RH blood group system and molecular basis of Rh-deficiency.
Rhesus (Rh) antigens are defined by a complex association of membrane polypeptides that are missing or severely deficient from the red cells of rare Rhnull individuals who suffer a clinical syndrome of varying severity characterized by abnormalities of the red cell shape, cation transport and membrane phospholipid organization. The Rhnull phenotype is an inherited condition that may arise from homozygosity either for a 'suppressor' gene unrelated to the RH locus ('regulator type') or for a silent allele at the RH locus itself ('amorph type'). A current model suggests that the proteins of the Rh complex (Rh, RhAG, CD47, LW, GPB) are assembled by non-covalent bonds and that it is not assembled or transported to the cell surface when one subunit is missing. Rh and RhAG proteins belong to the same protein family and are quantitatively the major components that form the core of the complex, which is firmly linked to the membrane skeleton. Molecular analysis of Rhnull individuals has revealed that abnormalities occur only at the RHAG and RH loci, without alteration of the genes encoding the accessory chains. Mutations of the RHAG gene, but not of RH, occur in all Rhnull individuals of the regulator type (including Rhmod) investigated so far (13 cases), strongly suggesting that RHAG mutants act as 'suppressors' and not as transcriptional regulators of the RH genes and that variable expression of the RHAG alleles may account for the Rhmod phenotypes (exhibiting weak expression of Rh antigens). Conversely, mutations of the RHCE gene, but not of RHAG, occur in two unrelated Rhnull individuals of the amorph type, supporting the view that RH mutants result from a 'silent' allele at the RH locus. These findings strongly support the Rh complex model since when either the Rh or RhAG protein is missing, the assembly and/or transport of the Rh complex is defective. Transcriptional as well as post-transcriptional mechanisms may account for the molecular abnormalities, but experimental evidence based on expression models is required to test these hypotheses, in the hope that they may help to clarify the biological role of the Rh proteins in the red cell membrane.
Cartron
J P
JP
INSERM Unité U76, Institut National de la Transfusion Sanguine, Paris, France.
D000743:Anemia, Hemolytic / Q000097:blood / Q000235:genetics; D001798:Blood Proteins / Q000172:deficiency* / Q000235:genetics; D004910:Erythrocyte Membrane / Q000737:chemistry / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D008562:Membrane Glycoproteins / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D012204:Rh-Hr Blood-Group System / Q000737:chemistry / Q000235:genetics*
D001798:Blood Proteins; D008562:Membrane Glycoproteins; C498523:RHAG protein, human; D012204:Rh-Hr Blood-Group System