Diego, CA: Academic Press; 2004;

PII: S0037-1963(06)00232-0

doi: 10.1053/j.seminhematol.2006.09.010

Seminars in Hematology
Volume 44, Issue 1 , Pages 42-50 , January 2007