*111680 RHESUS BLOOD GROUP, D ANTIGEN; RHD
Alternative
titles; symbols
BLOOD GROUP--RHESUS SYSTEM D POLYPEPTIDE
table OF
CONTENTS
Gene Map Locus: 1p36.2-p34
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TEXT
Individuals are classified as Rh-positive and
Rh-negative according to the presence or the
absence of the major D antigen on the surface of
their erythrocytes, but more than 46 other
antigens, including those of the CcEe series, have
been identified (Issitt,
1989). By Southern blot analysis, Colin
et al. (1991) showed that the Rh 'locus' is
composed of 2 homologous structural genes, one
encoding the Rh D polypeptide and the other
encoding both the Cc and the Ee polypeptides
(111700).
Alternative splicing of a primary transcript was
considered the likely mechanism of the encoding of
the Cc and Ee polypeptides by a single gene
(Le Van Kim et al.,
1992). Le Van Kim et al.
(1992) cloned cDNAs for representing the RHD
gene. They found that the predicted translation
product is a 417-amino acid protein of molecular
mass 45,500 with a membrane organization of 13
bipolar-spanning domains similar to that of the
polypeptide encoded by the CcEe gene. The D and
CeEe polypeptides differ by 36 amino acids (8.4%
divergence), but the NH2- and COOH-terminal regions
of the 2 proteins are well conserved. The sequence
homology supports the concept that the genes evolve
by duplication of a common ancestral gene. It is
evident that the controversy between Wiener
(1944), who espoused the existence of a single
gene with multiple epitopic sites, and the
Fisher-Race school (Race,
1944), which held to the existence of 2 closely
linked genes, has now been resolved with the
conclusion that each view was partially right and
partially wrong. None of the 3 researchers survived
to see the definitive resolution of the issue.
Arce et al. (1993)
likewise cloned the RHD gene.
Bennett et al. (1993)
demonstrated that DNA testing can be used to
determine RhD type in chorionic villus samples or
amniotic cells. An RhD-negative woman whose partner
is heterozygous may have preexisting anti-RhD
antibodies that may or may not affect a subsequent
fetus, depending on whether it is heterozygous. A
safe method of determining fetal RhD type early in
pregnancy would eliminate the risks to an
RhD-negative fetus of fetal blood sampling or
serial amniocenteses.
Cartron (1994)
provided a comprehensive review of the molecular
genetics of the Rh blood group antigens. These
antigens are carried by a family of nonglycosylated
hydrophobic transmembrane proteins of 30 to 32 kD,
which are missing from the red cells of rare
Rh-null individuals. The Rh proteins are
erythroid-specific and share no sequence homology
with any known protein. The RhD and non-D proteins
exhibit 92% sequence identity. The RHD and RHCE
genes (111700)
are organized in tandem on 1p36-p34 and presumably
originated by duplication of a common ancestral
gene. This concept is supported by the
identification of RH-like genes in nonhuman
primates. The C/c and E/e proteins are presumably
produced through alternative splicing of a
pre-messenger RNA; most RhD-negative haplotypes
represent absence of the RHD gene and the presence
of only 1 structural gene, RHCE. The correlation
between the blood group D epitopes and the amino
acid polymorphism of the Rh proteins had not been
established, but in the case of the RHCE gene, the
polymorphism ser103-to-pro had been shown to be
responsible for the C/c specificity (111700.0002)
and pro226-to-ala for the E/e specificity
(111700.0001).
Gene conversion appears to be the principal
mechanism responsible for polymorphism and gene
diversity in the RH system; however, gene deletions
have also been identified.
In his review of the molecular genetics of the
Rh blood group antigens, Cartron
(1994) pointed out the desirability of an early
and safe prenatal diagnosis of Rh status for use in
pregnancies at risk of Rh alloimmunization. Such
became possible when the structure and organization
of the RH locus in RhD-positive and RhD-negative
individuals was determined. The general approach
was based on the detection of D genomic sequences
by PCR in fetal DNA samples from chorionic villus
biopsy or amniocentesis. Huang
et al. (1996) used a set of SphI RFLPs that are
tightly linked with the Rh structural genes to
demonstrate linkage disequilibrium that allowed
determination of Rh-positive or Rh-negative status
(D/D, D/d, and d/d).
Smythe et al. (1996)
provided definitive proof that the RHD gene encodes
the D and G antigens and the RHCE gene encodes the
c and E antigens. They did this by
retroviral-mediated gene transfer using cDNA
transcripts of the RHD and RHCE genes and isolated
clones that expressed one or the other of these
pairs of antigens. Both c and E antigens were
expressed after transduction of the test 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, as had been
suggested.
Huang et al. (1996)
described a family study of the Evans (also known
as 'D..') phenotype, a codominant trait associated
with both qualitative and quantitative changes in
D-antigen expression. A cataract-causing mutation
was also inherited in this family and was
apparently cotransmitted with Evans, suggesting
chromosomal linkage of these 2 otherwise unrelated
traits. Southern blot analysis and allele-specific
PCR showed the linkage of Evans with a SphI RFLP
marker and the presence of a hybrid gene in the RH
locus. To delineate the pattern of gene expression,
Huang et al (1996)
characterized the composition and structure of
RH-polypeptide transcripts were characterized by
RT-PCR and nucleotide sequencing. They identified a
novel Rh transcript expressed only in the
Evans-positive erythroid cells. Sequence analysis
showed that the transcript maintained a normal open
reading frame but occurred as a CE-D-CE composite
in which exons 2-6 of the RHCE gene were replaced
by the homologous counterpart of the D gene. This
hybrid gene was predicted to encode a CD-D-CE
fusion protein whose surface expression correlates
with the Evans phenotype. The mode and consequence
of such a recombination of events suggested the
occurrence, in the RH locus, of a segmental DNA
transfer via the mechanism of gene conversion,
although unequal homologous recombination through
double crossover could not be excluded formally.
Congenital cataract of the Volkmann type (CCV;
115665)
has been mapped to the RH region, specifically to
1pter-p36.13. The family studied by Huang
et al. (1996) was ascertained through the East
of Scotland Blood Transfusion Service, in Dundee,
Scotland (Huang, 1996).
Race and Sanger
(1975) referred to the unpublished observations
on the Evans antigen in an English family by Weiner
in 1966. The antibody against the Evans antigen
caused hemolytic disease of the newborn in the
Evans family. Outside the original family, one
positive was found in 480 random British people.
All 4 Evans-positive members of the original family
had an Rh complex like, but not identical to,
--D--, whereas all 3 Evans-negative blood relatives
did not. The Evans antibody did not react with
cells of true --D-- homozygotes or heterozygotes.
Kemp et al. (1996)
examined 5 unrelated Rh D-- homozygotes and found
that, in 4 of them, RHCE sequences have been
replaced by Rh D sequences. The 5-prime end of
these rearrangements all 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.
In Caucasian RhD-negative individuals, the RHD
gene has not been found by any investigators except
Hyland et al. (1994). In
Japanese, Okuda et al.
(1997) found a different situation. Whereas
27.7% of RhD-negative donors demonstrated the
presence of the gene, others showed gross or
partial deletion of the RHD gene. Additionally, the
RHD gene detected in the RhD-negative donors seemed
to be intact through sequencing of the RhD
polypeptide cDNA and the promoter region of the RHD
gene. The phenotypes of these donors with the RHD
gene were CC or Cc, but not cc. The discrepant data
on the RHD gene in RhD-negative donors between
Japanese and Caucasians appeared to be derived from
the difference in the frequency of RhD-negative and
RhC-positive phenotypes. The possibility that the
differences might be related to differences in the
Rhesus blood group-associated glycoprotein, the
Rh50 comolecule, was to be investigated.
Bowman (1998) pointed
out that hemolytic disease of the fetus and newborn
was first described by a French midwife in 1609 in
a set of twins: the first twin was hydropic and
stillborn, and the second was deeply jaundiced and
subsequently died of kernicterus. Diamond
et al. (1932) demonstrated that hydrops and
kernicterus are 2 aspects of the same disease in
which hemolysis of the red blood cells of fetuses
and neonates results in extramedullary
erythropoiesis, causing hepatosplenomegaly and an
outpouring of erythroblasts into the circulation, a
condition they termed erythroblastosis fetalis.
Kernicterus was subsequently shown to be due to the
deposition of unconjugated bilirubin in the brain.
It is usually fatal; the 10% of affected infants
who survive have spastic choreoathetosis, deafness,
and mental retardation.
Levine et al. (1941)
showed that hemolytic disease of the fetus occurs
in an RhD-positive fetus carried by an RhD-negative
woman who has been immunized by transplacental
passage of RhD-positive red cells during a previous
pregnancy. When the father of the fetus being
carried by a sensitized RhD-negative woman is
heterozygous for RhD, as more than 50% of people
are, half the fetuses will be RhD-negative and
therefore require no treatment to avoid
erythroblastosis fetalis. The others will be
RhD-positive and require sophisticated
investigative measures and treatments. Lo
et al. (1998) described a noninvasive method of
determining fetal RhD status by analyzing maternal
plasma. Using a fluorescent-based PCR assay that
was sensitive enough to detect the amount of RhD
DNA found in a single cell, they determined the RhD
status of singleton fetuses from 57 RhD-negative
women whose partners were heterozygous for the RhD
gene. This method correctly identified the RhD
status of 10 of 12 fetuses whose mothers were in
their first trimester of pregnancy, that of all 30
fetuses whose mothers were in their second
trimester, and that of all 15 fetuses whose mothers
were in their third trimester. The method they
described was rapid, providing results within 1
day, and represented a major advance in RhD
genotyping.
About 0.2% to 1% of whites have red blood cells
with a reduced expression of the D antigen, known
as weak D, formerly known as D(u). Wagner
et al. (1999) sequenced all 10 RHD exons and
their splice sites in 161 samples from southwest
Germany that were identified as weak D. A total of
16 different molecular weak D types plus 2 alleles
characteristic of partial D were identified. The
amino acid substitutions of weak D types were
located in intracellular and transmembrane protein
segments and clustered in 4 regions of the protein
(amino acid positions 2 to 13, around 149, amino
acids 179 to 225, and amino acids 267 to 397).
Wagner et al. (1999)
concluded that most, if not all, weak D phenotypes
carry altered RhD proteins, suggesting a causal
relationship. They suggested that genotyping of
weak D may guide Rhesus-negative tranfusion policy
for such molecular weak D types that were prone to
develop anti-D.
ALLELIC
VARIANTS
-
-
.0001
RHD-NEGATIVE POLYMORPHISM [RHD,
DEL]
Colin et al. (1991)
showed that Rh-negative (dd) individuals are
homozygous for a deletion of the RHD
gene.
-
-
.0002 RHD
CATEGORY D-VII [RHD, LEU110PRO]
Although the presence or absence of the major
antigen, D, at the red blood cell surface
determines the Rh-positive or Rh-negative
phenotypes, respectively, some rare Rh-positive
variants that belong to 1 of the 7 D category
phenotypes, D(II) to D(VII) and DFR, can develop
anti-D antibodies following immunization by
pregnancy or transfusion; their RBCs do not
express some of the 9 determinants (epD1 through
epD9), which normally compose the so-called D
mosaic structure. Rouillac
et al. (1995) analyzed the modification of
the RHD gene associated with the D(VII)
category, characterized by the lack of epD8 and
the expression of the low frequency antigen
Rh40. They showed that Rh40 and the lack of epD8
are associated with a single point mutation,
329T-C, in exon 2 of the RHD gene. This
nucleotide polymorphism resulted in a leucine to
proline substitution at amino acid position 110
of the RhD polypeptide.
-
-
.0003 WEAK D,
TYPE I [RHD, VAL270GLY ]
Wagner et al.
(1999) identified 16 different mutations in
the RHD gene in patients with the weak D
phenotype. The most common by far was a T-to-G
transversion at nucleotide 809 resulting in a
valine-to-glycine substitution at codon 270 in
exon 6. This mutation is located in the
transmembrane domain and was identified in
70.29% of weak D alleles in a southwest German
population for a haplotype frequency of 1 in
277.
REFERENCES
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Thompson, E. S.; Wagner, S.; Coyne, K. E.;
Ferdman, B. A.; Lublin, D. M. :
- Molecular cloning of RhD cDNA
derived from a gene present in RhD-positive, but
not RhD-negative individuals.
Blood 82: 651-655, 1993.
PubMed ID : 8329718
- 2. Bennett, P. R.;
Le Van Kim, C.; Colin, Y.; Warwick, R. M.;
Cherif-Zahar, B.; Fisk, N. M.; Cartron, J.-P.
:
- Prenatal determination of fetal RhD
type by DNA amplification. New Eng.
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PubMed ID : 8341334
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:
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newborn. (Editorial) New Eng. J.
Med. 339: 1775-1777, 1998.
PubMed ID : 9845715
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:
- Defining the Rh blood group
antigens: biochemistry and molecular
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199-212, 1994.
PubMed ID : 7888828
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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 ID : 1824267
- 6. Diamond, L. K.;
Blackfan, K. D.; Baty, J. M. :
- Erythroblastosis fetalis and its
association with universal edema of the fetus,
icterus gravis neonatorum and anemia of the
newborn. J. Pediat. 1:
269-309, 1932.
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Personal Communication. New York City, N. Y.,
10/11/1996.
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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 ID : 8808597
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Reid, M. E.; Chen, Y.; Coghlan, G.; Okubo, Y.
:
- Molecular definition of red cell Rh
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RFLPs. Am. J. Hum. Genet. 58:
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PubMed ID : 8554049
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Wolter, L. C.; Liew, Y. W.; Saul, A. :
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:
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Poulter, M.; Carritt, B. :
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PubMed ID : 8900235
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Cherif-Zahar, B.; Raynal, V.; Mouro, I.; Lopez,
M.; Cartron, J. P.; Colin, Y. :
- Multiple Rh messenger RNA isoforms
are produced by alternative splicing.
Blood 80: 1074-1078, 1992.
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Mouro, I.; Cherif-Zahar, B.; Raynal, V.;
Cherrier, C.; Cartron, J.-P.; Colin, Y. :
- Molecular cloning and primary
structure of the human blood group RhD
polypeptide. Proc. Nat. Acad.
Sci. 89: 10925-10929, 1992.
PubMed ID : 1438298
- 15. Levine, P.;
Katzin, E. M.; Burnham, L. :
- Isoimmunization in pregnancy: its
possible bearing on the etiology of
erythroblastosis foetalis.
J.A.M.A. 116: 825-827, 1941.
- 16. Lo, Y. M. D.;
Hjelm, N. M.; Fidler, C.; Sargent, I. L.;
Murphy, M. F.; Chamberlain, P. F.; Poon, P. M.
K.; Redman, C. W. G.; Wainscoat, J. S. :
- Prenatal diagnosis of fetal RhD
status by molecular analysis of maternal
plasma. New Eng. J. Med. 339:
1734-1738, 1998.
PubMed ID : 9845707
- 17. Okuda, H.;
Kawano, M.; Iwamoto, S.; Tanaka, M.; Seno, T.;
Okubo, Y.; Kajii, E. :
- The RHD gene is highly detectable in
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Clin. Invest. 100: 373-379, 1997.
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:
- An 'incomplete' antibody in human
serum. (Letter) Nature 153:
771-772, 1944.
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Sanger, R. :
- Blood Groups in Man.
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- 20. Rouillac, C.;
Le Van Kim, C.; Beolet, M.; Cartron, J.-P.;
Colin, Y. :
- Leu110-to-pro substitution in the
RhD polypeptide is responsible for the D(VII)
category blood group phenotype. Am.
J. Hemat. 49: 87-88, 1995.
PubMed ID : 7741145
- 21. 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 ID : 8639918
- 22. Wagner, F. F.;
Gassner, C.; Muller, T. H.; Schonitzer, D.;
Schunter, F.; Flegel, W. A. :
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:
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Ada Hamosh - updated : 5/11/1999
Victor A. McKusick - updated : 12/11/1998
Victor A. McKusick - updated : 9/2/1997
Moyra Smith - updated : 10/26/1996
Victor A. McKusick : 12/6/1988
EDIT HISTORY
alopez : 5/14/1999
terry : 5/11/1999
mgross : 3/10/1999
carol : 12/22/1998
terry : 12/11/1998
alopez : 7/16/1998
jenny : 9/9/1997
terry : 9/2/1997
mark : 12/29/1996
terry : 12/20/1996
mark : 11/9/1996
mark : 10/26/1996
terry : 10/17/1996
mark : 5/9/1996
terry : 5/2/1996
mark : 1/25/1996
terry : 1/22/1996
mark : 11/14/1995
carol : 2/13/1995
pfoster : 5/12/1994
warfield : 3/15/1994
carol : 10/19/1993
carol : 9/28/1993
ALLELIC VARIANTS
- Mutation : RHD, VAL270GLY
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