Alternative titles; symbols
HGNC Approved Gene Symbol: RHCE
Cytogenetic location: 1p36.11 Genomic coordinates (GRCh38): 1:25,362,249-25,430,203 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.11 | Rh-null disease, amorph type | 617970 | Autosomal recessive | 3 |
The RHCE gene encodes the C/c and E/e antigens of the Rhesus (Rh) blood group system (111680).
Cherif-Zahar et al. (1990) isolated cDNA clones encoding a human blood group Rh polypeptide from a human bone marrow cDNA library using a PCR amplified DNA fragment encoding the known common N-terminal region of the Rh proteins. Translation of the open reading frame indicated that the Rh protein is composed of 417 amino acids, including the initiator methionine, which is removed in the mature protein, that it lacks a cleavable N-terminal sequence, and that it has no consensus site for potential N-glycosylation. Hydropathy analysis and predictions of secondary structure suggested the presence of 13 membrane-spanning domains, indicating that the Rh polypeptide is highly hydrophobic and deeply buried within the phospholipid bilayer. In Northern analysis, the Rh cDNA probe detected a major 1.7-kb and a minor 3.5-kb mRNA species in erythroid tissues but not in adult liver and kidney tissues or lymphoid and promyelocytic cell lines.
Using cDNAs amplified from reticulocyte mRNA, Mouro et al. (1993) investigated CcEe gene differences in Rh-negative individuals homozygous for dCe, dcE, and dce haplotypes. The RNA analysis was followed by PCR amplification of specific exons using genomic DNA from donors carrying a range of common Rh haplotypes. The Ee polypeptide was shown to be synthesized from the full-length transcript of the CcEe gene and to be identical in length (417 residues) and very similar in sequence to the D polypeptide. The Cc polypeptides were synthesized from shorter transcripts of the same CcEe gene sequence, but spliced so as to exclude exons 4, 5, and 6 or exons 4, 5 and 8. In both cases, the residue at 226 in exon 5 associated with Ee antigenicity was omitted from the polypeptide product; see 111700.0001 and 111700.0002. Also see review by Hopkinson (1993).
By in situ hybridization using an Rh protein probe, Cherif-Zahar et al. (1991) mapped the Rh blood group locus, which includes the RHCE gene, to chromosome 1p36.1-p34.3.
Cherif-Zahar et al. (1994) demonstrated that the RHCE gene has 10 exons distributed over 75 kb. Exons 4 to 8 are alternatively spliced in the different RNA isoforms. Primary extension analysis indicated that the transcription initiation site is located 83 bp upstream of the initiation codon. Study of hematopoietic and nonhematopoietic (HeLa) cell lines and Northern blot analysis suggested that the expression of the RH locus is restricted to the erythroid/megakaryocytic lineage. Consistent with this, putative binding sites for SP1, GATA-1, and Ets proteins, nuclear factors known to be involved in erythroid and megakaryocytic gene expression, were identified in the promoter of the RHCE gene.
Suto et al. (2000) analyzed the organization of the RH genes by 2-color fluorescence in situ hybridization on DNA fibers released from lymphocytes (fiber-FISH) and by using DNA probes of introns 3 and 7 of the RHCE and RHD genes. Six Rh-positive samples (2 with the D+C-c+E+e-, 2 with the D+C+c-E-e+, and 2 with the D+C+c+E+e+ phenotype) showed the presence of 2 RH genes within a region of less than 200 kb. Of great interest was the finding that the genes were arranged in antidromic order starting from the telomere: tel--RHCE (5-prime to 3-prime)--RHD (3-prime to 5-prime)--centromere. On the other hand, 2 typical Rh-negative samples (D-C-c+E+e+) showed the presence of only 1 RHCE gene, as expected.
Wagner and Flegel (2000) showed that the RH locus represents a gene cluster: RHD (111680) and RHCE face each other by their 3-prime tail ends, and a third gene, SMP1 (605348), is interspersed between the 2 rhesus genes. The RHD gene deletion was parsimoniously explained by an unequal crossing-over event. The inverse orientation of the RH genes may facilitate gene conversion among both rhesus genes, which would explain the high frequency of hybrid alleles.
Cartron and Agre (1993) reviewed the protein and gene structure of the Rh blood group antigens. In summary, Rh-positive persons have 2 Rh genes, 1 encoding the Cc- and Ee-bearing protein or, more likely, proteins, and a second encoding the D-bearing protein, while Rh-negative persons have only 1 Rh gene, the first of the 2 described above.
Cartron et al. (1995) defended the 2-gene model of the Rh blood group system. They suggested that the RHCE gene encodes the C/c and E/e proteins through alternative splicing of the primary transcript. D-positive and D-negative individuals differ on the basis of the presence or absence of the RHD gene (111680), as a rule; in some Australian Aborigines and Blacks, a fragment of the RHD gene or a nonfunctional RHD gene is present. Smythe et al. (1996) found that both c and E antigens were expressed after transduction of K562 cells with a single cDNA, indicating that the c antigen does not arise by alternative splicing (exon skipping) of the product of the RHCE gene.
Rh-Null, Amorph Type
The Rh-null phenotype is of 2 types. The most common type, called the 'regulator type,' occurs by an inhibition mechanism; see RHNR, 268150. This form is caused by homozygosity for an autosomal recessive suppressor gene that is genetically independent of the Rh locus, mapping to chromosome 3 rather than to chromosome 1. The second type of Rh-null, which was first described in a Japanese family (Ishimori and Hasekura, 1967), is called the 'amorph type' (RHNA; 617970) and results from homozygosity for a silent allele at the Rh locus.
In a survey of 42 examples of the Rh-null phenotype, Nash and Shojania (1987) found that only 5 were of the amorph type. Perez-Perez et al. (1992) described a Spanish family in which a silent Rh gene was segregating, giving rise to the amorph type of Rh-null in the proposita whose parents were first cousins. She suffered from severe hemolytic anemia. Western blot analysis carried out with glycosylation-independent antibodies directed against the Rh polypeptide and the LW glycoprotein, respectively, confirmed that these protein components were absent from the red cells of the proposita.
Evans Phenotype
In a 3-generation family ascertained through the East of Scotland Blood Transfusion Service in Dundee, Scotland, Huang et al. (1996) found that a cataract-causing mutation was cosegregating with an autosomal dominant anomaly of Rh type known as the Evans phenotype. The geography and the genetic linkage suggested that the form of cataract may be the same as that in the Danish family (see 115665). The red cell Evans phenotype is produced by a hybrid RH gene in which exons 2-6 from the RHD gene is transferred to the RHCE gene. Kemp et al. (1996) also examined 5 unrelated Rh D-- homozygotes and found that, in 4 of them, RHCE sequences had been replaced by RHD sequences. The 5-prime end of these rearrangements occurred within a 4.2-kb interval around exon 2. There was, however, heterogeneity at the 3-prime end of the rearranged genes, indicating that they were not identical by descent, but rather that independent recombination events had occurred within a small genomic interval--a recombination hotspot.
Other Associations
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Valenzuela et al. (1991) reported a strong association between plasma total iron binding capacity (TIBC) and Cc Rh specificity in a Chilean primary school population in Santiago. Valenzuela et al. (1995) found similar results in university students from Medellin, Colombia.
The high degree of homology between the coding regions of the RHCE and RHD genes is consistent with an ancestral gene duplication. Carritt et al. (1997) concluded that the human lineage started with the haplotype cDe. This is consistent with its very high incidence in black Africans and their descendants (0.4 to 0.5, compared to less than 0.1 elsewhere). The common haplotype underlying the RhD- phenotype (cde) almost certainly represented a loss of RHD from cDe. This haplotype is entirely absent from some aboriginal groups, e.g., Australian, Eskimo, and Navajo. How the RhD- haplotype became established in a predominantly RhD+ population, given the moderate to strong selection against RHD+/- heterozygotes imposed by fetomaternal incompatibility, was still unknown. As first pointed out in 1942 by Haldane (1942) and reexamined by Hogben (1943), Li (1953), and others, selection against heterozygotes results in unstable population equilibria. In an extended simulation study, Feldman et al. (1969) concluded that, while reproductive compensation on the part of RhD- mothers can, in principle, lead to stable equilibria in the face of such selection, other forces, for example, heterozygote advantage, must operate to maintain RhD+:RhD- ratios at their observed levels.
Fisher and Race (1946) proposed a model for the evolution of the RH polymorphism in which the less common haplotypes (CDE, Cde, cdE, and CdE) are generated and maintained by recombination from those found at higher frequency. The frequency ratios of the supposed parental and recombinant haplotypes suggested that the arrangement D-C-E was most likely under the crossing-over hypothesis. At the time, they assumed that the 3 series of antigens were encoded in 3 separate genes; the work outlined earlier indicated that there are 2. Thus recombination between the sites encoding C/c and E/e would be intragenic, and occur between exons that are separated by approximately 30 kb (Cherif-Zahar et al., 1994). Carritt et al. (1997) presented direct evidence for nonreciprocal intergenic exchange (gene conversion) occurring once in human history to generate the common RHCE allele, Ce. They also used new polymorphisms to construct haplotypes which suggested that intragenic recombination played a major role in the generation of the less common haplotypes, but only if RHD lies 3-prime of RHCE, i.e., the order is C-E-D. They provided both genetic and physical evidence supporting this arrangement.
The duplication of the rhesus gene occurred during primate evolution (Matassi et al., 1999), giving rise to the RHD and RHCE genes in humans. Thus nonprimate mammals, such as mice, may reveal the ancient state of the RH locus. With this in mind, Wagner and Flegel (2002) analyzed the sequence of the region. Based on the gene positions and orientations, RHCE was determined to represent the ancestral state. The close proximity of SMP1 and RH known in humans was also observed in the mouse RH locus. Wagner and Flegel (2002) concluded that RHD arose by duplication of RHCE. The orientation of RHD was probably inverted during this event. The so-called rhesus boxes, two 9,000-bp DNA segments of identical orientation flanking the RHD gene, may have been instrumental for the duplication.
Rh, elliptocytosis (611804), PGM1 (171900), and 6PGD (172200) are all on the same chromosome. The first 2 loci appear to lie between the latter 2 (Renwick, 1971). Information from cell hybridization studies placed the Rh-elliptocytosis-PGM(1)-6PGD linkage group on chromosome 1. Jacobs et al. (1970) reported data suggesting a loose linkage between a translocation breakpoint near the end of the long arm of chromosome 1 and Rh. Lamm et al. (1970) published family data consistent with loose linkage of Duffy (110700) and PGM1. Renwick (1971) suggested that PGM1 is on the side of Rh, remote from 6PGD and about 30 centimorgans from Rh. Cook et al. (1972) confirmed this interval. Although the Rh and Duffy loci are both on chromosome 1, they are too far apart to demonstrate linkage in family studies (Sanger et al., 1973).
Marsh et al. (1974) found Rh-negative erythrocytes in an Rh-positive man suffering from myelofibrosis. Nucleated hemopoietic precursors were circulating in his blood, and these cells had an abnormal chromosome complement from which part of the short arm of chromosome 1 had been deleted. They concluded that the Rh locus probably lies on the distal segment of the short arm at some point between 1p32 and the end of the short arm. The conclusion is consistent with the finding of Douglas et al. (1973) that the PGM1 locus, which is linked to Rh, is on the short arm of chromosome 1. Since the patient of Marsh et al. (1974) did not have deletion of the PGM1 locus in the mutant clone, the Rh locus is probably distal to the PGM1 locus.
Corney et al. (1977) observed only 1 recombination in 58 opportunities between the alpha-fucosidase locus (FUCA1; 612280) and the Rh locus. Rh antigen still eludes chemical definition (Tippett, 1978), but it is thought to be a lipoprotein. No completely certain example of recombination within a postulated gene complex has been described.
Steinberg (1965) described a Hutterite family in which the father was CDe-cde, mother cde-cde, 4 children cde-cde, 3 children CDe-cde, and 1 child (the 6th born) Cde-cde. Steinberg (1965) thought this was an instance of crossing-over. Mutation and, much less likely, a recessive suppressor of the D antigen were mentioned as other possibilities. Race and Sanger (1975) considered a recessive suppressor likely. (Illegitimacy was excluded by the mores of the sect and by marker studies.) Rosenfield (1981) wrote: 'We still know nothing about Rh. Except for Steinberg's one crossover, there have been no exceptions to the inheritance of Rh antigens in tight haplotype packages. Hopefully, Rh antigen will be isolated for characterisation but there has been nothing published since the report of Plapp et al. (1979).'
Steinberg et al. (1984) reexamined the Hutterite family, making use of other markers thought to be on 1p (6PGD, Colton, UMPK1) and concluded that crossover or mutation indeed had occurred. (Colton is probably not on chromosome 1p; UMPK1 was not informative in the critical parent (Lewis, 1989).) They concluded further that if, as seems likely from other evidence, C lies between D and E, their data indicate that the D gene (116800) is distal (telomeric) in the Rh complex. This order is consistent with the rare Rh haplotype D. Race et al. (1950, 1951) considered this haplotype to represent a probable or possible deletion in a human Rh chromosome. Race and Sanger (1975) listed 20 homozygotes for this haplotype. Originating from various populations, they were, in about 80% of the cases, the products of consanguineous matings. Olafsdottir et al. (1983) concluded that this Rhesus haplotype is not very rare in Iceland. They estimated the frequency to be about 1 in 214 persons. They discovered the haplotype in 2 unrelated women because of difficulty with crossmatching. Both had formed Rh antibodies, one provoked by transfusions and the other by 3 pregnancies.
Saboori et al. (1988) purified Rh protein in relatively large amounts from Rh(D)-positive and -negative blood. Differences in the peptide maps of the 2 proteins were found. Blanchard et al. (1988) presented indirect data based on immunologic and biochemical investigations demonstrating that the Rh D, c, and E polypeptides of the erythrocyte membrane are homologous but distinct molecular species that can be physically separated and analyzed. These polypeptides have a molecular weight of about 32,000. Polypeptides c and E were found by Blanchard et al. (1988) to be more closely related to each other than to D. All the observations were consistent with partial divergence among homologous members of a family of Rh proteins. In a review completed in early 1988, Issitt (1988) suggested that current molecular genetic methods could finally end 50 years of speculation as to the genetic determination of the Rh blood groups.
Rosenfield (1989) described the bitter disagreements between Wiener and Levine, particularly over priority of discovery. Mollison (1994) reviewed the disagreement between A. S. Wiener, who postulated multiple alleles at a single locus (Wiener, 1943), and R. A. Fisher, who interpreted the data of R. R. Race (1944) as most compatible with the existence of 3 closely linked genes.
Whether the 3 sets of Rh antigens--D, Cc, and Ee--that are inherited en bloc represent separate epitopes on a single protein (as maintained by Wiener, 1944) or multiple independent proteins encoded by closely linked genes (as first suggested by Fisher in 1944 (Race, 1944)) had been controversial since the discovery of the Rh antigens in the early 1940s. Cherif-Zahar et al. (1990) quoted work of Blanchard et al. (1988) suggesting that the Rh D, c, and E antigens are carried by 3 distinct but homologous membrane proteins that share a common N-terminal protein sequence. It is possible that these are the product of one gene with multiple splicing alternatives. See also review by Agre and Cartron (1991).
Colin et al. (1991) used Rh cDNA as a probe in Southern analysis of the Rh locus. They demonstrated that in all Rh D-positive persons 2 strongly related Rh genes are present per haploid genome, whereas 1 of these 2 genes is missing in Rh D-negative donors. Colin et al. (1991) concluded that 1 of the 2 genes of the Rh locus encodes the Rh C/c and Rh E/e polypeptides while the other encodes the Rh D protein. (Both Fisher and Wiener were partly right.) The absence of any D gene and of its postulated allelic form d in the Rh D-negative genome explains why no Rh d antigen has ever been demonstrated.
Investigations by Cherif-Zahar et al. (1993) failed to reveal any alteration of the RH genes and transcripts in Rh-null of the silent type, and they suspected that these variants have a transcriptional or post-transcriptional alteration of RH genes. Cherif-Zahar et al. (1996) analyzed the RH locus and sequenced the Rh transcripts from 5 Rh-deficient phenotypes caused by an autosomal suppressor gene (reg and mod types). They were unable to detect any abnormality; these variants did not express RH genes but did convey a functional RH locus from one generation to the next. They also detected no gross alteration in the CD47 gene structure; transcripts were easily amplified and the nucleotide sequence was identical to that from controls. This agreed with binding studies indicating that CD47 is present on the red cell surface of Rh-deficient cells, although severely reduced (10-15% of controls). In general, their findings suggested that the low expression of CD47 on Rh-null erythrocytes results from the defective assembly or transport to the cell surface when Rh proteins are absent.
Mouro et al. (1993) showed that the difference between the classic allelic antithetical E and e antigens depends on a point mutation in exon 5 which changes proline to alanine at residue 226 in the e allele.
Mouro et al. (1993) showed that the difference between the classic allelic antithetical C and c antigens depends on point mutations leading to 4 amino acid substitutions in exons 1 and 2 in the c allele.
As noted earlier, RH-null disease, which includes the amorphic and regulator (see 268150) types, is a rare genetic disorder characterized by stomatocytosis and chronic hemolytic anemia. Huang et al. (1998) studied a German family transmitting a putative amorph Rh-null (RHNA; 617970) disease gene. They analyzed the genomic and transcript structure of Rh30, Rh50 (180297), and CD47 (601028), the 3 loci thought to be most critical for expression of the Rh complex in the red blood cell membrane. They showed that in this family the Rh50 and CD47 transcripts were normal in primary sequence. However, the Rh30 locus contained an unusual double mutation in exon 7 of the RHCE gene, in addition to a deletion of the RhD gene. The mutation targeted 2 adjacent codons in multiple arrangements, probably via the mechanism of microgene conversion. One scheme entailed a noncontiguous deletion of 2 nucleotides, ATT(ile322) to AT and CAC(his323) to CC, whereas the other involved a T-to-C transition, ATT(ile322) to ATC, and a dinucleotide deletion, CAC(his323) to C. They caused the same shift in open reading frame predicted to encode a short protein with 398 amino acids. The loss of 2 transmembrane domains and gain of a new C-terminal sequence probably altered the protein conformation and impaired the Rh complex assembly. The findings established the molecular identity of an amorph Rh-null disease gene, showing that Rh30 and Rh50 are both essential for the functioning of the Rh structures as a multisubunit complex in the plasma membrane. The affected subs in this family were originally described by Seidl et al. (1972).
Cherif-Zahar et al. (1998) analyzed one of the patients (DR) studied by Huang et al. (1998) and described the nucleotide change as TCA-C in exon 7, resulting in a novel C-terminal sequence from residue 323 and a truncated protein of 398 amino acids (vs 417 in the wildtype protein).
In a Spanish patient (DAA) with Rh-null amorph phenotype (RHNA; 617970) from a consanguineous family, previously reported by Perez-Perez et al. (1992), Cherif-Zahar et al. (1998) detected a homozygous splice site mutation at the donor site of intron 4 of the RHCE gene (IVS4+1G-T). The mutation activated at least 3 cryptic splice sites. One such site in exon 4 generated all aberrant transcripts. Southern blot analysis demonstrated deletion of the RHD gene (111680).
In a 23-year-old Caucasian Brazilian woman and her sister with Rh-null amorph phenotype (RHNA; 617970), Rosa et al. (2005) detected homozygosity for deletion of a single G nucleotide within the quadruple GGGG between nucleotide positions 960 and 963 in exon 7 of the RHCE gene. This deletion introduced a frameshift after gly231 and a premature stop codon at position 358. The consanguineous parents and a brother were heterozygous for the mutation. PCR demonstrated absence of the RHD gene (111680) in both sisters.
In a 32-year-old Libyan woman with Rh-null amorph phenotype (RHNA; 617970) from a consanguineous family, Silvy et al. (2015) detected homozygosity for a 7-bp duplication (c.1044_1050dup) in exon 7 of the RHCE gene. The duplication was present in heterozygosity in her parents and 1 brother. The RHD gene was deleted in the proposita, her mother, and 1 brother, while her father and another brother carried a wildtype RHD allele.
Agre, P., Cartron, J.-P. Molecular biology of the Rh antigens. Blood 78: 551-563, 1991. [PubMed: 1907207]
Blanchard, D., Bloy, C., Hermand, P., Cartron, J.-P., Saboori, A. M., Smith, B. L., Agre, P. Two-dimensional iodopeptide mapping demonstrates that erythrocyte Rh D, c, and E polypeptides are structurally homologous but nonidentical. Blood 72: 1424-1427, 1988. [PubMed: 3139107]
Carritt, B., Kemp, T. J., Poulter, M. Evolution of the human RH (rhesus) blood group genes: a 50 year old prediction (partially) fulfilled. Hum. Molec. Genet. 6: 843-850, 1997. Note: Erratum: Hum. Molec. Genet. 6: 1390 only, 1997. [PubMed: 9175729] [Full Text: https://doi.org/10.1093/hmg/6.6.843]
Cartron, J.-P., Agre, P. Rh blood group antigens: protein and gene structure. Semin. Hemat. 30: 193-208, 1993. [PubMed: 8211223]
Cartron, J.-P., Le Van Kim, C., Cherif-Zahar, B., Mouro, I., Rouillac, C., Colin, Y. The two-gene model of the RH blood-group locus. (Letter) Biochem. J. 306: 877-878, 1995. [PubMed: 7702587] [Full Text: https://doi.org/10.1042/bj3060877]
Cherif-Zahar, B., Bloy, C., Le Van Kim, C., Blanchard, D., Bailly, P., Hermand, P., Salmon, C., Cartron, J.-P., Colin, Y. Molecular cloning and protein structure of a human blood group Rh polypeptide. Proc. Nat. Acad. Sci. 87: 6243-6247, 1990. [PubMed: 1696722] [Full Text: https://doi.org/10.1073/pnas.87.16.6243]
Cherif-Zahar, B., Le Van Kim, C., Rouillac, C., Raynal, V., Cartron, J.-P., Colin, Y. Organization of the gene (RHCE) encoding the human blood group RhCcEe antigens and characterization of the promoter region. Genomics 19: 68-74, 1994. [PubMed: 8188244] [Full Text: https://doi.org/10.1006/geno.1994.1014]
Cherif-Zahar, B., Matassi, G., Raynal, V., Gane, P., Mempel, W., Perez, C., Cartron, J.-P. Molecular defects of the RHCE gene in Rh-deficient individuals of the amorph type. Blood 92: 639-646, 1998. [PubMed: 9657766]
Cherif-Zahar, B., Mattei, M. G., Le Van Kim, C., Bailly, P., Cartron, J.-P., Colin, Y. Localization of the human Rh blood group gene structure to chromosome region 1p34.3-1p36.1 by in situ hybridization. Hum. Genet. 86: 398-400, 1991. [PubMed: 1900257] [Full Text: https://doi.org/10.1007/BF00201843]
Cherif-Zahar, B., Raynal, V., Gane, P., Mattei, M.-G., Bailly, P., Gibbs, B., Colin, Y., Cartron, J.-P. Candidate gene acting as a suppressor of the RH locus in most cases of Rh-deficiency. Nature Genet. 12: 168-173, 1996. [PubMed: 8563755] [Full Text: https://doi.org/10.1038/ng0296-168]
Cherif-Zahar, B., Raynal, V., Le Van Kim, C., D'Ambrosio, A. M., Bailly, P., Cartron, J. P., Colin, Y. Structure and expression of the RH locus in the Rh-deficiency syndrome. Blood 82: 656-662, 1993. [PubMed: 8329719]
Colin, Y., Cherif-Zahar, B., Le Van Kim, C., Raynal, V., Van Huffel, V., Cartron, J.-P. Genetic basis of the RhD-positive and RhD-negative blood group polymorphism as determined by Southern analysis. Blood 78: 2747-2752, 1991. [PubMed: 1824267]
Cook, P. J. L., Noades, J., Hopkinson, D. A., Robson, E. B., Cleghorn, T. E. Demonstration of a sex difference in recombination fraction in the loose linkage, Rh and PGM(1). Ann. Hum. Genet. 35: 239-242, 1972. [PubMed: 4627353] [Full Text: https://doi.org/10.1111/j.1469-1809.1957.tb01397.x]
Corney, G., Fisher, R. A., Cook, P. J. L., Noades, J., Robson, E. B. Linkage between alpha-fucosidase and rhesus blood groups. Ann. Hum. Genet. 40: 403-405, 1977. [PubMed: 406826]
Douglas, G. R., McAlpine, P. J., Hamerton, J. L. Sub-regional localization of human Pep C, PGM1 and PGD on chromosome 1 using Chinese hamster-human somatic cell hybrids. (Abstract) Genetics 74: S65, 1973.
Feldman, M. W., Nabholz, M., Bodmer, W. F. Evolution of the Rh polymorphism: a model for the interaction of incompatibility, reproductive compensation, and heterozygote advantage. Am. J. Hum. Genet. 21: 171-193, 1969. [PubMed: 4976959]
Fisher, R. A., Race, R. R. Rh gene frequencies in Britain. (Letter) Nature 157: 48-49, 1946. [PubMed: 21013978] [Full Text: https://doi.org/10.1038/157048b0]
Haldane, J. B. S. Selection against heterozygosis in man. Ann. Eugenics 11: 333-340, 1942.
Hogben, L. Mutation and the Rhesus reaction. (Letter) Nature 152: 721-722, 1943.
Hopkinson, D. A. The long [E/e] and the short [C/c] of the rhesus polymorphism. Nature Genet. 5: 6-7, 1993. [PubMed: 8220425] [Full Text: https://doi.org/10.1038/ng0993-6]
Huang, C.-H., Chen, Y., Reid, M. E., Seidl, C. Rh(null) disease: the amorph type results from a novel double mutation in RhCe gene on D-negative background. Blood 92: 664-671, 1998. [PubMed: 9657769]
Huang, C.-H., Chen, Y., Reid, M., Ghosh, S. Genetic recombination at the human RH locus: a family study of the red-cell Evans phenotype reveals a transfer of exons 2-6 from the RHD to the RHCE gene. Am. J. Hum. Genet. 59: 825-833, 1996. [PubMed: 8808597]
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. [PubMed: 6036671] [Full Text: https://doi.org/10.1111/j.1537-2995.1967.tb04845.x]
Issitt, P. D. Genetics of the Rh blood group system: some current concepts. Med. Lab. Sci. 45: 395-404, 1988. [PubMed: 3151909]
Jacobs, P. A., Brunton, M., Frackiewicz, A., Newton, M., Cook, P. J. L., Robson, E. B. Studies on a family with three cytogenetic markers. Ann. Hum. Genet. 33: 325-336, 1970.
Kemp, T. J., Poulter, M., Carritt, B. A recombination hot spot in the Rh genes revealed by analysis of unrelated donors with the rare D-- phenotype. Am. J. Hum. Genet. 59: 1066-1073, 1996. Note: Erratum: Am. J. Hum. Genet. 60: 749 only, 1997. [PubMed: 8900235]
Lamm, L. U., Kissmeyer-Nielsen, F., Henningsen, K. Linkage and association studies of two phosphoglucomutase loci (PGM-1 and PGM-3) to eighteen other markers. Hum. Hered. 20: 305-318, 1970. [PubMed: 4099123] [Full Text: https://doi.org/10.1159/000152326]
Levine, P., Celano, M. J., Wallace, J., Sanger, R. A human 'D-like' antibody. Nature 198: 596-597, 1963. [PubMed: 13930159] [Full Text: https://doi.org/10.1038/198596a0]
Lewis, M., Kaita, H., Chown, B., Giblett, E. R., Anderson, J. E. Relative positions of chromosome 1 loci Fy, PGM-1, Sc, UMPK, Rh, PGD and ENO-1 in man. Canad. J. Genet. Cytol. 19: 695-709, 1977. [PubMed: 416891] [Full Text: https://doi.org/10.1139/g77-076]
Lewis, M., Kaita, H., Chown, B. Genetic linkage between the human blood group loci Rh and Sc (Scianna). (Letter) Am. J. Hum. Genet. 28: 619-620, 1976. [PubMed: 827209]
Lewis, M. Personal Communication. Winnipeg, Manitoba, Canada 3/1989.
Li, C. C. Is Rh facing a crossroad? A critique of the compensation effect. Am. Naturalist 87: 257-261, 1953.
Marsh, W. L., Chaganti, R. S. K., Gardner, F. H., Mayer, K., Nowell, P. C., German, J. Mapping human autosomes: evidence supporting assignment of Rhesus to the short arm of chromosome no. 1. Science 183: 966-968, 1974. [PubMed: 4204206] [Full Text: https://doi.org/10.1126/science.183.4128.966]
Matassi, G., Cherif-Zahar, B., Pesole, G., Raynal, V., Cartron, J. P. The members of the RH gene family (RH50 and RH30) followed different evolutionary pathways. J. Mol. Evol. 48: 151-159, 1999. [PubMed: 9929383] [Full Text: https://doi.org/10.1007/pl00006453]
Mollison, P. L. The genetic basis of the Rh blood group system. Transfusion 34: 539-541, 1994. [PubMed: 8023398] [Full Text: https://doi.org/10.1046/j.1537-2995.1994.34694295073.x]
Mouro, I., Colin, Y., Cherif-Zahar, B., Cartron, J.-P., Le Van Kim, C. Molecular genetic basis of the human Rhesus blood group system. Nature Genet. 5: 62-65, 1993. [PubMed: 8220426] [Full Text: https://doi.org/10.1038/ng0993-62]
Nash, R., Shojania, A. M. Hematological aspect of Rh deficiency syndrome: a case report and a review of the literature. Am. J. Hemat. 24: 267-275, 1987. [PubMed: 3103426] [Full Text: https://doi.org/10.1002/ajh.2830240306]
Olafsdottir, S., Jensson, O., Thordarson, G., Sigurdardottir, S. An unusual Rhesus haplotype, -D-, in Iceland. Forensic Sci. Int. 22: 183-187, 1983. [PubMed: 6416954] [Full Text: https://doi.org/10.1016/0379-0738(83)90012-9]
Perez-Perez, C., Taliano, V., Mouro, I., Huet, M., Salat-Marti, A., Martinez, A., Rouger, P., Cartron, J.-P. Spanish Rh-null family caused by a silent Rh gene: hematological, serological, and biochemical studies. Am. J. Hemat. 40: 306-312, 1992. [PubMed: 1503086] [Full Text: https://doi.org/10.1002/ajh.2830400412]
Plapp, F. V., Kowalski, M. M., Tilzer, L., Brown, P. J., Evans, J., Chiga, M. Partial purification of Rh-0(D) antigen from Rh positive and negative erythrocytes. Proc. Nat. Acad. Sci. 76: 2964-2968, 1979. [PubMed: 111249] [Full Text: https://doi.org/10.1073/pnas.76.6.2964]
Race, R. R., Sanger, R., Selwyn, J. G. A probable deletion in a human Rh chromosome. Nature 166: 520, 1950. [PubMed: 14780126] [Full Text: https://doi.org/10.1038/166520a0]
Race, R. R., Sanger, R., Selwyn, J. G. A possible deletion in human Rh chromosome: a serological and genetical study. Brit. J. Exp. Path. 32: 124-135, 1951. [PubMed: 14848427]
Race, R. R., Sanger, R. Blood Groups in Man. (6th ed.) Oxford: Blackwell (pub.) 1975. Pp. 188-212.
Race, R. R. An 'incomplete' antibody in human serum. (Letter) Nature 153: 771-772, 1944.
Renwick, J. H. The Rhesus syntenic group in man. Nature 234: 475, 1971. [PubMed: 5002649] [Full Text: https://doi.org/10.1038/234475a0]
Rosa, K. A., Reid, M. E., Lomas-Francis, C., Powell, V. I., Costa, F. F., Stinghen, S. T., Watanabe, A. M., Carboni, E. K., Baldon, J. P., Jucksch, M. M. F., Castilho, L. Rh(null) syndrome: identification of a novel mutation in RHce. Transfusion 45: 1796-1798, 2005. [PubMed: 16271106] [Full Text: https://doi.org/10.1111/j.1537-2995.2005.00605.x]
Rosenfield, R. E., Allen, F. H., Jr., Rubenstein, P. Genetic model for the Rh blood-group system. Proc. Nat. Acad. Sci. 70: 1303-1307, 1973. [PubMed: 4123071] [Full Text: https://doi.org/10.1073/pnas.70.5.1303]
Rosenfield, R. E. Personal Communication. New York, N. Y. 6/30/1981.
Rosenfield, R. E. Who discovered Rh? A personal glimpse of the Levine-Wiener argument. Transfusion 29: 355-357, 1989. [PubMed: 2497569] [Full Text: https://doi.org/10.1046/j.1537-2995.1989.29489242804.x]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Saboori, A. M., Smith, B. L., Agre, P. Polymorphism in the M(r) 32,000 Rh protein purified from Rh(D)-positive and -negative erythrocytes. Proc. Nat. Acad. Sci. 85: 4042-4045, 1988. [PubMed: 3131772] [Full Text: https://doi.org/10.1073/pnas.85.11.4042]
Sanger, R., Tippett, P., Gavin, J., Race, R. R. Failure to demonstrate linkage between the loci for the Rh and Duffy blood groups. Ann. Hum. Genet. 36: 353-354, 1973. [PubMed: 4714425] [Full Text: https://doi.org/10.1111/j.1469-1809.1973.tb00597.x]
Schmidt, P. J. Hereditary hemolytic anemias and the null blood types. Arch. Intern. Med. 139: 570-571, 1979. [PubMed: 109058]
Seidl, S., Spielmann, W., Martin, H. Two siblings with Rh(null) disease. Vox Sang. 23: 182-189, 1972. [PubMed: 4627672] [Full Text: https://doi.org/10.1111/j.1423-0410.1972.tb04000.x]
Silvy, M., Beley, S., Peyrard, T., Ouchari, M., Abdelkefi, S., Yacoub, S. J., Chiaroni, J., Bailly, P. Short duplication within the RHCE gene associated with an in cis deleted RHD causing a Rh(null) amorph phenotype in an immunized pregnant woman with anti-Rh29. Transfusion 55: 1407-1410, 2015. [PubMed: 25413218] [Full Text: https://doi.org/10.1111/trf.12937]
Smythe, J. S., Avent, N. D., Judson, P. A., Parsons, S. F., Martin, P. G., Anstee, D. J. Expression of RHD and RHCE gene products using retroviral transduction of K562 cells establishes the molecular basis of Rh blood group antigens. Blood 87: 2968-2973, 1996. [PubMed: 8639918]
Steinberg, A. G., Giblett, E. R., Lewis, M., Zachary, A. A. A crossover or mutation in the Rh region revisited. Am. J. Hum. Genet. 36: 700-703, 1984. [PubMed: 6428223]
Steinberg, A. G. Evidence for a mutation or crossing over at the Rh locus. Vox Sang. 10: 721-724, 1965. [PubMed: 4955437]
Sturgeon, P. Hematological observations on the anemia associated with blood type Rh-null. Blood 36: 310-320, 1970. [PubMed: 4247573]
Suto, Y., Ishikawa, Y., Hyodo, H., Uchikawa, M., Juji, T. Gene organization and rearrangements at the human Rhesus blood group locus revealed by fiber-FISH analysis. Hum. Genet. 106: 164-171, 2000. [PubMed: 10746557] [Full Text: https://doi.org/10.1007/s004390051024]
Tippett, P. Depressed Rh phenotypes. Rev. Franc. Transfusion 21: 135-150, 1978. [PubMed: 418485] [Full Text: https://doi.org/10.1016/s0338-4535(78)80037-3]
Valenzuela, C. Y., Avendano, A., Harb, Z. Association between Rh and plasma iron binding (transferrin). Hum. Genet. 87: 438-440, 1991. [PubMed: 1908818] [Full Text: https://doi.org/10.1007/BF00197164]
Valenzuela, C. Y., Bravo, M. L., Alarcon, J. C. Rh-plasma iron binding capacity association: new evidence. Hum. Genet. 96: 219-220, 1995. [PubMed: 7635474] [Full Text: https://doi.org/10.1007/BF00207383]
Wagner, F. F., Flegel, W. A. RHD gene deletion occurred in the Rhesus box. Blood 95: 3662-3668, 2000. [PubMed: 10845894]
Wagner, F. F., Flegel, W. A. RHCE represents the ancestral RH position, while RHD is the duplicated gene. (Letter) Blood 99: 2272-2274, 2002. [PubMed: 11902138] [Full Text: https://doi.org/10.1182/blood-2001-12-0153]
Wiener, A. S. Genetic theory of the Rh blood types. Proc. Soc. Exp. Biol. Med. 54: 316-319, 1943.
Wiener, A. S. The Rh series of allelic genes. Science 100: 595-597, 1944. [PubMed: 17776134] [Full Text: https://doi.org/10.1126/science.100.2609.595]