Full text data of RHD
RHD
[Confidence: high (a blood group or CD marker)]
Blood group Rh(D) polypeptide (RHXIII; Rh polypeptide 2; RhPII; Rhesus D antigen; CD240D)
Blood group Rh(D) polypeptide (RHXIII; Rh polypeptide 2; RhPII; Rhesus D antigen; CD240D)
BGMUT
rh
561 rh RHD RHD reference reference D common: 61% Caucasians; 97% African-Americans; 99% Native Americans; 99% Asians 1438298; 8329718 X63094; L08429 Le van Kim et al.; Arce et al. 36 missense mutations differentiate RHD from RHCE; There are two nucleotide differences between L08429 and X63094.They correpond to silent changes: nt636C (GGC for 212Gly) and nt1036 (TTG for 346Leu) in L08429; nt636A (GGA for 212Gly) and nt1036 (CTG for 346Leu) in X63094 2006-11-13 19:40:06.680 NA
561 rh RHD RHD reference reference D common: 61% Caucasians; 97% African-Americans; 99% Native Americans; 99% Asians 1438298; 8329718 X63094; L08429 Le van Kim et al.; Arce et al. 36 missense mutations differentiate RHD from RHCE; There are two nucleotide differences between L08429 and X63094.They correpond to silent changes: nt636C (GGC for 212Gly) and nt1036 (TTG for 346Leu) in L08429; nt636A (GGA for 212Gly) and nt1036 (CTG for 346Leu) in X63094 2006-11-13 19:40:06.680 NA
UniProt
Q02161
ID RHD_HUMAN Reviewed; 417 AA.
AC Q02161; Q02162; Q07618; Q16147; Q16235; Q16355; Q5VSK0; Q5XLS9;
read moreAC Q5XLT1; Q5XLT2; Q9NPK0; Q9UQ20; Q9UQ21; Q9UQ22; Q9UQ23;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 3.
DT 22-JAN-2014, entry version 125.
DE RecName: Full=Blood group Rh(D) polypeptide;
DE AltName: Full=RHXIII;
DE AltName: Full=Rh polypeptide 2;
DE Short=RhPII;
DE AltName: Full=Rhesus D antigen;
DE AltName: CD_antigen=CD240D;
GN Name=RHD;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ILE-218.
RC TISSUE=Bone marrow;
RX PubMed=1438298; DOI=10.1073/pnas.89.22.10925;
RA le van Kim C., Mouro I., Cherif-Zahar B., Raynal V., Cherrier C.,
RA Cartron J.-P., Colin Y.;
RT "Molecular cloning and primary structure of the human blood group RhD
RT polypeptide.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:10925-10929(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Bone marrow;
RX PubMed=1379850;
RA le van Kim C., Cherif-Zahar B., Raynal V., Mouro I., Lopez M.,
RA Cartron J.-P., Colin Y.;
RT "Multiple Rh messenger RNA isoforms are produced by alternative
RT splicing.";
RL Blood 80:1074-1078(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8329718;
RA Arce M.A., Thompson E.S., Wagner S., Coyne K.E., Ferdman B.A.,
RA Lublin D.M.;
RT "Molecular cloning of RhD cDNA derived from a gene present in RhD-
RT positive, but not RhD-negative individuals.";
RL Blood 82:651-655(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=7916743; DOI=10.1007/BF00222717;
RA Kajii E., Umenishi F., Iwamoto S., Ikemoto S.;
RT "Isolation of a new cDNA clone encoding an Rh polypeptide associated
RT with the Rh blood group system.";
RL Hum. Genet. 91:157-162(1993).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=8180407;
RA Westhoff C.M., Wylie D.E.;
RT "Identification of a new RhD-specific mRNA from K562 cells.";
RL Blood 83:3098-3100(1994).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT CYS-16.
RX PubMed=7606008;
RA Huang C.-H., Reid M.E., Chen Y.;
RT "Identification of a partial internal deletion in the RH locus causing
RT the human erythrocyte D-phenotype.";
RL Blood 86:784-790(1995).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RX PubMed=8080999;
RA Suyama K., Lunn R., Haller S., Goldstein J.;
RT "Rh(D) antigen expression and isolation of a new Rh(D) cDNA isoform in
RT human erythroleukemic K562 cells.";
RL Blood 84:1975-1981(1994).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 4; 5 AND 6), AND ALTERNATIVE
RP SPLICING.
RX PubMed=16510313; DOI=10.1016/j.transci.2005.10.001;
RA Shao C.P., Xiong W., Zhou Y.Y.;
RT "Multiple isoforms excluding normal RhD mRNA detected in Rh blood
RT group Del phenotype with RHD 1227A allele.";
RL Transfus. Apher. Sci. 34:145-152(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS VAL-223; GLN-233; MET-238 AND
RP LEU-245.
RA Hyodo H., Ishikawa Y., Kashiwase K., Ogawa A., Watanabe Y.,
RA Tsuneyama H., Toyoda C., Uchikawa M., Akaza T., Fujii T.;
RT "Polymorphisms of RhDVa in Japanese.";
RL Submitted (OCT-1998) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [11]
RP PROTEIN SEQUENCE OF 2-33.
RX PubMed=3146980;
RA Avent N.D., Ridgwell K., Mawby W.J., Tanner M.J.A., Anstee D.J.,
RA Kumpel B.;
RT "Protein-sequence studies on Rh-related polypeptides suggest the
RT presence of at least two groups of proteins which associate in the
RT human red-cell membrane.";
RL Biochem. J. 256:1043-1046(1988).
RN [12]
RP PROTEIN SEQUENCE OF 2-21.
RX PubMed=3131772; DOI=10.1073/pnas.85.11.4042;
RA Saboori A.M., Smith B.L., Agre P.;
RT "Polymorphism in the Mr 32,000 Rh protein purified from Rh(D)-positive
RT and -negative erythrocytes.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:4042-4045(1988).
RN [13]
RP PROTEIN SEQUENCE OF 2-17.
RX PubMed=3135863;
RA Bloy C., Blanchard D., Dahr W., Beyreuther K., Salmon C.,
RA Cartron J.-P.;
RT "Determination of the N-terminal sequence of human red cell Rh(D)
RT polypeptide and demonstration that the Rh(D), (c), and (E) antigens
RT are carried by distinct polypeptide chains.";
RL Blood 72:661-666(1988).
RN [14]
RP PROTEIN SEQUENCE OF 401-407.
RX PubMed=1898705;
RA Suyama K., Goldstein J., Aebersold R., Kent S.;
RT "Regarding the size of Rh proteins.";
RL Blood 77:411-411(1991).
RN [15]
RP VARIANT TAR ANTIGEN PRO-110.
RX PubMed=7741145; DOI=10.1002/ajh.2830490115;
RA Rouillac C., le van Kim C., Beolet M., Cartron J.-P., Colin Y.;
RT "Leu110Pro substitution in the RhD polypeptide is responsible for the
RT DVII category blood group phenotype.";
RL Am. J. Hematol. 49:87-88(1995).
RN [16]
RP VARIANT [LARGE SCALE ANALYSIS] CYS-103.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: May be part of an oligomeric complex which is likely to
CC have a transport or channel function in the erythrocyte membrane.
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=Long;
CC IsoId=Q02161-1; Sequence=Displayed;
CC Name=2; Synonyms=Short 1;
CC IsoId=Q02161-2; Sequence=VSP_005706;
CC Name=3; Synonyms=Short 2;
CC IsoId=Q02161-3; Sequence=VSP_005707, VSP_005708;
CC Name=4;
CC IsoId=Q02161-4; Sequence=VSP_047797;
CC Name=5;
CC IsoId=Q02161-5; Sequence=VSP_047796;
CC Name=6;
CC IsoId=Q02161-6; Sequence=VSP_047795, VSP_047798;
CC -!- TISSUE SPECIFICITY: Restricted to tissues or cell lines expressing
CC erythroid characters.
CC -!- POLYMORPHISM: RHD and RHCE are responsible for the Rh blood group
CC system. The molecular basis of the Tar=Rh40 blood group antigen is
CC a polymorphism in position 110.
CC -!- SIMILARITY: Belongs to the ammonium transporter (TC 2.A.49)
CC family. Rh subfamily.
CC -!- WEB RESOURCE: Name=dbRBC/BGMUT; Note=Blood group antigen gene
CC mutation database;
CC URL="http://www.ncbi.nlm.nih.gov/gv/mhc/xslcgi.cgi?cmd=bgmut/systems_info&system;=rh";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/RHD";
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DR EMBL; X63097; CAA44811.1; -; mRNA.
DR EMBL; X63094; CAA44808.1; -; mRNA.
DR EMBL; L08429; AAA02679.1; -; mRNA.
DR EMBL; S57971; AAB26081.1; -; mRNA.
DR EMBL; S70174; AAB30756.1; -; mRNA.
DR EMBL; S78509; AAB34852.1; -; mRNA.
DR EMBL; S73913; AAB31911.1; -; mRNA.
DR EMBL; AY751492; AAU93636.1; -; mRNA.
DR EMBL; AY751493; AAU93637.1; -; mRNA.
DR EMBL; AY751495; AAU93639.1; -; mRNA.
DR EMBL; AB018966; BAA81899.1; -; mRNA.
DR EMBL; AB018967; BAA81900.1; -; mRNA.
DR EMBL; AB018968; BAA81901.1; -; mRNA.
DR EMBL; AB018969; BAA82159.1; -; mRNA.
DR EMBL; AL928711; CAH72602.1; -; Genomic_DNA.
DR PIR; A46368; A46368.
DR PIR; I52615; I52615.
DR RefSeq; NP_001121163.1; NM_001127691.2.
DR RefSeq; NP_001269797.1; NM_001282868.1.
DR RefSeq; NP_001269798.1; NM_001282869.1.
DR RefSeq; NP_001269800.1; NM_001282871.1.
DR RefSeq; NP_057208.2; NM_016124.4.
DR UniGene; Hs.449968; -.
DR ProteinModelPortal; Q02161; -.
DR SMR; Q02161; 40-308.
DR TCDB; 1.A.11.4.3; the ammonia transporter channel (amt) family.
DR PhosphoSite; Q02161; -.
DR DMDM; 296452980; -.
DR PaxDb; Q02161; -.
DR PRIDE; Q02161; -.
DR DNASU; 6007; -.
DR Ensembl; ENST00000328664; ENSP00000331871; ENSG00000187010.
DR Ensembl; ENST00000342055; ENSP00000339577; ENSG00000187010.
DR Ensembl; ENST00000357542; ENSP00000350150; ENSG00000187010.
DR Ensembl; ENST00000417538; ENSP00000396420; ENSG00000187010.
DR Ensembl; ENST00000454452; ENSP00000413849; ENSG00000187010.
DR GeneID; 6007; -.
DR KEGG; hsa:6007; -.
DR UCSC; uc009vrm.3; human.
DR CTD; 6007; -.
DR GeneCards; GC01P025599; -.
DR HGNC; HGNC:10009; RHD.
DR MIM; 111680; gene.
DR neXtProt; NX_Q02161; -.
DR Orphanet; 71275; Rh deficiency syndrome.
DR PharmGKB; PA34387; -.
DR eggNOG; NOG314742; -.
DR HOVERGEN; HBG004374; -.
DR KO; K06579; -.
DR OMA; TCGVHYT; -.
DR OrthoDB; EOG73NG3C; -.
DR PhylomeDB; Q02161; -.
DR GeneWiki; RHD_(gene); -.
DR GenomeRNAi; 6007; -.
DR NextBio; 23439; -.
DR PRO; PR:Q02161; -.
DR ArrayExpress; Q02161; -.
DR Bgee; Q02161; -.
DR Genevestigator; Q02161; -.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0008519; F:ammonium transmembrane transporter activity; IEA:InterPro.
DR GO; GO:0072488; P:ammonium transmembrane transport; IEA:GOC.
DR InterPro; IPR024041; NH4_transpt_AmtB-like_dom.
DR InterPro; IPR002229; RhesusRHD.
DR Pfam; PF00909; Ammonium_transp; 1.
DR PRINTS; PR00342; RHESUSRHD.
DR SUPFAM; SSF111352; SSF111352; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Blood group antigen; Complete proteome;
KW Direct protein sequencing; Membrane; Polymorphism; Reference proteome;
KW Transmembrane; Transmembrane helix.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 417 Blood group Rh(D) polypeptide.
FT /FTId=PRO_0000168190.
FT TRANSMEM 12 32 Helical; (Potential).
FT TRANSMEM 44 64 Helical; (Potential).
FT TRANSMEM 77 97 Helical; (Potential).
FT TRANSMEM 107 127 Helical; (Potential).
FT TRANSMEM 130 150 Helical; (Potential).
FT TRANSMEM 167 187 Helical; (Potential).
FT TRANSMEM 203 223 Helical; (Potential).
FT TRANSMEM 238 258 Helical; (Potential).
FT TRANSMEM 287 307 Helical; (Potential).
FT TRANSMEM 334 354 Helical; (Potential).
FT TRANSMEM 358 378 Helical; (Potential).
FT VAR_SEQ 314 409 Missing (in isoform 2).
FT /FTId=VSP_005706.
FT VAR_SEQ 314 378 GCCNRVLGIPHSSIMGYNFSLLGLLGEIIYIVLLVLDTVGA
FT GNGMIGFQVLLSIGELSLAIVIAL -> DWLPGPPQHWGTQ
FT LGHRDSSHVWSPDSFLIWLLDFKQKHPRKTRPVQKQDNFLS
FT LLPAFVREKRS (in isoform 6).
FT /FTId=VSP_047795.
FT VAR_SEQ 316 316 C -> S (in isoform 3).
FT /FTId=VSP_005707.
FT VAR_SEQ 317 417 Missing (in isoform 3).
FT /FTId=VSP_005708.
FT VAR_SEQ 358 417 MIGFQVLLSIGELSLAIVIALMSGLLTGLLLNLKIWKAPHE
FT AKYFDDQVFWKFPHLAVGF -> IFLIWLLDFKQKHPRKTR
FT PVQKQDNFLSLLPAFVREKRS (in isoform 5).
FT /FTId=VSP_047796.
FT VAR_SEQ 359 417 IGFQVLLSIGELSLAIVIALMSGLLTGLLLNLKIWKAPHEA
FT KYFDDQVFWKFPHLAVGF -> SLGWNLAVKMAEAGDEELM
FT RLDVSQRNHGGAAVPTGSWMPSTETTIAPNYRDHISVVSSF
FT GCWILSKSIQEKQGLFKNKTTSSHCCLHLYVRNAHDSKVSN
FT VRAGTGVRENGVESFLCHSLRRISPFIMHCRIQQ (in
FT isoform 4).
FT /FTId=VSP_047797.
FT VAR_SEQ 379 417 Missing (in isoform 6).
FT /FTId=VSP_047798.
FT VARIANT 16 16 W -> C (in dbSNP:rs586178).
FT /FTId=VAR_034455.
FT VARIANT 103 103 S -> C (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035615.
FT VARIANT 110 110 L -> P (in Tar antigen).
FT /FTId=VAR_006919.
FT VARIANT 193 193 E -> K (in dbSNP:rs17418091).
FT /FTId=VAR_034456.
FT VARIANT 201 201 T -> R (in dbSNP:rs17418098).
FT /FTId=VAR_034457.
FT VARIANT 218 218 M -> I (in dbSNP:rs141540728).
FT /FTId=VAR_006920.
FT VARIANT 223 223 F -> V (in RhDVa(FK) and RhDVa(TT);
FT dbSNP:rs1053356).
FT /FTId=VAR_013304.
FT VARIANT 233 233 E -> Q (in RhDVa(FK), RhDVa(TO),
FT RhDVa(TT) and RhDYo; dbSNP:rs1053359).
FT /FTId=VAR_013305.
FT VARIANT 238 238 V -> M (in RhDVa(TO) and RhDVa(TT);
FT dbSNP:rs1053360).
FT /FTId=VAR_013306.
FT VARIANT 245 245 V -> L (in RhDVa(TT); dbSNP:rs150073306).
FT /FTId=VAR_013307.
FT VARIANT 263 263 G -> R (in dbSNP:rs3118454).
FT /FTId=VAR_047996.
FT VARIANT 306 306 V -> I (in dbSNP:rs590813).
FT /FTId=VAR_047997.
FT VARIANT 311 311 Y -> C (in dbSNP:rs590787).
FT /FTId=VAR_047998.
FT CONFLICT 39 39 E -> G (in Ref. 4; AAB26081).
FT CONFLICT 103 103 S -> P (in Ref. 4; AAB26081).
FT CONFLICT 127 127 V -> A (in Ref. 4; AAB26081).
FT CONFLICT 174 174 V -> M (in Ref. 6; AAB34852).
FT CONFLICT 182 182 S -> T (in Ref. 4; AAB26081).
FT CONFLICT 314 314 G -> V (in Ref. 4; AAB26081 and 7;
FT AAB31911).
FT CONFLICT 323 323 P -> H (in Ref. 4; AAB26081).
FT CONFLICT 379 379 M -> T (in Ref. 1; CAA44811/CAA44808, 3;
FT AAA02679, 4; AAB26081, 6; AAB34852 and 8;
FT BAA81899/BAA81900/BAA81901/BAA82159).
FT CONFLICT 398 398 E -> V (in Ref. 6; AAB34852).
SQ SEQUENCE 417 AA; 45211 MW; 38721BFA664AE199 CRC64;
MSSKYPRSVR RCLPLWALTL EAALILLFYF FTHYDASLED QKGLVASYQV GQDLTVMAAI
GLGFLTSSFR RHSWSSVAFN LFMLALGVQW AILLDGFLSQ FPSGKVVITL FSIRLATMSA
LSVLISVDAV LGKVNLAQLV VMVLVEVTAL GNLRMVISNI FNTDYHMNMM HIYVFAAYFG
LSVAWCLPKP LPEGTEDKDQ TATIPSLSAM LGALFLWMFW PSFNSALLRS PIERKNAVFN
TYYAVAVSVV TAISGSSLAH PQGKISKTYV HSAVLAGGVA VGTSCHLIPS PWLAMVLGLV
AGLISVGGAK YLPGCCNRVL GIPHSSIMGY NFSLLGLLGE IIYIVLLVLD TVGAGNGMIG
FQVLLSIGEL SLAIVIALMS GLLTGLLLNL KIWKAPHEAK YFDDQVFWKF PHLAVGF
//
ID RHD_HUMAN Reviewed; 417 AA.
AC Q02161; Q02162; Q07618; Q16147; Q16235; Q16355; Q5VSK0; Q5XLS9;
read moreAC Q5XLT1; Q5XLT2; Q9NPK0; Q9UQ20; Q9UQ21; Q9UQ22; Q9UQ23;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 3.
DT 22-JAN-2014, entry version 125.
DE RecName: Full=Blood group Rh(D) polypeptide;
DE AltName: Full=RHXIII;
DE AltName: Full=Rh polypeptide 2;
DE Short=RhPII;
DE AltName: Full=Rhesus D antigen;
DE AltName: CD_antigen=CD240D;
GN Name=RHD;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ILE-218.
RC TISSUE=Bone marrow;
RX PubMed=1438298; DOI=10.1073/pnas.89.22.10925;
RA le van Kim C., Mouro I., Cherif-Zahar B., Raynal V., Cherrier C.,
RA Cartron J.-P., Colin Y.;
RT "Molecular cloning and primary structure of the human blood group RhD
RT polypeptide.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:10925-10929(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Bone marrow;
RX PubMed=1379850;
RA le van Kim C., Cherif-Zahar B., Raynal V., Mouro I., Lopez M.,
RA Cartron J.-P., Colin Y.;
RT "Multiple Rh messenger RNA isoforms are produced by alternative
RT splicing.";
RL Blood 80:1074-1078(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8329718;
RA Arce M.A., Thompson E.S., Wagner S., Coyne K.E., Ferdman B.A.,
RA Lublin D.M.;
RT "Molecular cloning of RhD cDNA derived from a gene present in RhD-
RT positive, but not RhD-negative individuals.";
RL Blood 82:651-655(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=7916743; DOI=10.1007/BF00222717;
RA Kajii E., Umenishi F., Iwamoto S., Ikemoto S.;
RT "Isolation of a new cDNA clone encoding an Rh polypeptide associated
RT with the Rh blood group system.";
RL Hum. Genet. 91:157-162(1993).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=8180407;
RA Westhoff C.M., Wylie D.E.;
RT "Identification of a new RhD-specific mRNA from K562 cells.";
RL Blood 83:3098-3100(1994).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT CYS-16.
RX PubMed=7606008;
RA Huang C.-H., Reid M.E., Chen Y.;
RT "Identification of a partial internal deletion in the RH locus causing
RT the human erythrocyte D-phenotype.";
RL Blood 86:784-790(1995).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RX PubMed=8080999;
RA Suyama K., Lunn R., Haller S., Goldstein J.;
RT "Rh(D) antigen expression and isolation of a new Rh(D) cDNA isoform in
RT human erythroleukemic K562 cells.";
RL Blood 84:1975-1981(1994).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 4; 5 AND 6), AND ALTERNATIVE
RP SPLICING.
RX PubMed=16510313; DOI=10.1016/j.transci.2005.10.001;
RA Shao C.P., Xiong W., Zhou Y.Y.;
RT "Multiple isoforms excluding normal RhD mRNA detected in Rh blood
RT group Del phenotype with RHD 1227A allele.";
RL Transfus. Apher. Sci. 34:145-152(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS VAL-223; GLN-233; MET-238 AND
RP LEU-245.
RA Hyodo H., Ishikawa Y., Kashiwase K., Ogawa A., Watanabe Y.,
RA Tsuneyama H., Toyoda C., Uchikawa M., Akaza T., Fujii T.;
RT "Polymorphisms of RhDVa in Japanese.";
RL Submitted (OCT-1998) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [11]
RP PROTEIN SEQUENCE OF 2-33.
RX PubMed=3146980;
RA Avent N.D., Ridgwell K., Mawby W.J., Tanner M.J.A., Anstee D.J.,
RA Kumpel B.;
RT "Protein-sequence studies on Rh-related polypeptides suggest the
RT presence of at least two groups of proteins which associate in the
RT human red-cell membrane.";
RL Biochem. J. 256:1043-1046(1988).
RN [12]
RP PROTEIN SEQUENCE OF 2-21.
RX PubMed=3131772; DOI=10.1073/pnas.85.11.4042;
RA Saboori A.M., Smith B.L., Agre P.;
RT "Polymorphism in the Mr 32,000 Rh protein purified from Rh(D)-positive
RT and -negative erythrocytes.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:4042-4045(1988).
RN [13]
RP PROTEIN SEQUENCE OF 2-17.
RX PubMed=3135863;
RA Bloy C., Blanchard D., Dahr W., Beyreuther K., Salmon C.,
RA Cartron J.-P.;
RT "Determination of the N-terminal sequence of human red cell Rh(D)
RT polypeptide and demonstration that the Rh(D), (c), and (E) antigens
RT are carried by distinct polypeptide chains.";
RL Blood 72:661-666(1988).
RN [14]
RP PROTEIN SEQUENCE OF 401-407.
RX PubMed=1898705;
RA Suyama K., Goldstein J., Aebersold R., Kent S.;
RT "Regarding the size of Rh proteins.";
RL Blood 77:411-411(1991).
RN [15]
RP VARIANT TAR ANTIGEN PRO-110.
RX PubMed=7741145; DOI=10.1002/ajh.2830490115;
RA Rouillac C., le van Kim C., Beolet M., Cartron J.-P., Colin Y.;
RT "Leu110Pro substitution in the RhD polypeptide is responsible for the
RT DVII category blood group phenotype.";
RL Am. J. Hematol. 49:87-88(1995).
RN [16]
RP VARIANT [LARGE SCALE ANALYSIS] CYS-103.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: May be part of an oligomeric complex which is likely to
CC have a transport or channel function in the erythrocyte membrane.
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=Long;
CC IsoId=Q02161-1; Sequence=Displayed;
CC Name=2; Synonyms=Short 1;
CC IsoId=Q02161-2; Sequence=VSP_005706;
CC Name=3; Synonyms=Short 2;
CC IsoId=Q02161-3; Sequence=VSP_005707, VSP_005708;
CC Name=4;
CC IsoId=Q02161-4; Sequence=VSP_047797;
CC Name=5;
CC IsoId=Q02161-5; Sequence=VSP_047796;
CC Name=6;
CC IsoId=Q02161-6; Sequence=VSP_047795, VSP_047798;
CC -!- TISSUE SPECIFICITY: Restricted to tissues or cell lines expressing
CC erythroid characters.
CC -!- POLYMORPHISM: RHD and RHCE are responsible for the Rh blood group
CC system. The molecular basis of the Tar=Rh40 blood group antigen is
CC a polymorphism in position 110.
CC -!- SIMILARITY: Belongs to the ammonium transporter (TC 2.A.49)
CC family. Rh subfamily.
CC -!- WEB RESOURCE: Name=dbRBC/BGMUT; Note=Blood group antigen gene
CC mutation database;
CC URL="http://www.ncbi.nlm.nih.gov/gv/mhc/xslcgi.cgi?cmd=bgmut/systems_info&system;=rh";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/RHD";
CC -----------------------------------------------------------------------
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DR EMBL; X63097; CAA44811.1; -; mRNA.
DR EMBL; X63094; CAA44808.1; -; mRNA.
DR EMBL; L08429; AAA02679.1; -; mRNA.
DR EMBL; S57971; AAB26081.1; -; mRNA.
DR EMBL; S70174; AAB30756.1; -; mRNA.
DR EMBL; S78509; AAB34852.1; -; mRNA.
DR EMBL; S73913; AAB31911.1; -; mRNA.
DR EMBL; AY751492; AAU93636.1; -; mRNA.
DR EMBL; AY751493; AAU93637.1; -; mRNA.
DR EMBL; AY751495; AAU93639.1; -; mRNA.
DR EMBL; AB018966; BAA81899.1; -; mRNA.
DR EMBL; AB018967; BAA81900.1; -; mRNA.
DR EMBL; AB018968; BAA81901.1; -; mRNA.
DR EMBL; AB018969; BAA82159.1; -; mRNA.
DR EMBL; AL928711; CAH72602.1; -; Genomic_DNA.
DR PIR; A46368; A46368.
DR PIR; I52615; I52615.
DR RefSeq; NP_001121163.1; NM_001127691.2.
DR RefSeq; NP_001269797.1; NM_001282868.1.
DR RefSeq; NP_001269798.1; NM_001282869.1.
DR RefSeq; NP_001269800.1; NM_001282871.1.
DR RefSeq; NP_057208.2; NM_016124.4.
DR UniGene; Hs.449968; -.
DR ProteinModelPortal; Q02161; -.
DR SMR; Q02161; 40-308.
DR TCDB; 1.A.11.4.3; the ammonia transporter channel (amt) family.
DR PhosphoSite; Q02161; -.
DR DMDM; 296452980; -.
DR PaxDb; Q02161; -.
DR PRIDE; Q02161; -.
DR DNASU; 6007; -.
DR Ensembl; ENST00000328664; ENSP00000331871; ENSG00000187010.
DR Ensembl; ENST00000342055; ENSP00000339577; ENSG00000187010.
DR Ensembl; ENST00000357542; ENSP00000350150; ENSG00000187010.
DR Ensembl; ENST00000417538; ENSP00000396420; ENSG00000187010.
DR Ensembl; ENST00000454452; ENSP00000413849; ENSG00000187010.
DR GeneID; 6007; -.
DR KEGG; hsa:6007; -.
DR UCSC; uc009vrm.3; human.
DR CTD; 6007; -.
DR GeneCards; GC01P025599; -.
DR HGNC; HGNC:10009; RHD.
DR MIM; 111680; gene.
DR neXtProt; NX_Q02161; -.
DR Orphanet; 71275; Rh deficiency syndrome.
DR PharmGKB; PA34387; -.
DR eggNOG; NOG314742; -.
DR HOVERGEN; HBG004374; -.
DR KO; K06579; -.
DR OMA; TCGVHYT; -.
DR OrthoDB; EOG73NG3C; -.
DR PhylomeDB; Q02161; -.
DR GeneWiki; RHD_(gene); -.
DR GenomeRNAi; 6007; -.
DR NextBio; 23439; -.
DR PRO; PR:Q02161; -.
DR ArrayExpress; Q02161; -.
DR Bgee; Q02161; -.
DR Genevestigator; Q02161; -.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0008519; F:ammonium transmembrane transporter activity; IEA:InterPro.
DR GO; GO:0072488; P:ammonium transmembrane transport; IEA:GOC.
DR InterPro; IPR024041; NH4_transpt_AmtB-like_dom.
DR InterPro; IPR002229; RhesusRHD.
DR Pfam; PF00909; Ammonium_transp; 1.
DR PRINTS; PR00342; RHESUSRHD.
DR SUPFAM; SSF111352; SSF111352; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Blood group antigen; Complete proteome;
KW Direct protein sequencing; Membrane; Polymorphism; Reference proteome;
KW Transmembrane; Transmembrane helix.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 417 Blood group Rh(D) polypeptide.
FT /FTId=PRO_0000168190.
FT TRANSMEM 12 32 Helical; (Potential).
FT TRANSMEM 44 64 Helical; (Potential).
FT TRANSMEM 77 97 Helical; (Potential).
FT TRANSMEM 107 127 Helical; (Potential).
FT TRANSMEM 130 150 Helical; (Potential).
FT TRANSMEM 167 187 Helical; (Potential).
FT TRANSMEM 203 223 Helical; (Potential).
FT TRANSMEM 238 258 Helical; (Potential).
FT TRANSMEM 287 307 Helical; (Potential).
FT TRANSMEM 334 354 Helical; (Potential).
FT TRANSMEM 358 378 Helical; (Potential).
FT VAR_SEQ 314 409 Missing (in isoform 2).
FT /FTId=VSP_005706.
FT VAR_SEQ 314 378 GCCNRVLGIPHSSIMGYNFSLLGLLGEIIYIVLLVLDTVGA
FT GNGMIGFQVLLSIGELSLAIVIAL -> DWLPGPPQHWGTQ
FT LGHRDSSHVWSPDSFLIWLLDFKQKHPRKTRPVQKQDNFLS
FT LLPAFVREKRS (in isoform 6).
FT /FTId=VSP_047795.
FT VAR_SEQ 316 316 C -> S (in isoform 3).
FT /FTId=VSP_005707.
FT VAR_SEQ 317 417 Missing (in isoform 3).
FT /FTId=VSP_005708.
FT VAR_SEQ 358 417 MIGFQVLLSIGELSLAIVIALMSGLLTGLLLNLKIWKAPHE
FT AKYFDDQVFWKFPHLAVGF -> IFLIWLLDFKQKHPRKTR
FT PVQKQDNFLSLLPAFVREKRS (in isoform 5).
FT /FTId=VSP_047796.
FT VAR_SEQ 359 417 IGFQVLLSIGELSLAIVIALMSGLLTGLLLNLKIWKAPHEA
FT KYFDDQVFWKFPHLAVGF -> SLGWNLAVKMAEAGDEELM
FT RLDVSQRNHGGAAVPTGSWMPSTETTIAPNYRDHISVVSSF
FT GCWILSKSIQEKQGLFKNKTTSSHCCLHLYVRNAHDSKVSN
FT VRAGTGVRENGVESFLCHSLRRISPFIMHCRIQQ (in
FT isoform 4).
FT /FTId=VSP_047797.
FT VAR_SEQ 379 417 Missing (in isoform 6).
FT /FTId=VSP_047798.
FT VARIANT 16 16 W -> C (in dbSNP:rs586178).
FT /FTId=VAR_034455.
FT VARIANT 103 103 S -> C (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035615.
FT VARIANT 110 110 L -> P (in Tar antigen).
FT /FTId=VAR_006919.
FT VARIANT 193 193 E -> K (in dbSNP:rs17418091).
FT /FTId=VAR_034456.
FT VARIANT 201 201 T -> R (in dbSNP:rs17418098).
FT /FTId=VAR_034457.
FT VARIANT 218 218 M -> I (in dbSNP:rs141540728).
FT /FTId=VAR_006920.
FT VARIANT 223 223 F -> V (in RhDVa(FK) and RhDVa(TT);
FT dbSNP:rs1053356).
FT /FTId=VAR_013304.
FT VARIANT 233 233 E -> Q (in RhDVa(FK), RhDVa(TO),
FT RhDVa(TT) and RhDYo; dbSNP:rs1053359).
FT /FTId=VAR_013305.
FT VARIANT 238 238 V -> M (in RhDVa(TO) and RhDVa(TT);
FT dbSNP:rs1053360).
FT /FTId=VAR_013306.
FT VARIANT 245 245 V -> L (in RhDVa(TT); dbSNP:rs150073306).
FT /FTId=VAR_013307.
FT VARIANT 263 263 G -> R (in dbSNP:rs3118454).
FT /FTId=VAR_047996.
FT VARIANT 306 306 V -> I (in dbSNP:rs590813).
FT /FTId=VAR_047997.
FT VARIANT 311 311 Y -> C (in dbSNP:rs590787).
FT /FTId=VAR_047998.
FT CONFLICT 39 39 E -> G (in Ref. 4; AAB26081).
FT CONFLICT 103 103 S -> P (in Ref. 4; AAB26081).
FT CONFLICT 127 127 V -> A (in Ref. 4; AAB26081).
FT CONFLICT 174 174 V -> M (in Ref. 6; AAB34852).
FT CONFLICT 182 182 S -> T (in Ref. 4; AAB26081).
FT CONFLICT 314 314 G -> V (in Ref. 4; AAB26081 and 7;
FT AAB31911).
FT CONFLICT 323 323 P -> H (in Ref. 4; AAB26081).
FT CONFLICT 379 379 M -> T (in Ref. 1; CAA44811/CAA44808, 3;
FT AAA02679, 4; AAB26081, 6; AAB34852 and 8;
FT BAA81899/BAA81900/BAA81901/BAA82159).
FT CONFLICT 398 398 E -> V (in Ref. 6; AAB34852).
SQ SEQUENCE 417 AA; 45211 MW; 38721BFA664AE199 CRC64;
MSSKYPRSVR RCLPLWALTL EAALILLFYF FTHYDASLED QKGLVASYQV GQDLTVMAAI
GLGFLTSSFR RHSWSSVAFN LFMLALGVQW AILLDGFLSQ FPSGKVVITL FSIRLATMSA
LSVLISVDAV LGKVNLAQLV VMVLVEVTAL GNLRMVISNI FNTDYHMNMM HIYVFAAYFG
LSVAWCLPKP LPEGTEDKDQ TATIPSLSAM LGALFLWMFW PSFNSALLRS PIERKNAVFN
TYYAVAVSVV TAISGSSLAH PQGKISKTYV HSAVLAGGVA VGTSCHLIPS PWLAMVLGLV
AGLISVGGAK YLPGCCNRVL GIPHSSIMGY NFSLLGLLGE IIYIVLLVLD TVGAGNGMIG
FQVLLSIGEL SLAIVIALMS GLLTGLLLNL KIWKAPHEAK YFDDQVFWKF PHLAVGF
//
MIM
111680
*RECORD*
*FIELD* NO
111680
*FIELD* TI
*111680 RHESUS BLOOD GROUP, D ANTIGEN; RHD
;;BLOOD GROUP--RHESUS SYSTEM D POLYPEPTIDE
read more*FIELD* TX
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 (111700) genes 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.
To understand the mechanism underlying the acquisition of a new function
by duplicated genes, Innan (2003) studied the evolutionary process
within a relatively short time after gene duplication. Innan (2003)
theorized that the pattern of allelic variation in duplicated genes is
determined mainly by the balance between gene conversion, which operates
against diversification of the duplicated gene, and selection, which
favors diversification. Innan (2003) applied this theory to the human
RHCE and RHD genes. The very high level of amino acid divergence between
the 2 genes was observed only in a short region around exon 7. This exon
encodes amino acids that characterize the difference between the RHCE
and RHD antigens. The observed pattern of DNA variation in this region
was considered consistent with the selection model, suggesting that
strong selection might be working to maintain the RHCE/RHD antigen
variation in the 2-locus system.
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 transfusion policy for such molecular weak D types that
were prone to develop anti-D.
In chronically transfused patients, conventional blood group typing may
be impossible because of mixed-field agglutination (Spanos et al., 1990;
Garratty, 1997). Legler et al. (1999) performed PCR genotyping for D,
RHD and RHCE on 27 patients with congenital anemia and lifelong
transfusion history and compared the results with serologic blood group
typing results in their medical records. They found that serologic
methods frequently led to false blood group results in mixed blood
samples. Moreover, blood group determinations were frequently incomplete
or doubtful. In such a situation, pretransfusion genotyping for D, RHD,
and RHCE makes Rh-matched transfusions possible, at least in whites. The
genetic background of the RH genes has to be elucidated in other ethnic
groups before genotyping can be applied without restriction.
Wagner and Flegel (2000) determined that the open reading frames of the
RHD and RHCE genes have opposite orientations. The 3-prime ends of the
genes face each other and are separated by about 30,000 bp that contain
the SMP1 gene (605348). The RHD gene is flanked by 2 DNA segments,
dubbed Rhesus boxes by Wagner and Flegel (2000), with a length of
approximately 9,000 bp, 98.6% homology, and identical orientation. The
breakpoints of the RHD deletion in the prevalent RHD-negative haplotypes
are located in the 1,463-bp identity region of the Rhesus boxes. Wagner
and Flegel (2000) established technical procedures for specifically
detecting the RHD gene deletion in the common RHD-negative haplotypes.
The molecular structure of the RH gene explains the mechanisms for both
the RHD deletion and the generation of RHD/RHCE hybrid alleles.
Miyoshi et al. (2001) described 2 individuals who were mosaic for the Rh
blood group phenotype, one erythrocyte population being D-positive and
the other D-negative. In both individuals, biparental disomic patterns
of markers spanning chromosome 1 were present in peripheral blood
leukocytes, whereas only paternal alleles were detected in hair or hair
roots in 1 patient and in one-fourth of hair roots in the second
patient. Miyoshi et al. (2001) emphasized that isodisomy for chromosome
1 is not infrequent and may cause an unusual RhD phenotype.
D-positive individuals harboring a 'partial' D antigen may produce an
allo-anti-D similar to that generated in D-negative individuals. Among
Europeans, the population frequency of all known partial D phenotypes
combined is less than 1%. The molecular basis is generally a gene
conversion, in which parts of the RHD gene were substituted by the
respective segments of the RHCE gene, and single missense mutations. The
situation is more intricate in Africans, however, because the occurrence
of aberrant RHD alleles and anti-D immunizations in D-positive
individuals is much more frequent than in Europeans (du Toit et al.,
1989). Wagner et al. (2002) described 5 RHD alleles, designated DAU-0 to
DAU-4, that share a thr379-to-met (T379M) substitution. Four of the
alleles expressed a partial D phenotype characterized by the lack of
distinct D epitopes or by an anti-D immunization event. Wagner et al.
(2002) provided a detailed RHD phylogeny in which the variant alleles
formed a previously unknown cluster.
*FIELD* AV
.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
RHD, 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.
*FIELD* RF
1. Arce, M. A.; 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.
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. J. Med. 329: 607-610, 1993.
3. Bowman, J. M.: RhD hemolytic disease of the newborn. (Editorial) New
Eng. J. Med. 339: 1775-1777, 1998.
4. Cartron, J.-P.: Defining the Rh blood group antigens: biochemistry
and molecular genetics. Blood Rev. 8: 199-212, 1994.
5. 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.
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.
7. du Toit, E. D.; Martell, R. W.; Botha, I.; Kriel, C. J.: Anti-D
antibodies in the Rh-positive mothers. (Letter) S. Afr. Med. J. 75:
452 only, 1989.
8. Garratty, G.: Severe reactions associated with transfusion of
patients with sickle cell disease. Transfusion 37: 357-361, 1997.
9. Huang, C.-H.: Personal Communication. New York City, N. Y.
10/11/1996.
10. 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.
11. Huang, C.-H.; Reid, M. E.; Chen, Y.; Coghlan, G.; Okubo, Y.:
Molecular definition of red cell Rh haplotypes by tightly linked SphI
RFLPs. Am. J. Hum. Genet. 58: 133-142, 1996.
12. Hyland, C. A.; Wolter, L. C.; Liew, Y. W.; Saul, A.: A Southern
analysis of Rh blood group genes: association between restriction
fragment length polymorphism patterns and Rh serotypes. Blood 83:
566-572, 1994.
13. Innan, H.: A two-locus gene conversion model with selection and
its application to the human RHCE and RHD genes. Proc. Nat. Acad.
Sci. 100: 8793-8798, 2003.
14. Issitt, P. D.: The Rh blood group system, 1988: eight new antigens
in nine years and some observations on the biochemistry and genetics
of the system. Transfusion Med. Rev. 3: 1-12, 1989.
15. 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.
16. Legler, T. J.; Eber, S. W.; Lakomek, M.; Lynen, R.; Maas, J. H.;
Pekrun, A.; Repas-Humpe, M.; Schroter, W.; Kohler, M.: Application
of RHD and RHCE genotyping for correct blood group determination in
chronically transfused patients. Transfusion 39: 852-855, 1999.
17. Le Van Kim, C.; 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.
18. Le Van Kim, C.; 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.
19. Levine, P.; Katzin, E. M.; Burnham, L.: Isoimmunization in pregnancy:
its possible bearing on the etiology of erythroblastosis foetalis. JAMA 116:
825-827, 1941.
20. 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.
21. Miyoshi, O.; Yabe, R.; Wakui, K.; Fukushima, Y.; Koizumi, S.;
Uchikawa, M.; Kajii, T.; Numakura, C.; Takahashi, S.; Hayasaka, K.;
Niikawa, N.: Two cases of mosaic RhD blood-group phenotypes and paternal
isodisomy for chromosome 1. Am. J. Med. Genet. 104: 250-256, 2001.
22. Okuda, H.; Kawano, M.; Iwamoto, S.; Tanaka, M.; Seno, T.; Okubo,
Y.; Kajii, E.: The RHD gene is highly detectable in RhD-negative
Japanese donors. J. Clin. Invest. 100: 373-379, 1997.
23. Race, R. R.: An 'incomplete' antibody in human serum. (Letter) Nature 153:
771-772, 1944.
24. Race, R. R.; Sanger, R.: Blood Groups in Man. Oxford: Blackwell
(pub.) (6th ed.): 1975.
25. 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.
26. 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.
27. Spanos, T.; Karageorga, M.; Ladis, V.; Peristeri, J.; Hatziliami,
A.; Kattamis, C.: Red cell alloantibodies in patients with thalassemia. Vox
Sang. 58: 50-55, 1990.
28. Wagner, F. F.; Flegel, W. A.: RHD gene deletion occurred in the
Rhesus box. Blood 95: 3662-3668, 2000.
29. Wagner, F. F.; Gassner, C.; Muller, T. H.; Schonitzer, D.; Schunter,
F.; Flegel, W. A.: Molecular basis of weak D phenotypes. Blood 93:
385-393, 1999.
30. Wagner, F. F.; Ladewig, B.; Angert, K. S.; Heymann, G. A.; Eicher,
N. I.; Flegel, W. A.: The DAU allele cluster of the RHD gene. Blood 100:
306-311, 2002.
31. Wiener, A. S.: The Rh series of allelic genes. Science 100:
595-597, 1944.
*FIELD* CN
Victor A. McKusick - updated: 8/27/2003
Victor A. McKusick - updated: 9/19/2002
Victor A. McKusick - updated: 12/4/2001
Victor A. McKusick - updated: 10/18/2000
Wilson H. Y. Lo - updated: 12/2/1999
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
*FIELD* CD
Victor A. McKusick: 12/6/1988
*FIELD* ED
terry: 05/29/2012
terry: 9/8/2010
terry: 6/3/2009
carol: 2/3/2004
terry: 8/27/2003
tkritzer: 11/19/2002
tkritzer: 9/25/2002
tkritzer: 9/20/2002
carol: 9/19/2002
carol: 7/9/2002
carol: 1/2/2002
mcapotos: 12/10/2001
terry: 12/4/2001
carol: 10/18/2000
terry: 2/28/2000
carol: 12/13/1999
carol: 12/6/1999
terry: 12/2/1999
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
*RECORD*
*FIELD* NO
111680
*FIELD* TI
*111680 RHESUS BLOOD GROUP, D ANTIGEN; RHD
;;BLOOD GROUP--RHESUS SYSTEM D POLYPEPTIDE
read more*FIELD* TX
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 (111700) genes 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.
To understand the mechanism underlying the acquisition of a new function
by duplicated genes, Innan (2003) studied the evolutionary process
within a relatively short time after gene duplication. Innan (2003)
theorized that the pattern of allelic variation in duplicated genes is
determined mainly by the balance between gene conversion, which operates
against diversification of the duplicated gene, and selection, which
favors diversification. Innan (2003) applied this theory to the human
RHCE and RHD genes. The very high level of amino acid divergence between
the 2 genes was observed only in a short region around exon 7. This exon
encodes amino acids that characterize the difference between the RHCE
and RHD antigens. The observed pattern of DNA variation in this region
was considered consistent with the selection model, suggesting that
strong selection might be working to maintain the RHCE/RHD antigen
variation in the 2-locus system.
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 transfusion policy for such molecular weak D types that
were prone to develop anti-D.
In chronically transfused patients, conventional blood group typing may
be impossible because of mixed-field agglutination (Spanos et al., 1990;
Garratty, 1997). Legler et al. (1999) performed PCR genotyping for D,
RHD and RHCE on 27 patients with congenital anemia and lifelong
transfusion history and compared the results with serologic blood group
typing results in their medical records. They found that serologic
methods frequently led to false blood group results in mixed blood
samples. Moreover, blood group determinations were frequently incomplete
or doubtful. In such a situation, pretransfusion genotyping for D, RHD,
and RHCE makes Rh-matched transfusions possible, at least in whites. The
genetic background of the RH genes has to be elucidated in other ethnic
groups before genotyping can be applied without restriction.
Wagner and Flegel (2000) determined that the open reading frames of the
RHD and RHCE genes have opposite orientations. The 3-prime ends of the
genes face each other and are separated by about 30,000 bp that contain
the SMP1 gene (605348). The RHD gene is flanked by 2 DNA segments,
dubbed Rhesus boxes by Wagner and Flegel (2000), with a length of
approximately 9,000 bp, 98.6% homology, and identical orientation. The
breakpoints of the RHD deletion in the prevalent RHD-negative haplotypes
are located in the 1,463-bp identity region of the Rhesus boxes. Wagner
and Flegel (2000) established technical procedures for specifically
detecting the RHD gene deletion in the common RHD-negative haplotypes.
The molecular structure of the RH gene explains the mechanisms for both
the RHD deletion and the generation of RHD/RHCE hybrid alleles.
Miyoshi et al. (2001) described 2 individuals who were mosaic for the Rh
blood group phenotype, one erythrocyte population being D-positive and
the other D-negative. In both individuals, biparental disomic patterns
of markers spanning chromosome 1 were present in peripheral blood
leukocytes, whereas only paternal alleles were detected in hair or hair
roots in 1 patient and in one-fourth of hair roots in the second
patient. Miyoshi et al. (2001) emphasized that isodisomy for chromosome
1 is not infrequent and may cause an unusual RhD phenotype.
D-positive individuals harboring a 'partial' D antigen may produce an
allo-anti-D similar to that generated in D-negative individuals. Among
Europeans, the population frequency of all known partial D phenotypes
combined is less than 1%. The molecular basis is generally a gene
conversion, in which parts of the RHD gene were substituted by the
respective segments of the RHCE gene, and single missense mutations. The
situation is more intricate in Africans, however, because the occurrence
of aberrant RHD alleles and anti-D immunizations in D-positive
individuals is much more frequent than in Europeans (du Toit et al.,
1989). Wagner et al. (2002) described 5 RHD alleles, designated DAU-0 to
DAU-4, that share a thr379-to-met (T379M) substitution. Four of the
alleles expressed a partial D phenotype characterized by the lack of
distinct D epitopes or by an anti-D immunization event. Wagner et al.
(2002) provided a detailed RHD phylogeny in which the variant alleles
formed a previously unknown cluster.
*FIELD* AV
.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
RHD, 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.
*FIELD* RF
1. Arce, M. A.; 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.
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. J. Med. 329: 607-610, 1993.
3. Bowman, J. M.: RhD hemolytic disease of the newborn. (Editorial) New
Eng. J. Med. 339: 1775-1777, 1998.
4. Cartron, J.-P.: Defining the Rh blood group antigens: biochemistry
and molecular genetics. Blood Rev. 8: 199-212, 1994.
5. 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.
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,
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7. du Toit, E. D.; Martell, R. W.; Botha, I.; Kriel, C. J.: Anti-D
antibodies in the Rh-positive mothers. (Letter) S. Afr. Med. J. 75:
452 only, 1989.
8. Garratty, G.: Severe reactions associated with transfusion of
patients with sickle cell disease. Transfusion 37: 357-361, 1997.
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10/11/1996.
10. 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.
11. Huang, C.-H.; Reid, M. E.; Chen, Y.; Coghlan, G.; Okubo, Y.:
Molecular definition of red cell Rh haplotypes by tightly linked SphI
RFLPs. Am. J. Hum. Genet. 58: 133-142, 1996.
12. Hyland, C. A.; Wolter, L. C.; Liew, Y. W.; Saul, A.: A Southern
analysis of Rh blood group genes: association between restriction
fragment length polymorphism patterns and Rh serotypes. Blood 83:
566-572, 1994.
13. Innan, H.: A two-locus gene conversion model with selection and
its application to the human RHCE and RHD genes. Proc. Nat. Acad.
Sci. 100: 8793-8798, 2003.
14. Issitt, P. D.: The Rh blood group system, 1988: eight new antigens
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of the system. Transfusion Med. Rev. 3: 1-12, 1989.
15. Kemp, T. J.; Poulter, M.; Carritt, B.: A recombination hot spot
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rare D-- phenotype. Am. J. Hum. Genet. 59: 1066-1073, 1996. Note:
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16. Legler, T. J.; Eber, S. W.; Lakomek, M.; Lynen, R.; Maas, J. H.;
Pekrun, A.; Repas-Humpe, M.; Schroter, W.; Kohler, M.: Application
of RHD and RHCE genotyping for correct blood group determination in
chronically transfused patients. Transfusion 39: 852-855, 1999.
17. Le Van Kim, C.; 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.
18. Le Van Kim, C.; 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.
19. Levine, P.; Katzin, E. M.; Burnham, L.: Isoimmunization in pregnancy:
its possible bearing on the etiology of erythroblastosis foetalis. JAMA 116:
825-827, 1941.
20. 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
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21. Miyoshi, O.; Yabe, R.; Wakui, K.; Fukushima, Y.; Koizumi, S.;
Uchikawa, M.; Kajii, T.; Numakura, C.; Takahashi, S.; Hayasaka, K.;
Niikawa, N.: Two cases of mosaic RhD blood-group phenotypes and paternal
isodisomy for chromosome 1. Am. J. Med. Genet. 104: 250-256, 2001.
22. Okuda, H.; Kawano, M.; Iwamoto, S.; Tanaka, M.; Seno, T.; Okubo,
Y.; Kajii, E.: The RHD gene is highly detectable in RhD-negative
Japanese donors. J. Clin. Invest. 100: 373-379, 1997.
23. Race, R. R.: An 'incomplete' antibody in human serum. (Letter) Nature 153:
771-772, 1944.
24. Race, R. R.; Sanger, R.: Blood Groups in Man. Oxford: Blackwell
(pub.) (6th ed.): 1975.
25. 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.
26. 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.
27. Spanos, T.; Karageorga, M.; Ladis, V.; Peristeri, J.; Hatziliami,
A.; Kattamis, C.: Red cell alloantibodies in patients with thalassemia. Vox
Sang. 58: 50-55, 1990.
28. Wagner, F. F.; Flegel, W. A.: RHD gene deletion occurred in the
Rhesus box. Blood 95: 3662-3668, 2000.
29. Wagner, F. F.; Gassner, C.; Muller, T. H.; Schonitzer, D.; Schunter,
F.; Flegel, W. A.: Molecular basis of weak D phenotypes. Blood 93:
385-393, 1999.
30. Wagner, F. F.; Ladewig, B.; Angert, K. S.; Heymann, G. A.; Eicher,
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595-597, 1944.
*FIELD* CN
Victor A. McKusick - updated: 8/27/2003
Victor A. McKusick - updated: 9/19/2002
Victor A. McKusick - updated: 12/4/2001
Victor A. McKusick - updated: 10/18/2000
Wilson H. Y. Lo - updated: 12/2/1999
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
*FIELD* CD
Victor A. McKusick: 12/6/1988
*FIELD* ED
terry: 05/29/2012
terry: 9/8/2010
terry: 6/3/2009
carol: 2/3/2004
terry: 8/27/2003
tkritzer: 11/19/2002
tkritzer: 9/25/2002
tkritzer: 9/20/2002
carol: 9/19/2002
carol: 7/9/2002
carol: 1/2/2002
mcapotos: 12/10/2001
terry: 12/4/2001
carol: 10/18/2000
terry: 2/28/2000
carol: 12/13/1999
carol: 12/6/1999
terry: 12/2/1999
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