Rh is the most complex of the blood groups systems, embracing over 45 distinct antigens, the absence or presence of which combine to exhibit an individual's Rh blood group type. The most clinical important antigen, D or Rho, was the first discovered in 1940 and has been generally referred to as the Rh antigen, being present in over 85% of the random population. Those individuals that lack the D antigen are considered to be Rh negative.
The Rh antigens are encoded by two highly homologous and closely linked genes on the short arm of chromosome 1. The RHD gene producing the D antigen, or most of its components; RhCE gene producing the Cc and Ee antigens or their variants. The majority of the antigens within this system represent products of gene cross-over, point mutations or deletions within one or both genes.
The Rh antigens appear to be red cell specific, appearing early during development of red blood cells, and have not been found on other body tissues. Antibodies against the Rh antigens have caused severe and fatal transfusion reactions and hemolytic disease of the newborn. The importance of the Rh antigens in the erythroid membrane is exemplified by the fact that in many examples of auto-immune hemolytic anemia, auto-Rh antibodies are frequently found.
Moreover, in hematological testing the extremely rare (only 32 known throughout the world) individuals who have no detectable Rh antigens, Rhnull individuals, a shortened red cell survival is quite common. Rhnull cells exhibit stomatocytosis and spherocytosis, and have increased permeability to potassium suggesting that they lack a crucial membrane component. A current model suggests that Rh assembles in the membrane as a complex with CD47, LW, RhAG and glycophorin B. Mutations of the RhAG gene accounts for most examples of Rhnull
It is truly ironic that this blood group system received this name because it was originally thought to be similar to an antibody produced in rabbits that had been immunized with rhesus monkey cells. By the time it was scientifically proven that they were two distinct antibody specificities there were too many publications referring to the Rh factor as the product of the D gene and the symbol Rh was well entrenched for this blood group system. Hence, the rhesus association to the system name had been made, but in fact, there is no association with rhesus monkeys what so ever. That antibody produced in rabbits to rhesus monkey cells, and the similar human antibody specificities, have been named after the two original investigators, Landsteiner and Wiener (refer to LW blood group system). 
Rh incompatible transfusion may result in death of patients. Rh incompatibility is still the leading cause of hemolytic disease of the newborn (HDN) and may involve some forms of graft-versus-host (GVH) disease in organ transplantation. Absence or severely reduced expression of all Rh30 polypeptides and/or their associated Rh antigens is referred to as Rhnull or Rhmod (also known as Rh deficiency syndrome). This autosomal recessive disorder manifests a varying degree of compensated hemolytic anemia and spherostomatocytosis. The responsible mutations are located at either the RHCED (antigen) locus proper or at the suppressor locus RHAG.
Rh incompatibility is the major cause of hemolytic disease of the newborn, however very few searches have been made for any other kinds of disease associations of the Rh groups.
For an illustration and explantion of Rh incompatibility, see:
Rh- status is largely a European gene (40%), with its highest frequency among the Basques of Spain, a remarkably homogenous group, originally late paleolithic or early mesolithic inhabitants of the Pyrenee Mountains. The U.S population is approximately 15% Rh- and 85% Rh+.
Antigens of the Rh blood group system are products of RHD and RHCE (collectively referred to as RH30 or RHCED), two tightly linked and highly homologous genes. RhD carries the D antigen, the most potent blood group immunogen. The D epitope is not expressed in a relatively large segment of the population (i.e., Rh-negative phenotype), as a result of RHD gene deletion or other gene alterations.
RHCE exists in four allelic forms and each allele determines the expression of two antigens in Ce, ce, cE or CE combination (RHCE is the collective name of the four alleles). RHD and RHCE genes, each, contain 10 exons and span ~75 kb DNA sequence. Complex formation with Rh50 glycoprotein, the product of another single copy gene RHAG (also refered to as RH50) is essential for the presentation of the Rh antigenic activity. RHAG is similarily organized into 10 exons and shares 36% sequence identity with RHCED but it is located at a separate locus. While alterations in the RHAG locus are relatively rare, the RHCED locus harbors a large repertoire of allelic diversity at the level of population. The open reading frames of RHCE and RHD may occur in opposite orientation - their 3'ends facing each other and being separated by about a 30kb region that contains the SMP1 gene; in addition, two 9kb highly homologous sequences, named "Rhesus Boxes", are located at the 5' and 3' ends of RHD. It is proposed that the deletion of RHD , frequently observed in the population, occurs through unequal homologous recombination confined to these homologous regions (Wagner and Flegel, Blood, 95:3662, 2000, and in Blood, 99, 2272, 2002).
Products of both RHCED and RHAG are integral membrane proteins showing a similar 12-transmembrane helix topology; Rh 30 polypeptides are palmitolyated and their epitopes are defined by five specific amino acids located on the extracellular loops. Rh 50 is N-glycosylated at a single site, Asn37.
The existence of two non-erythroid homologues of RHAG, named RHBG and RHCG, was demonstrated; they show a high level of homology but their patterns of expression are not identical (Liu et al., J. Biol. Chem., 275, 25641, 2000; Liu et al., J. Biol. Chem., 276, 1424, 2001; Huang and Liu, Blood Cells, Molecules, and Diseases, 27, 90, 2001).
Chromosomal location of RHAG is at 6p11-21.1; RHD and RHCE at 1p34-36 - the open reading frames of latter two genes may occur in opposite orientation - their 3'ends facing each other and being separated by about a 30kb region that contains the SMP1 gene (Wagner and Flegel, Blood, 95:3662, 2000). Function of proteins
Role in erythrocyte membrane integrity; RHAG,RHBG and RHCG may function as ammonium transporters (Huang et al., J. Biol. Chem., 276, 1424, 2001 and 275, 25641, 2000; Marini et al., Nature Genet. 26, 341, 2000, Westhoff et al., J. Biol. Chem., 277, 12499, 2002). In addition, a study in green algae showed that these Rh proteins may function as a gas channel for CO2 (Soupeneset al., PNAS USA, 99, 7769, 2002).
Expression of RHCE, RHD and RHAG is confined to erythroid tissues; products of the non-erythroid homologues are expressed in kidney, liver, skin, testis and brain.
About the alleles
Gene recombinations between the RHD and RHCE alleles, as well as other mutations at the RHCED locus are responsible for the origin of a large number of rare alleles whose expression is apparent from serological studies. Because of the opposite orientation of the two genes, it has been proposed that gene recombinations occur predominantly through gene conversion rather than unequal homologous recombination. In the RHCED locus, gene conversion is implicated in both large- and small-scale transfers of genetic material from donor to the recipient; they are defined as macroconversions or microconversion events, respectively. Unequal homologous recombination occurring within thes"Rhesus Boxes" flanking the RHD gene may be responsible for its deletion (Wagner and Flegel, Blood 95:3662, 2000). Other molecular mechanisms include missense changes, nonsense mutations and small in-frame and out-of-frame deletions.
In the list of alleles, designation of the hybrid alleles is based on their hybrid structures when entire exons or their portions are transferred (exons are shown in parenthesis); designation of all other alleles, including those where microconversions occur, incorporates the nature of the alteration at the protein level (Antorakis et al., Human Mutation, 11:1, 1998; also, frsh=frame shift); the generic "CE" will be used to designate the RHCE alleles when their exact allele specificity is not known.
The most common phenotypic alteration includes the absence of expression of the D antigen (RhD-negative, gene frequency in Caucasian population is 45%). This may be due to deletion of the entire gene, gene rearrangements, or mutations, as well as deletions or insertions resulting in frameshifts. In all these instances the D epitope is absent or unavailable.
The incidence of variants of RHCE and RHD alleles in the population still lacks complete documentation; whereas in some cases, less than 0.1% of the population tested show the variant phenotype and the occurrence of some phenotypes has been documented in single families only, the incidence of other variants may be much higher. A recent report documents the prevalence of a RHD pseudogene in a large segment of RhD-negative African populations (Singleton et al., Blood, 95, 12, 2000). In most cases the sites of recombinations are known but the breakpoints, which most often occur within introns, have not been defined or are ambiguous because of a high sequence identity. Complementary or additional information on the RHD alleles can be obtained on the Rhesus Site.
Rare Alleles of Rh Deficiency Syndrome - Because the Rh antigens are expressed as a complex of RHCED and RHAG products, alterations in either locus can result in Rh deficiency syndrome. Rh null refers to the complete absence of Rh antigens and is classified as amorph or regulator type. The amorph type defines mutations in the RHCED antigen locus proper, whereas the regulator type defines mutations in the RHAG locus that supresses the expression of Rh antigens. The Rh mod phenotype reflects either incomplete penetrance of RHAG mutations or other, as yet, unknown mutations. To date, three types of mutations have been shown to cause the Rh null phenotype: missense changes, small exonic deletions or splice site mutations. Missense mutations result in single amino acid replacements, whereas the other two types eventually lead to frameshift and premature chain terminations. In the amorph type of Rh null, a homozygous mutation in the RHCE gene generally occurs on the genetic background of RHD gene deletion. In the regulator type Rh null, the location of mutations appears to be clustered in the RHAG gene. In one subject, the Rh mod phenotype has been shown to result from a defective translation initiation, together with alternative use of downstream ATG codons in the Rh50 mutant.
RH blood groups and diabetic disorders: is there an effect on glycosylated hemoglobin level?
Hum Biol. 2000 Apr;72(2):287-94.
Gloria-Bottini F, Antonacci E, Bottini N, Ogana A, Borgiani P, De Santis G, Lucarini N.
- Recent cloning of RH genes has elucidated their structure, suggesting that RH proteins are part of an oligomeric complex with transport function in the erythrocyte. This observation prompted us to investigate a possible relationship between the RH system and the glycosylated hemoglobin level (Hb A(1c)) in diabetes. This compound is considered an important indicator- of glycemic control in diabetic disorders. We studied 278 subjects with non-insulin-dependent diabetes mellitus (NIDDM) from the population of Penne, Italy. Glycemic and glycosylated hemoglobin (Hb A(1c)) levels are associated with RH phenotype. Glucose and Hb A(1c) levels are increased in DCcEe subjects and decreased in ddccee subjects as compared to the mean values for other genotypes. Sex, age at onset of disease, duration of disease, and age of patients were also considered. Correlation analysis suggests that these variables influence glycemia directly and Hb A(1c) indirectly. The RH system, on the other hand, seems to influence the Hb A(1c) level directly. Preliminary data on 53 children with insulin-dependent diabetes mellitus (IDDM) from Sardinia seem to confirm the relationship between RH and Hb A(1c) observed in NIDDM. Since glycosylated hemoglobin is found inside red blood cells, the relationship between RH genetic variability and Hb A(1c) level suggests that RH proteins may influence glucose transport through red cell membrane and/or hemoglobin glycation.
- This article is licensed under the GNU Free Documentation License. Sections excerpted from Blood Group Antigen Gene Mutation Database. See: 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. Human Mutation. 2004 Jan; 23(1):8-16. PubMed ID: 14695527