RBCC Red Blood Cell Collection

RHCE (RHC, RHE) [Confidence: high (a blood group or CD marker)]
Blood group Rh(CE) polypeptide (Rh polypeptide 1; RhPI; Rh30A; RhIXB; Rhesus C/E antigens; CD240CE)

hRBCD IPI00329565
IPI00329565 RhD protein RhD protein membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 7 2 n/a n/a n/a n/a n/a n/a 3 7 integral membrane protein n/a found at its expected molecular weight found at molecular weight

BGMUT rh
1286 rh RHCE hybrid CE(1)DIVa.2(2,3)CE(4)D(5)CE(6-10) RHCE hybrid CE(1)DIVa.2(2,3)CE(4)D(5)CE(6-10) hybrid CE(1)DIVa.2(2,3)CE(4)D(5)CE(6-10) hybrid CE(1)DIVa.2(2,3)CE(4)D(5)CE(6-10) exons 1 to 8 in gDNA and 1 to 10 in cDNA, in RHD and RHCE DcE or Dce (different donors), Goa,Rh33,Riv,FPTT rare;found in three donors of African descent 21729099 JF436968 Hipsky and al. Vox Sang 2012 102 167-170 Blumenfeld OO 2012-02-16 21:35:31.657 NA

UniProt P18577
ID RHCE_HUMAN Reviewed; 417 AA.
AC P18577; A7DW68; B7UDF3; B7UDF4; B7UDF5; B7UDF6; B7UDF7; B7UDF8;
read moreAC B7UDF9; B7UDG0; B7UDG1; B7UDG2; B7UDG3; Q02163; Q02164; Q02165;
AC Q16160; Q2MJW0; Q2VC86; Q3LTM6; Q6AZX5; Q6J2U3; Q7RU06; Q8IZT2;
AC Q8IZT3; Q8IZT4; Q8IZT5; Q9UD13; Q9UD14; Q9UD15; Q9UD16; Q9UD73;
AC Q9UD74; Q9UEC2; Q9UEC3; Q9UPN0;
DT 01-NOV-1990, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 127.
DE RecName: Full=Blood group Rh(CE) polypeptide;
DE AltName: Full=Rh polypeptide 1;
DE Short=RhPI;
DE AltName: Full=Rh30A;
DE AltName: Full=RhIXB;
DE AltName: Full=Rhesus C/E antigens;
DE AltName: CD_antigen=CD240CE;
GN Name=RHCE; Synonyms=RHC, RHE;
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 RHI).
RC TISSUE=Bone marrow;
RX PubMed=2123099;
RA Avent N.D., Ridgwell K., Tanner M.J.A., Anstee D.J.;
RT "cDNA cloning of a 30 kDa erythrocyte membrane protein associated with
RT Rh (Rhesus)-blood-group-antigen expression.";
RL Biochem. J. 271:821-825(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM RHI), AND PARTIAL PROTEIN
RP SEQUENCE.
RC TISSUE=Bone marrow;
RX PubMed=1696722; DOI=10.1073/pnas.87.16.6243;
RA Cherif-Zahar B., Bloy C., le van Kim C., Blanchard D., Bailly P.,
RA Hermand P., Salmon C., Cartron J.-P., Colin Y.;
RT "Molecular cloning and protein structure of a human blood group Rh
RT polypeptide.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:6243-6247(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS RHIV; RHVI AND RHVIII).
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 [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM RHI).
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 RHI), VARIANT CYS-16, AND VARIANT
RP E/RH5 ANTIGEN ALA-226.
RX PubMed=11380456; DOI=10.1046/j.1365-2141.2001.02803.x;
RA Westhoff C.M., Silberstein L.E., Wylie D.E., Skavdahl M., Reid M.E.;
RT "16Cys encoded by the RHce gene is associated with altered expression
RT of the e antigen and is frequent in the R0 haplotype.";
RL Br. J. Haematol. 113:666-671(2001).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM RHI), AND VARIANTS ILE-60; SER-68;
RP SER-103; VAL-127; ASP-128; RHEKH THR-154; RHEFM GLU-233 AND RHEFM
RP VAL-238.
RX PubMed=11724987; DOI=10.1046/j.1537-2995.2001.41111408.x;
RA Kashiwase K., Ishikawa Y., Hyodo H., Watanabe Y., Ogawa A.,
RA Tsuneyama H., Toyoda C., Uchikawa M., Akaza T., Omine M., Juji T.;
RT "E variants found in Japanese and c antigenicity alteration without
RT substitution in the second extracellular loop.";
RL Transfusion 41:1408-1412(2001).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM RHI), AND VARIANTS CYS-16;
RP ALA-226; VAL-238; VAL-245; GLY-263 AND LYS-267.
RX PubMed=12393640; DOI=10.1182/blood-2002-01-0229;
RA Noizat-Pirenne F., Lee K., Le Pennec P.-Y., Simon P., Kazup P.,
RA Bachir D., Rouzaud A.M., Roussel M., Juszczak G., Menanteau C.,
RA Rouger P., Kotb R., Cartron J.-P., Ansart-Pirenne H.;
RT "Rare RHCE phenotypes in black individuals of Afro-Caribbean origin:
RT identification and transfusion safety.";
RL Blood 100:4223-4231(2002).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM RHI), AND VARIANTS CYS-16; ILE-60;
RP SER-68; SER-103 AND ALA-226.
RA Yan L., Xu X., Zhu F.;
RT "A new RhCe allele in Chinese Han population.";
RL Submitted (APR-2004) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM RHI), AND VARIANTS CYS-16;
RP ALA-226; GLU-233 AND VAL-245.
RA Westhoff C.M., Vege S.;
RT "Molecular basis for Crawford antigen expression.";
RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM RHI), AND VARIANTS CYS-16; ILE-60;
RP SER-68 AND SER-103.
RA Vege S., Westhoff C.M.;
RT "RHCE gene, allele CE, antigen CE.";
RL Submitted (OCT-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM RHI), AND VARIANT ALA-226.
RA Westhoff C.M., Vege S.;
RT "RHCE gene, allele RHce, ce antigen.";
RL Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS CYS-16; ILE-60;
RP SER-68; SER-103; ALA-226 AND GLU-398.
RA Wei Q., Flegel W.A.;
RT "RHD allele and RH haplotype distribution in Tibetans.";
RL Submitted (AUG-2006) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS CYS-16; ILE-60;
RP SER-68; SER-103; ALA-226 AND LYS-267.
RA Bugert P., Scharberg E.A., Geisen C., von Zabern I., Flegel W.A.;
RL Submitted (NOV-2008) to the EMBL/GenBank/DDBJ databases.
RN [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANTS CYS-16 AND
RP ALA-226.
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 [15]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM RHI), AND VARIANTS
RP CYS-16; ILE-60; SER-68; SER-103 AND ALA-226.
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [16]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-11.
RX PubMed=8188244; DOI=10.1006/geno.1994.1014;
RA Cherif-Zahar B., le van Kim C., Rouillac C., Raynal V., Cartron J.-P.,
RA Colin Y.;
RT "Organization of the gene (RHCE) encoding the human blood group RhCcEe
RT antigens and characterization of the promoter region.";
RL Genomics 19:68-74(1994).
RN [17]
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 [18]
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 [19]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 141-417 (ISOFORMS 1C; 1D; 1H; 2E; 4G;
RP 7A; 8A; 8E; 8H; RHIV AND RHVI), AND ALTERNATIVE SPLICING.
RC TISSUE=Blood;
RX PubMed=7789951; DOI=10.1007/BF00209483;
RA Kajii E., Umenishi F., Omi T., Ikemoto S.;
RT "Intricate combinatorial patterns of exon splicing generate multiple
RT Rh-related isoforms in human erythroid cells.";
RL Hum. Genet. 95:657-665(1995).
RN [20]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 201-417 (ISOFORMS 4G AND RHPI-ALPHA),
RP AND TISSUE SPECIFICITY.
RC TISSUE=Erythroblast;
RX PubMed=8117271; DOI=10.1006/bbrc.1994.1161;
RA Umenishi F., Kajii E., Ikemoto S.;
RT "Identification of two Rh mRNA isoforms expressed in immature
RT erythroblasts.";
RL Biochem. Biophys. Res. Commun. 198:1135-1142(1994).
RN [21]
RP PROTEIN SEQUENCE OF 402-409.
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 [22]
RP IDENTIFICATION, AND VARIANTS CYS-16 AND ALA-226.
RX PubMed=11902138; DOI=10.1182/blood-2001-12-0153;
RA Wagner F.F., Flegel W.A.;
RT "RHCE represents the ancestral RH position, while RHD is the
RT duplicated gene.";
RL Blood 99:2272-2273(2002).
RN [23]
RP VARIANTS BLOOD GROUP C AND E.
RX PubMed=8220426; DOI=10.1038/ng0993-62;
RA Mouro I., Colin Y., Cherif-Zahar B., Cartron J.-P., le van Kim C.;
RT "Molecular genetic basis of the human Rhesus blood group system.";
RL Nat. Genet. 5:62-65(1993).
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=14;
CC Name=RHI;
CC IsoId=P18577-1; Sequence=Displayed;
CC Name=RHIV; Synonyms=1e;
CC IsoId=P18577-2; Sequence=VSP_005703, VSP_005704;
CC Name=RHVI; Synonyms=7c;
CC IsoId=P18577-3; Sequence=VSP_005702, VSP_005705;
CC Name=RHVIII;
CC IsoId=P18577-4; Sequence=VSP_005701;
CC Name=1c;
CC IsoId=P18577-5; Sequence=VSP_005705;
CC Name=1d;
CC IsoId=P18577-6; Sequence=VSP_037514;
CC Name=1h;
CC IsoId=P18577-7; Sequence=VSP_037513;
CC Name=2e;
CC IsoId=P18577-8; Sequence=VSP_037510, VSP_037512;
CC Name=4g; Synonyms=RhPI-Beta;
CC IsoId=P18577-9; Sequence=VSP_037509;
CC Name=7a;
CC IsoId=P18577-10; Sequence=VSP_005702;
CC Name=8a;
CC IsoId=P18577-11; Sequence=VSP_037506, VSP_037511;
CC Name=8e;
CC IsoId=P18577-12; Sequence=VSP_037507, VSP_037508;
CC Name=8h;
CC IsoId=P18577-13; Sequence=VSP_037505;
CC Name=RhPI-Alpha;
CC IsoId=P18577-14; Sequence=VSP_038405, VSP_038406;
CC -!- TISSUE SPECIFICITY: Restricted to tissues or cell lines expressing
CC erythroid characters. Isoform 4g and isoform RhPI-Alpha are
CC expressed in immature erythroblasts but not in mature
CC erythroblasts.
CC -!- POLYMORPHISM: RhCE and RhD are responsible for the RH blood group
CC system. The molecular basis of the E=Rh3/e=Rh5 blood group
CC antigens is a single variation in position 226; Pro-226
CC corresponds to Rh3 and Ala-226 to Rh5. The molecular basis of the
CC C=Rh2/c=Rh4 blood group antigens is a single variation in position
CC 102; Ser-103 corresponds to Rh2 and Pro-103 to Rh4.
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/RHCE";
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DR EMBL; X54534; CAA38401.1; -; mRNA.
DR EMBL; M34015; AAA36567.1; -; mRNA.
DR EMBL; X63095; CAA44809.1; -; mRNA.
DR EMBL; X63096; CAA44810.1; -; mRNA.
DR EMBL; X63098; CAA44812.1; -; mRNA.
DR EMBL; S57967; AAB26080.1; -; mRNA.
DR EMBL; DQ266400; ABB69097.1; -; mRNA.
DR EMBL; AB018644; BAA33927.1; -; mRNA.
DR EMBL; AB018645; BAA33928.1; -; mRNA.
DR EMBL; AB030388; BAA82627.1; -; mRNA.
DR EMBL; AB049753; BAB16597.1; -; mRNA.
DR EMBL; AF510065; AAN75121.1; -; mRNA.
DR EMBL; AF510066; AAN75122.1; -; mRNA.
DR EMBL; AF510067; AAN75123.1; -; mRNA.
DR EMBL; AF510068; AAN75124.1; -; mRNA.
DR EMBL; AY603478; AAT35811.1; -; mRNA.
DR EMBL; DQ178642; ABA25912.1; -; mRNA.
DR EMBL; DQ266353; ABB97471.1; -; mRNA.
DR EMBL; DQ322275; ABC55358.1; -; mRNA.
DR EMBL; AM398146; CAL44958.1; -; Genomic_DNA.
DR EMBL; FJ486155; ACK75562.1; -; Genomic_DNA.
DR EMBL; FJ486156; ACK75563.1; -; Genomic_DNA.
DR EMBL; FJ486157; ACK75564.1; -; Genomic_DNA.
DR EMBL; FJ486158; ACK75565.1; -; Genomic_DNA.
DR EMBL; FJ486159; ACK75566.1; -; Genomic_DNA.
DR EMBL; FJ486160; ACK75567.1; -; Genomic_DNA.
DR EMBL; FJ486161; ACK75568.1; -; Genomic_DNA.
DR EMBL; FJ486162; ACK75569.1; -; Genomic_DNA.
DR EMBL; FJ486163; ACK75570.1; -; Genomic_DNA.
DR EMBL; FJ486164; ACK75571.1; -; Genomic_DNA.
DR EMBL; FJ486165; ACK75572.1; -; Genomic_DNA.
DR EMBL; AL031284; CAM12858.1; -; Genomic_DNA.
DR EMBL; AL928711; CAM12858.1; JOINED; Genomic_DNA.
DR EMBL; AL928711; CAH72605.1; -; Genomic_DNA.
DR EMBL; AL031284; CAH72605.1; JOINED; Genomic_DNA.
DR EMBL; BC075081; AAH75081.1; -; mRNA.
DR EMBL; BC139905; AAI39906.1; -; mRNA.
DR EMBL; S70456; AAD14061.1; -; Genomic_DNA.
DR EMBL; BN000065; CAD29850.1; -; Genomic_DNA.
DR PIR; A30405; A30405.
DR PIR; I54193; I54193.
DR PIR; PC2032; PC2032.
DR PIR; PC2033; PC2033.
DR PIR; S78478; S78478.
DR PIR; S78479; S78479.
DR PIR; S78480; S78480.
DR RefSeq; NP_065231.3; NM_020485.4.
DR RefSeq; NP_619522.3; NM_138616.3.
DR RefSeq; NP_619523.3; NM_138617.3.
DR RefSeq; NP_619524.3; NM_138618.3.
DR UniGene; Hs.449968; -.
DR UniGene; Hs.523054; -.
DR ProteinModelPortal; P18577; -.
DR SMR; P18577; 3-414.
DR TCDB; 1.A.11.4.3; the ammonia transporter channel (amt) family.
DR PhosphoSite; P18577; -.
DR DMDM; 132558; -.
DR PaxDb; P18577; -.
DR PRIDE; P18577; -.
DR Ensembl; ENST00000294413; ENSP00000294413; ENSG00000188672.
DR GeneID; 6006; -.
DR KEGG; hsa:6006; -.
DR UCSC; uc001bkf.3; human.
DR CTD; 6006; -.
DR GeneCards; GC01M025688; -.
DR H-InvDB; HIX0023511; -.
DR HGNC; HGNC:10008; RHCE.
DR MIM; 111690; phenotype.
DR MIM; 111700; gene+phenotype.
DR neXtProt; NX_P18577; -.
DR Orphanet; 71275; Rh deficiency syndrome.
DR PharmGKB; PA34386; -.
DR eggNOG; NOG314742; -.
DR HOVERGEN; HBG004374; -.
DR InParanoid; P18577; -.
DR KO; K06579; -.
DR OrthoDB; EOG73NG3C; -.
DR GeneWiki; RHCE_(gene); -.
DR GenomeRNAi; 6006; -.
DR NextBio; 23427; -.
DR PRO; PR:P18577; -.
DR ArrayExpress; P18577; -.
DR Bgee; P18577; -.
DR CleanEx; HS_RHCE; -.
DR Genevestigator; P18577; -.
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(CE) polypeptide.
FT /FTId=PRO_0000168189.
FT TRANSMEM 12 32 Helical; (Potential).
FT TRANSMEM 44 64 Helical; (Potential).
FT TRANSMEM 77 97 Helical; (Potential).
FT TRANSMEM 125 145 Helical; (Potential).
FT TRANSMEM 172 192 Helical; (Potential).
FT TRANSMEM 203 223 Helical; (Potential).
FT TRANSMEM 238 258 Helical; (Potential).
FT TRANSMEM 265 285 Helical; (Potential).
FT TRANSMEM 287 307 Helical; (Potential).
FT TRANSMEM 331 351 Helical; (Potential).
FT TRANSMEM 358 378 Helical; (Potential).
FT VAR_SEQ 163 409 Missing (in isoform 8h).
FT /FTId=VSP_037505.
FT VAR_SEQ 163 313 Missing (in isoform RHVIII).
FT /FTId=VSP_005701.
FT VAR_SEQ 163 220 Missing (in isoform 8a).
FT /FTId=VSP_037506.
FT VAR_SEQ 163 203 TDYHMNLRHFYVFAAYFGLTVAWCLPKPLPKGTEDNDQRAT
FT -> DWLPGPPQHWGTQLGHRDSSHVWSPDRFAPKSQNMEST
FT SCG (in isoform 8e).
FT /FTId=VSP_037507.
FT VAR_SEQ 164 268 Missing (in isoform RHVI and isoform 7a).
FT /FTId=VSP_005702.
FT VAR_SEQ 204 417 Missing (in isoform 8e).
FT /FTId=VSP_037508.
FT VAR_SEQ 212 384 Missing (in isoform 4g).
FT /FTId=VSP_037509.
FT VAR_SEQ 227 242 LLRSPIQRKNAMFNTY -> DRFAPKSQNMESTSCG (in
FT isoform RhPI-Alpha).
FT /FTId=VSP_038405.
FT VAR_SEQ 243 417 Missing (in isoform RhPI-Alpha).
FT /FTId=VSP_038406.
FT VAR_SEQ 268 308 TYVHSAVLAGGVAVGTSCHLIPSPWLAMVLGLVAGLISIGG
FT -> DWLPGPPQHWGTQLGHRDSSHVWSPDRFAPKSQNMEST
FT SCG (in isoform 2e).
FT /FTId=VSP_037510.
FT VAR_SEQ 301 313 Missing (in isoform 8a).
FT /FTId=VSP_037511.
FT VAR_SEQ 309 417 Missing (in isoform 2e).
FT /FTId=VSP_037512.
FT VAR_SEQ 314 409 Missing (in isoform 1h).
FT /FTId=VSP_037513.
FT VAR_SEQ 314 354 VCCNRVLGIHHISVMHSIFSLLGLLGEITYIVLLVLHTVWN
FT -> DWLPGPPQHWGTQLGHRDSSHVWSPDRFAPKSQNMEST
FT SCG (in isoform RHIV).
FT /FTId=VSP_005703.
FT VAR_SEQ 355 417 Missing (in isoform RHIV).
FT /FTId=VSP_005704.
FT VAR_SEQ 358 417 MIGFQVLLSIGELSLAIVIALTSGLLTGLLLNLKIWKAPHV
FT AKYFDDQVFWKFPHLAVGF -> IFLIWLLDFKQKHPRKTR
FT PVQKQDNFLSLLPAVREKRS (in isoform 1d).
FT /FTId=VSP_037514.
FT VAR_SEQ 359 417 IGFQVLLSIGELSLAIVIALTSGLLTGLLLNLKIWKAPHVA
FT KYFDDQVFWKFPHLAVGF -> FAPKSQNMESTSCG (in
FT isoform RHVI and isoform 1c).
FT /FTId=VSP_005705.
FT VARIANT 16 16 W -> C (associated with altered
FT expression of E antigen).
FT /FTId=VAR_006911.
FT VARIANT 36 36 A -> T (in C(X)/Rh9 antigen).
FT /FTId=VAR_006912.
FT VARIANT 41 41 Q -> R (in C(W)/Rh8 antigen;
FT dbSNP:rs138268848).
FT /FTId=VAR_006913.
FT VARIANT 60 60 L -> I (in dbSNP:rs181860403).
FT /FTId=VAR_006914.
FT VARIANT 68 68 N -> S (in dbSNP:rs1053344).
FT /FTId=VAR_006915.
FT VARIANT 103 103 P -> S (in C/Rh2 antigen;
FT dbSNP:rs676785).
FT /FTId=VAR_006916.
FT VARIANT 127 127 A -> V (in dbSNP:rs1053346).
FT /FTId=VAR_055260.
FT VARIANT 128 128 G -> D (in dbSNP:rs1053347).
FT /FTId=VAR_055261.
FT VARIANT 154 154 R -> T (in RhEKH).
FT /FTId=VAR_013301.
FT VARIANT 182 182 T -> S (in dbSNP:rs1053350).
FT /FTId=VAR_055262.
FT VARIANT 198 198 N -> K (in dbSNP:rs1053354).
FT /FTId=VAR_055263.
FT VARIANT 226 226 P -> A (in E/Rh5 antigen;
FT dbSNP:rs609320).
FT /FTId=VAR_006917.
FT VARIANT 233 233 Q -> E (in RhEFM).
FT /FTId=VAR_013302.
FT VARIANT 238 238 M -> V (in RhEFM; dbSNP:rs144163296).
FT /FTId=VAR_013303.
FT VARIANT 245 245 L -> V (in VS antigen; dbSNP:rs1053361).
FT /FTId=VAR_006918.
FT VARIANT 263 263 R -> G (in dbSNP:rs1132763).
FT /FTId=VAR_057987.
FT VARIANT 267 267 M -> K (in dbSNP:rs1132764).
FT /FTId=VAR_057988.
FT VARIANT 323 323 H -> P (in dbSNP:rs1053366).
FT /FTId=VAR_055264.
FT VARIANT 325 325 I -> S (in dbSNP:rs1053367).
FT /FTId=VAR_055265.
FT VARIANT 329 329 H -> D (in dbSNP:rs1053370).
FT /FTId=VAR_055266.
FT VARIANT 329 329 H -> R (in dbSNP:rs1053371).
FT /FTId=VAR_055267.
FT VARIANT 330 330 S -> Y (in dbSNP:rs1053372).
FT /FTId=VAR_055268.
FT VARIANT 331 331 I -> N (in dbSNP:rs1053373).
FT /FTId=VAR_055269.
FT VARIANT 398 398 V -> E (in dbSNP:rs630612).
FT /FTId=VAR_057989.
FT CONFLICT 10 10 R -> W (in Ref. 13; ACK75562).
FT CONFLICT 12 12 C -> L (in Ref. 18; AA sequence).
FT CONFLICT 53 53 D -> G (in Ref. 3; CAA44812).
FT CONFLICT 61 61 G -> C (in Ref. 3; CAA44812).
FT CONFLICT 114 114 R -> W (in Ref. 7; AAN75123).
FT CONFLICT 115 115 L -> P (in Ref. 13; ACK75563/ACK75565).
FT CONFLICT 121 121 M -> L (in Ref. 6; BAB16597/BAA82627).
FT CONFLICT 122 122 S -> P (in Ref. 13; ACK75564).
FT CONFLICT 125 125 I -> N (in Ref. 13; ACK75565).
FT CONFLICT 152 152 T -> N (in Ref. 6; BAB16597/BAA82627).
FT CONFLICT 155 155 M -> V (in Ref. 8; AAT35811).
FT CONFLICT 166 166 H -> L (in Ref. 13; ACK75566).
FT CONFLICT 169 169 L -> Q (in Ref. 13; ACK75567).
FT CONFLICT 201 201 R -> T (in Ref. 13; ACK75568).
FT CONFLICT 217 217 W -> R (in Ref. 13; ACK75569).
FT CONFLICT 241 241 T -> I (in Ref. 13; ACK75570).
FT CONFLICT 250 250 V -> M (in Ref. 7; AAN75124).
FT CONFLICT 273 273 A -> V (in Ref. 7; AAN75122).
FT CONFLICT 303 303 L -> Q (in Ref. 13; ACK75572).
FT CONFLICT 378 378 L -> V (in Ref. 7; AAN75122).
FT CONFLICT 408 409 WK -> DI (in Ref. 21; AA sequence).
SQ SEQUENCE 417 AA; 45560 MW; 29D33E778D9053DF CRC64;
MSSKYPRSVR RCLPLWALTL EAALILLFYF FTHYDASLED QKGLVASYQV GQDLTVMAAL
GLGFLTSNFR RHSWSSVAFN LFMLALGVQW AILLDGFLSQ FPPGKVVITL FSIRLATMSA
MSVLISAGAV LGKVNLAQLV VMVLVEVTAL GTLRMVISNI FNTDYHMNLR HFYVFAAYFG
LTVAWCLPKP LPKGTEDNDQ RATIPSLSAM LGALFLWMFW PSVNSPLLRS PIQRKNAMFN
TYYALAVSVV TAISGSSLAH PQRKISMTYV HSAVLAGGVA VGTSCHLIPS PWLAMVLGLV
AGLISIGGAK CLPVCCNRVL GIHHISVMHS IFSLLGLLGE ITYIVLLVLH TVWNGNGMIG
FQVLLSIGEL SLAIVIALTS GLLTGLLLNL KIWKAPHVAK YFDDQVFWKF PHLAVGF
//

MIM 111690
*RECORD*
*FIELD* NO
111690
*FIELD* TI
#111690 BLOOD GROUP--RHESUS SYSTEM E POLYPEPTIDE; RHE
*FIELD* TX
A number sign (#) is used with this entry because Colin et al. (1991)
read morepresented evidence indicating that one gene codes both C/c and E/e
specificities (see 111700), whereas another gene codes Rh D specificity
(111680).

*FIELD* RF
1. 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.

*FIELD* CD
Victor A. McKusick: 12/6/1988

*FIELD* ED
carol: 9/13/1993
supermim: 3/16/1992
carol: 3/4/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 12/6/1988

MIM 111700
*RECORD*
*FIELD* NO
111700
*FIELD* TI
+111700 RHESUS BLOOD GROUP, CcEe ANTIGENS; RHCE
;;BLOOD GROUP--RHESUS SYSTEM Cc/Ee POLYPEPTIDE;;
read moreRHC;;
RHE
RH-NULL DISEASE, AMORPH TYPE, INCLUDED
*FIELD* TX
Rh, elliptocytosis, PGM1, and 6PGD are all on the same chromosome. The
first 2 loci appear to lie between the latter 2 (Renwick, 1971).
Information from cell hybridization studies placed the
Rh-elliptocytosis-PGM(1)-6PGD linkage group on chromosome 1. Jacobs et
al. (1970) reported data suggesting a loose linkage between a
translocation breakpoint near the end of the long arm of chromosome 1
and Rh. Lamm et al. (1970) published family data consistent with loose
linkage of Duffy and PGM1. Renwick (1971) suggested that PGM1 is on the
side of Rh, remote from 6PGD and about 30 centimorgans from Rh. Cook et
al. (1972) confirmed this interval. Although the Rh and Duffy loci are
both on chromosome 1, they are too far apart to demonstrate linkage in
family studies (Sanger et al., 1973). Marsh et al. (1974) found
Rh-negative erythrocytes in an Rh-positive man suffering from
myelofibrosis. Nucleated hemopoietic precursors were circulating in his
blood, and these cells had an abnormal chromosome complement from which
part of the short arm of chromosome 1 had been deleted. They concluded
that the Rh locus probably lies on the distal segment of the short arm
at some point between 1p32 and the end of the short arm. The conclusion
is consistent with the finding of Douglas et al. (1973) that the PGM1
locus, which is linked to Rh, is on the short arm of chromosome 1. Since
the patient of Marsh et al. (1974) did not have deletion of the PGM1
locus in the mutant clone, the Rh locus is probably distal to the PGM1
locus. Corney et al. (1977) observed only 1 recombination in 58
opportunities between the alpha-fucosidase locus (FUCA1; 612280) and the
Rh locus. Rh antigen still eludes chemical definition (Tippett, 1978),
but it is thought to be a lipoprotein. No completely certain example of
recombination within a postulated gene complex has been described.
Steinberg (1965) described a Hutterite family in which the father was
CDe-cde, mother cde-cde, 4 children cde-cde, 3 children CDe-cde, and 1
child (the 6th born) Cde-cde. Steinberg (1965) thought this was an
instance of crossing-over. Mutation and, much less likely, a recessive
suppressor of the D antigen were mentioned as other possibilities. Race
and Sanger (1975) considered a recessive suppressor likely.
(Illegitimacy was excluded by the mores of the sect and by marker
studies.) Rosenfield (1981) wrote: 'We still know nothing about Rh.
Except for Steinberg's one crossover, there have been no exceptions to
the inheritance of Rh antigens in tight haplotype packages. Hopefully,
Rh antigen will be isolated for characterisation but there has been
nothing published since the report of Plapp et al. (1979).' Steinberg et
al. (1984) reexamined the Hutterite family, making use of other markers
thought to be on 1p (6PGD, Colton, UMPK1) and concluded that crossover
or mutation indeed had occurred. (Colton is probably not on chromosome
1p; UMPK1 was not informative in the critical parent (Lewis, 1989).)
They concluded further that if, as seems likely from other evidence, C
lies between D and E, their data indicate that the D gene (116800) is
distal (telomeric) in the Rh complex. This order is consistent with the
rare Rh haplotype D. Race et al. (1950, 1951) considered this haplotype
to represent a probable or possible deletion in a human Rh chromosome.
Race and Sanger (1975) listed 20 homozygotes for this haplotype.
Originating from various populations, they were, in about 80% of the
cases, the products of consanguineous matings. Olafsdottir et al. (1983)
concluded that this Rhesus haplotype is not very rare in Iceland. They
estimated the frequency to be about 1 in 214 persons. They discovered
the haplotype in 2 unrelated women because of difficulty with
crossmatching. Both had formed Rh antibodies, one provoked by
transfusions and the other by 3 pregnancies.

Saboori et al. (1988) purified Rh protein in relatively large amounts
from Rh(D)-positive and -negative blood. Differences in the peptide maps
of the 2 proteins were found. Blanchard et al. (1988) presented indirect
data based on immunologic and biochemical investigations demonstrating
that the Rh D, c, and E polypeptides of the erythrocyte membrane are
homologous but distinct molecular species that can be physically
separated and analyzed. These polypeptides have a molecular weight of
about 32,000. Polypeptides c and E were found by Blanchard et al. (1988)
to be more closely related to each other than to D. All the observations
were consistent with partial divergence among homologous members of a
family of Rh proteins. In a review completed in early 1988, Issitt
(1988) suggested that current molecular genetic methods could finally
end 50 years of speculation as to the genetic determination of the Rh
blood groups. Cherif-Zahar et al. (1990) isolated cDNA clones encoding a
human blood group Rh polypeptide from a human bone marrow cDNA library
using a PCR amplified DNA fragment encoding the known common N-terminal
region of the Rh proteins. Translation of the open reading frame
indicated that the Rh protein is composed of 417 amino acids, including
the initiator methionine, which is removed in the mature protein, that
it lacks a cleavable N-terminal sequence, and that it has no consensus
site for potential N-glycosylation. Hydropathy analysis and predictions
of secondary structure suggested the presence of 13 membrane-spanning
domains, indicating that the Rh polypeptide is highly hydrophobic and
deeply buried within the phospholipid bilayer. In Northern analysis, the
Rh cDNA probe detected a major 1.7-kb and a minor 3.5-kb mRNA species in
erythroid tissues but not in adult liver and kidney tissues or lymphoid
and promyelocytic cell lines. By in situ hybridization using an Rh
protein probe, Cherif-Zahar et al. (1991) mapped the Rh gene to
1p36.1-p34.3.

Whether the 3 sets of Rh antigens--D, Cc, and Ee--that are inherited en
bloc represent separate epitopes on a single protein (as maintained by
Wiener, 1944) or multiple independent proteins encoded by closely linked
genes (as first suggested by Fisher in 1944 (Race, 1944)) has been
controversial since the discovery of the Rh antigens in the early 1940s.
Cherif-Zahar et al. (1990) quoted work of Blanchard et al. (1988)
suggesting that the Rh D, c, and E antigens are carried by 3 distinct
but homologous membrane proteins that share a common N-terminal protein
sequence. It is possible that these are the product of one gene with
multiple splicing alternatives. See also review by Agre and Cartron
(1991). Colin et al. (1991) used Rh cDNA as a probe in Southern analysis
of the Rh locus. They demonstrated that in all Rh D-positive persons 2
strongly related Rh genes are present per haploid genome, whereas 1 of
these 2 genes is missing in Rh D-negative donors. Colin et al. (1991)
concluded that 1 of the 2 genes of the Rh locus encodes the Rh C/c and
Rh E/e polypeptides while the other encodes the Rh D protein. (Both
Fisher and Wiener were partly right.) The absence of any D gene and of
its postulated allelic form d in the Rh D-negative genome explains why
no Rh d antigen has ever been demonstrated.

Using cDNAs amplified from reticulocyte mRNA, Mouro et al. (1993)
investigated CcEe gene differences in Rh-negative individuals homozygous
for dCe, dcE, and dce haplotypes. The RNA analysis was followed by PCR
amplification of specific exons using genomic DNA from donors carrying a
range of common Rh haplotypes. The Ee polypeptide was shown to be
synthesized from the full-length transcript of the CcEe gene and to be
identical in length (417 residues) and very similar in sequence to the D
polypeptide. The Cc polypeptides were synthesized from shorter
transcripts of the same CcEe gene sequence, but spliced so as to exclude
exons 4, 5, and 6 or exons 4, 5 and 8. In both cases, the residue at 226
in exon 5 associated with Ee antigenicity was omitted from the
polypeptide product; see 111700.0001 and 111700.0002. Also see review by
Hopkinson (1993).

The Rh-null phenotype is of 2 types. The most common type, called the
'regulator type,' occurs by an inhibition mechanism; see 268150. This
form is caused by homozygosity for an autosomal recessive suppressor
gene that is genetically independent of the Rh locus, mapping to
chromosome 3 rather than to chromosome 1. The second type of Rh-null,
which was first described in a Japanese family (Ishimori and Hasekura,
1967), is called the 'amorph type' and results from homozygosity for a
silent allele at the Rh locus. In a survey of 42 examples of the Rh-null
phenotype, Nash and Shojania (1987) found that only 5 were of the amorph
type. Perez-Perez et al. (1992) described a Spanish family in which a
silent Rh gene was segregating, giving rise to the amorph type of
Rh-null in the proposita whose parents were first cousins. She suffered
from severe hemolytic anemia. Western blot analysis carried out with
glycosylation-independent antibodies directed against the Rh polypeptide
and the LW glycoprotein, respectively, confirmed that these protein
components were absent from the red cells of the proposita.

Investigations by Cherif-Zahar et al. (1993) failed to reveal any
alteration of the RH genes and transcripts in Rh-null of the silent
type, and they suspected that these variants have a transcriptional or
post-transcriptional alteration of RH genes. Cherif-Zahar et al. (1996)
analyzed the RH locus and sequenced the Rh transcripts from 5
Rh-deficient phenotypes caused by an autosomal suppressor gene (reg and
mod types). They were unable to detect any abnormality; these variants
did not express RH genes but did convey a functional RH locus from one
generation to the next. They also detected no gross alteration in the
CD47 gene structure; transcripts were easily amplified and the
nucleotide sequence was identical to that from controls. This agreed
with binding studies indicating that CD47 is present on the red cell
surface of Rh-deficient cells, although severely reduced (10-15% of
controls). In general, their findings suggested that the low expression
of CD47 on Rh-null erythrocytes results from the defective assembly or
transport to the cell surface when Rh proteins are absent.

Cherif-Zahar et al. (1994) demonstrated that the RHCE gene has 10 exons
distributed over 75 kb. Exons 4 to 8 are alternatively spliced in the
different RNA isoforms. Primary extension analysis indicated that the
transcription initiation site is located 83 bp upstream of the
initiation codon. Study of hematopoietic and nonhematopoietic (HeLa)
cell lines and Northern blot analysis suggested that the expression of
the RH locus is restricted to the erythroid/megakaryocytic lineage.
Consistent with this, putative binding sites for SP1, GATA-1, and Ets
proteins, nuclear factors known to be involved in erythroid and
megakaryocytic gene expression, were identified in the promoter of the
RHCE gene.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

Mollison (1994) reviewed the genetic basis of the Rh blood group system,
giving a brief survey of the early history. Rosenfield (1989) had
described the bitter disagreements between Wiener and Levine,
particularly over priority of discovery. Mollison (1994) reviewed the
disagreement between A. S. Wiener, who postulated multiple alleles at a
single locus (Wiener, 1943), and R. A. Fisher, who interpreted the data
of R. R. Race (1944) as most compatible with the existence of 3 closely
linked genes. Cartron and Agre (1993) reviewed the protein and gene
structure of the Rh blood group antigens. In summary, Rh-positive
persons have 2 Rh genes, 1 encoding the Cc- and Ee-bearing protein or,
more likely, proteins, and a second encoding the D-bearing protein,
while Rh-negative persons have only 1 Rh gene, the first of the 2
described above.

Cartron et al. (1995) defended the 2-gene model of the Rh blood group
system. They suggested that the RHCE gene encodes the C/c and E/e
proteins through alternative splicing of the primary transcript.
D-positive and D-negative individuals differ on the basis of the
presence or absence of the RHD gene (111680), as a rule; in some
Australian Aborigines and Blacks, a fragment of the RHD gene or a
nonfunctional RHD gene is present. Smythe et al. (1996) found that both
c and E antigens were expressed after transduction of K562 cells with a
single cDNA, indicating that the c antigen does not arise by alternative
splicing (exon skipping) of the product of the RHCE gene.

Valenzuela et al. (1991) reported a strong association between plasma
total iron binding capacity (TIBC) and Cc Rh specificity in a Chilean
primary school population in Santiago. Valenzuela et al. (1995) found
similar results in university students from Medellin, Colombia.

In a 3-generation family ascertained through the East of Scotland Blood
Transfusion Service in Dundee, Scotland, Huang et al. (1996) found that
a cataract-causing mutation was cosegregating with an autosomal dominant
anomaly of Rh type known as the Evans phenotype. The geography and the
genetic linkage suggested that the form of cataract may be the same as
that in the Danish family. The red cell Evans phenotype is produced by a
hybrid RH gene in which exons 2-6 from the RHD gene is transferred to
the RHCE gene. Kemp et al. (1996) also examined 5 unrelated Rh D--
homozygotes and found that, in 4 of them, RHCE sequences had been
replaced by RHD sequences. The 5-prime end of these rearrangements
occurred within a 4.2-kb interval around exon 2. There was, however,
heterogeneity at the 3-prime end of the rearranged genes, indicating
that they were not identical by descent, but rather that independent
recombination events had occurred within a small genomic interval--a
recombination hotspot.

Fisher and Race (1946) proposed a model for the evolution of the RH
polymorphism in which the less common haplotypes (CDE, Cde, cdE, and
CdE) are generated and maintained by recombination from those found at
higher frequency. The frequency ratios of the supposed parental and
recombinant haplotypes suggested that the arrangement D-C-E was most
likely under the crossing-over hypothesis. At the time, they assumed
that the 3 series of antigens were encoded in 3 separate genes; the work
outlined earlier indicated that there are 2. Thus recombination between
the sites encoding C/c and E/e would be intragenic, and occur between
exons that are separated by approximately 30 kb (Cherif-Zahar et al.,
1994). Carritt et al. (1997) presented direct evidence for nonreciprocal
intergenic exchange (gene conversion) occurring once in human history to
generate the common RHCE allele, Ce. They also used new polymorphisms to
construct haplotypes which suggested that intragenic recombination
played a major role in the generation of the less common haplotypes, but
only if RHD lies 3-prime of RHCE, i.e., the order is C-E-D. They
provided both genetic and physical evidence supporting this arrangement.

The high degree of homology between the coding regions of the RHCE and
RHD genes is consistent with an ancestral gene duplication. Carritt et
al. (1997) concluded that the human lineage started with the haplotype
cDe. This is consistent with its very high incidence in black Africans
and their descendants (0.4 to 0.5, compared to less than 0.1 elsewhere).
The common haplotype underlying the RhD- phenotype (cde) almost
certainly represented a loss of RHD from cDe. This haplotype is entirely
absent from some aboriginal groups, e.g., Australian, Eskimo, and
Navajo. How the RhD- haplotype became established in a predominantly
RhD+ population, given the moderate to strong selection against RHD+/-
heterozygotes imposed by fetomaternal incompatibility, was still
unknown. As first pointed out in 1942 by Haldane (1942) and reexamined
by Hogben (1943), Li (1953), and others, selection against heterozygotes
results in unstable population equilibria. In an extended simulation
study, Feldman et al. (1969) concluded that, while reproductive
compensation on the part of RhD- mothers can, in principle, lead to
stable equilibria in the face of such selection, other forces, for
example, heterozygote advantage, must operate to maintain RhD+:RhD-
ratios at their observed levels.

Suto et al. (2000) analyzed the organization of the RH genes by 2-color
fluorescence in situ hybridization on DNA fibers released from
lymphocytes (fiber-FISH) and by using DNA probes of introns 3 and 7 of
the RHCE and RHD genes. Six Rh-positive samples (2 with the D+C-c+E+e-,
2 with the D+C+c-E-e+, and 2 with the D+C+c+E+e+ phenotype) showed the
presence of 2 RH genes within a region of less than 200 kb. Of great
interest was the finding that the genes were arranged in antidromic
order starting from the telomere: tel--RHCE (5-prime to 3-prime)--RHD
(3-prime to 5-prime)--centromere. On the other hand, 2 typical
Rh-negative samples (D-C-c+E+e+) showed the presence of only 1 RHCE
gene, as expected.

Wagner and Flegel (2000) showed that the RH locus represents a gene
cluster: RHD (111680) and RHCE face each other by their 3-prime tail
ends, and a third gene, SMP1 (605348), is interspersed between the 2
rhesus genes. The RHD gene deletion was parsimoniously explained by an
unequal crossing-over event. The inverse orientation of the RH genes may
facilitate gene conversion among both rhesus genes, which would explain
the high frequency of hybrid alleles.

The duplication of the rhesus gene occurred during primate evolution
(Matassi et al., 1999), giving rise to the RHD and RHCE genes in humans.
Thus nonprimate mammals, such as mice, may reveal the ancient state of
the RH locus. With this in mind, Wagner and Flegel (2002) analyzed the
sequence of the region. Based on the gene positions and orientations,
RHCE was determined to represent the ancestral state. The close
proximity of SMP1 and RH known in humans was also observed in the mouse
RH locus. Wagner and Flegel (2002) concluded that RHD arose by
duplication of RHCE. The orientation of RHD was probably inverted during
this event. The so-called rhesus boxes, two 9,000-bp DNA segments of
identical orientation flanking the RHD gene, may have been instrumental
for the duplication.

Avent and Reid (2000) provided a comprehensive review of the Rh blood
group system.

*FIELD* AV
.0001
RH E/e POLYMORPHISM
RHCE, PRO226ALA

Mouro et al. (1993) showed that the difference between the classic
allelic antithetical E and e antigens depends on a point mutation in
exon 5 which changes proline to alanine at residue 226 in the e allele.

.0002
RH C/c POLYMORPHISM
RHCE, CYS16TRP, ILE60LEU, SER68ASN, AND SER103PRO

Mouro et al. (1993) showed that the difference between the classic
allelic antithetical C and c antigens depends on point mutations leading
to 4 amino acid substitutions in exons 1 and 2 in the c allele.

.0003
RH-NULL DISEASE, AMORPH TYPE
RHCE, 2-BP DEL, 966T AND 968A

As noted earlier, RH-null disease (which includes the amorphic and
regulator (268150) types) is a rare genetic disorder characterized by
stomatocytosis and chronic hemolytic anemia. Huang et al. (1998) studied
a German family transmitting a putative amorph Rh-null disease gene.
They analyzed the genomic and transcript structure of Rh30, Rh50
(180297), and CD47 (601028), the 3 loci thought to be most critical for
expression of the Rh complex in the red blood cell membrane. They showed
that in this family the Rh50 and CD47 transcripts were normal in primary
sequence. However, the Rh30 locus contained an unusual double mutation
in exon 7 of the RHCE gene, in addition to a deletion of the RhD gene.
The mutation targeted 2 adjacent codons in multiple arrangements,
probably via the mechanism of microgene conversion. One scheme entailed
a noncontiguous deletion of 2 nucleotides, ATT(ile322) to AT and
CAC(his323) to CC, whereas the other involved a T-to-C transition,
ATT(ile322) to ATC, and a dinucleotide deletion, CAC(his323) to C. They
caused the same shift in open reading frame predicted to encode a short
protein with 398 amino acids. The loss of 2 transmembrane domains and
gain of a new C-terminal sequence probably altered the protein
conformation and impaired the Rh complex assembly. The findings
established the molecular identity of an amorph Rh-null disease gene,
showing that Rh30 and Rh50 are both essential for the functioning of the
Rh structures as a multisubunit complex in the plasma membrane.

*FIELD* SA
Levine et al. (1963); Lewis et al. (1976); Lewis et al. (1977); Rosenfield
et al. (1973); Schmidt (1979); Sturgeon (1970)
*FIELD* RF
1. Agre, P.; Cartron, J.-P.: Molecular biology of the Rh antigens. Blood 78:
551-563, 1991.

2. Avent, N. D.; Reid, M. E.: The Rh blood group system: a review. Blood 95:
375-387, 2000. Note: Erratum: Blood 95: 2197 only, 2000.

3. Blanchard, D.; Bloy, C.; Hermand, P.; Cartron, J.-P.; Saboori,
A. M.; Smith, B. L.; Agre, P.: Two-dimensional iodopeptide mapping
demonstrates that erythrocyte Rh D, c, and E polypeptides are structurally
homologous but nonidentical. Blood 72: 1424-1427, 1988.

4. Carritt, B.; Kemp, T. J.; Poulter, M.: Evolution of the human
RH (rhesus) blood group genes: a 50 year old prediction (partially)
fulfilled. Hum. Molec. Genet. 6: 843-850, 1997. Note: Erratum: Hum.
Molec. Genet. 6: 1390 only, 1997.

5. Cartron, J.-P.; Agre, P.: Rh blood group antigens: protein and
gene structure. Semin. Hemat. 30: 193-208, 1993.

6. Cartron, J.-P.; Le Van Kim, C.; Cherif-Zahar, B.; Mouro, I.; Rouillac,
C.; Colin, Y.: The two-gene model of the RH blood-group locus. (Letter) Biochem.
J. 306: 877-878, 1995.

7. Cherif-Zahar, B.; Bloy, C.; Le Van Kim, C.; Blanchard, D.; Bailly,
P.; Hermand, P.; Salmon, C.; Cartron, J.-P.; Colin, Y.: Molecular
cloning and protein structure of a human blood group Rh polypeptide. Proc.
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*FIELD* CN
Victor A. McKusick - updated: 5/13/2002
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Victor A. McKusick - updated: 6/23/1997
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