Full text data of RHAG
RHAG
(RH50)
[Confidence: high (a blood group or CD marker)]
Ammonium transporter Rh type A (Erythrocyte membrane glycoprotein Rh50; Erythrocyte plasma membrane 50 kDa glycoprotein; Rh50A; Rhesus blood group family type A glycoprotein; Rh family type A glycoprotein; Rh type A glycoprotein; Rhesus blood group-associated ammonia channel; Rhesus blood group-associated glycoprotein; CD241)
Ammonium transporter Rh type A (Erythrocyte membrane glycoprotein Rh50; Erythrocyte plasma membrane 50 kDa glycoprotein; Rh50A; Rhesus blood group family type A glycoprotein; Rh family type A glycoprotein; Rh type A glycoprotein; Rhesus blood group-associated ammonia channel; Rhesus blood group-associated glycoprotein; CD241)
hRBCD
IPI00024094
IPI00024094 Rhesus blood group-associated glycoprotein Rhesus blood group-associated glycoprotein membrane n/a n/a 2 2 2 2 4 n/a 6 n/a 2 2 n/a 1 1 n/a 1 3 n/a 2 integral membrane protein n/a found at its expected molecular weight found at molecular weight
IPI00024094 Rhesus blood group-associated glycoprotein Rhesus blood group-associated glycoprotein membrane n/a n/a 2 2 2 2 4 n/a 6 n/a 2 2 n/a 1 1 n/a 1 3 n/a 2 integral membrane protein n/a found at its expected molecular weight found at molecular weight
BGMUT
rhag
704 rhag RHAG RH mod (Japan) RHAG 1183delA 1183delA N395fs Rh mod (Japanese) rare 11961248 Kamesaki et al. Exon 9 mutated. Protein is 461 aa longer. 2011-08-09 01:24:01.517 NA
704 rhag RHAG RH mod (Japan) RHAG 1183delA 1183delA N395fs Rh mod (Japanese) rare 11961248 Kamesaki et al. Exon 9 mutated. Protein is 461 aa longer. 2011-08-09 01:24:01.517 NA
UniProt
Q02094
ID RHAG_HUMAN Reviewed; 409 AA.
AC Q02094; B2R8T8; O43514; O43515; Q7L8L3; Q9H454;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-DEC-2008, sequence version 2.
DT 22-JAN-2014, entry version 118.
DE RecName: Full=Ammonium transporter Rh type A;
DE AltName: Full=Erythrocyte membrane glycoprotein Rh50;
DE AltName: Full=Erythrocyte plasma membrane 50 kDa glycoprotein;
DE Short=Rh50A;
DE AltName: Full=Rhesus blood group family type A glycoprotein;
DE Short=Rh family type A glycoprotein;
DE Short=Rh type A glycoprotein;
DE AltName: Full=Rhesus blood group-associated ammonia channel;
DE AltName: Full=Rhesus blood group-associated glycoprotein;
DE AltName: CD_antigen=CD241;
GN Name=RHAG; Synonyms=RH50;
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 ASP-242.
RC TISSUE=Bone marrow, and Liver;
RX PubMed=1417776;
RA Ridgwell K., Spurr N.K., Laguda B., Macgeoch C., Avent N.D.,
RA Tanner M.J.A.;
RT "Isolation of cDNA clones for a 50 kDa glycoprotein of the human
RT erythrocyte membrane associated with Rh (rhesus) blood-group antigen
RT expression.";
RL Biochem. J. 287:223-228(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2).
RX PubMed=9442063; DOI=10.1074/jbc.273.4.2207;
RA Huang C.-H.;
RT "The human Rh50 glycoprotein gene. Structural organization and
RT associated splicing defect resulting in Rh(null) disease.";
RL J. Biol. Chem. 273:2207-2213(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP ILE-270.
RC TISSUE=Heart;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E.,
RA Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S.,
RA Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J.,
RA Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P.,
RA Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E.,
RA Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A.,
RA Frankland J., French L., Garner P., Garnett J., Ghori M.J.,
RA Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M.,
RA Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S.,
RA Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R.,
RA Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E.,
RA Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A.,
RA Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M.,
RA Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K.,
RA McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T.,
RA Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R.,
RA Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W.,
RA Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M.,
RA Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L.,
RA Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J.,
RA Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L.,
RA Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W.,
RA Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A.,
RA Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-52, AND TISSUE SPECIFICITY.
RX PubMed=9473510; DOI=10.1006/bbrc.1997.8023;
RA Iwamoto S., Omi T., Yamasaki M., Okuda H., Kawano M., Kajii E.;
RT "Identification of 5' flanking sequence of RH50 gene and the core
RT region for erythroid-specific expression.";
RL Biochem. Biophys. Res. Commun. 243:233-240(1998).
RN [7]
RP PROTEIN SEQUENCE OF 1-39.
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 [8]
RP FUNCTION.
RX PubMed=11062476; DOI=10.1038/81656;
RA Marini A.-M., Matassi G., Raynal V., Andre B., Cartron J.-P.,
RA Cherif-Zahar B.;
RT "The human Rhesus-associated RhAG protein and a kidney homologue
RT promote ammonium transport in yeast.";
RL Nat. Genet. 26:341-344(2000).
RN [9]
RP FUNCTION.
RX PubMed=11861637; DOI=10.1074/jbc.C200060200;
RA Westhoff C.M., Ferreri-Jacobia M., Mak D.-O.D., Foskett J.K.;
RT "Identification of the erythrocyte Rh blood group glycoprotein as a
RT mammalian ammonium transporter.";
RL J. Biol. Chem. 277:12499-12502(2002).
RN [10]
RP CHARACTERIZATION.
RX PubMed=14966114; DOI=10.1074/jbc.M311853200;
RA Westhoff C.M., Siegel D.L., Burd C.G., Foskett J.K.;
RT "Mechanism of genetic complementation of ammonium transport in yeast
RT by human erythrocyte Rh-associated glycoprotein.";
RL J. Biol. Chem. 279:17443-17448(2004).
RN [11]
RP VARIANT RHN ASN-79.
RX PubMed=8563755; DOI=10.1038/ng0296-168;
RA Cherif-Zahar B., Raynal V., Gane P., Mattei M.-G., Bailly P.,
RA Gibbs B., Colin Y., Cartron J.-P.;
RT "Candidate gene acting as a suppressor of the RH locus in most cases
RT of Rh-deficiency.";
RL Nat. Genet. 12:168-173(1996).
RN [12]
RP VARIANT RHN GLU-279.
RX PubMed=9454778;
RA Hyland C.A., Cherif-Zahar B., Cowley N., Raynal V., Parkes J.,
RA Saul A., Cartron J.-P.;
RT "A novel single missense mutation identified along the RH50 gene in a
RT composite heterozygous Rhnull blood donor of the regulator type.";
RL Blood 91:1458-1463(1998).
RN [13]
RP VARIANT RHN GLU-279.
RX PubMed=9716608;
RA Huang C.-H., Liu Z., Cheng G., Chen Y.;
RT "Rh50 glycoprotein gene and rhnull disease: a silent splice donor is
RT trans to a Gly279-->Glu missense mutation in the conserved
RT transmembrane segment.";
RL Blood 92:1776-1784(1998).
RN [14]
RP VARIANTS RHN ILE-270; ARG-280 AND VAL-380.
RX PubMed=10467273;
RX DOI=10.1002/(SICI)1096-8652(199909)62:1<25::AID-AJH5>3.0.CO;2-K;
RA Huang C.-H., Cheng G., Liu Z., Chen Y., Reid M.E., Halverson G.,
RA Okubo Y.;
RT "Molecular basis for Rh(null) syndrome: identification of three new
RT missense mutations in the Rh50 glycoprotein gene.";
RL Am. J. Hematol. 62:25-32(1999).
CC -!- FUNCTION: Associated with rhesus blood group antigen expression.
CC May be part of an oligomeric complex which is likely to have a
CC transport or channel function in the erythrocyte membrane.
CC -!- SUBUNIT: Heterotetramer.
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q02094-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q02094-2; Sequence=VSP_047629, VSP_047630;
CC -!- TISSUE SPECIFICITY: Erythrocytes.
CC -!- DISEASE: Regulator type Rh-null hemolytic anemia (RHN)
CC [MIM:268150]: Form of chronic hemolytic anemia in which the red
CC blood cells have a stomatocytosis and spherocytosis morphology, an
CC increased osmotic fragility, an altered ion transport system, and
CC abnormal membrane phospholipid organization. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the ammonium transporter (TC 2.A.49)
CC family. Rh subfamily.
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DR EMBL; X64594; CAA45883.1; -; mRNA.
DR EMBL; AF031548; AAC04247.1; -; mRNA.
DR EMBL; AF031549; AAC04248.1; -; mRNA.
DR EMBL; AF237387; AAF78209.1; -; Genomic_DNA.
DR EMBL; AF237382; AAF78209.1; JOINED; Genomic_DNA.
DR EMBL; AF237383; AAF78209.1; JOINED; Genomic_DNA.
DR EMBL; AF237384; AAF78209.1; JOINED; Genomic_DNA.
DR EMBL; AF237385; AAF78209.1; JOINED; Genomic_DNA.
DR EMBL; AF237386; AAF78209.1; JOINED; Genomic_DNA.
DR EMBL; AK313505; BAG36285.1; -; mRNA.
DR EMBL; AL121950; CAC10519.2; -; Genomic_DNA.
DR EMBL; AL590244; CAC10519.2; JOINED; Genomic_DNA.
DR EMBL; AL590244; CAI13085.1; -; Genomic_DNA.
DR EMBL; AL121950; CAI13085.1; JOINED; Genomic_DNA.
DR EMBL; CH471081; EAX04337.1; -; Genomic_DNA.
DR EMBL; CH471081; EAX04338.1; -; Genomic_DNA.
DR PIR; S29124; S29124.
DR RefSeq; NP_000315.2; NM_000324.2.
DR UniGene; Hs.120950; -.
DR ProteinModelPortal; Q02094; -.
DR SMR; Q02094; 1-407.
DR STRING; 9606.ENSP00000360217; -.
DR GuidetoPHARMACOLOGY; 1198; -.
DR TCDB; 1.A.11.4.3; the ammonia transporter channel (amt) family.
DR PhosphoSite; Q02094; -.
DR DMDM; 218511807; -.
DR PaxDb; Q02094; -.
DR PRIDE; Q02094; -.
DR DNASU; 6005; -.
DR Ensembl; ENST00000229810; ENSP00000229810; ENSG00000112077.
DR Ensembl; ENST00000371175; ENSP00000360217; ENSG00000112077.
DR GeneID; 6005; -.
DR KEGG; hsa:6005; -.
DR UCSC; uc010jzm.3; human.
DR CTD; 6005; -.
DR GeneCards; GC06M049619; -.
DR H-InvDB; HIX0005947; -.
DR HGNC; HGNC:10006; RHAG.
DR HPA; HPA055331; -.
DR MIM; 180297; gene.
DR MIM; 268150; phenotype.
DR neXtProt; NX_Q02094; -.
DR Orphanet; 3203; Overhydrated hereditary stomatocytosis.
DR Orphanet; 71275; Rh deficiency syndrome.
DR PharmGKB; PA34381; -.
DR eggNOG; NOG276393; -.
DR HOGENOM; HOG000007656; -.
DR HOVERGEN; HBG004374; -.
DR InParanoid; Q02094; -.
DR KO; K06580; -.
DR OMA; NEESAYY; -.
DR OrthoDB; EOG73NG3C; -.
DR PhylomeDB; Q02094; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_20679; Amine compound SLC transporters.
DR GeneWiki; RHAG; -.
DR GenomeRNAi; 6005; -.
DR NextBio; 23423; -.
DR PRO; PR:Q02094; -.
DR ArrayExpress; Q02094; -.
DR Bgee; Q02094; -.
DR CleanEx; HS_RHAG; -.
DR Genevestigator; Q02094; -.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0051739; F:ammonia transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0008519; F:ammonium transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0015701; P:bicarbonate transport; TAS:Reactome.
DR GO; GO:0015670; P:carbon dioxide transport; IDA:UniProtKB.
DR GO; GO:0006873; P:cellular ion homeostasis; IDA:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
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; Ammonia transport; Complete proteome;
KW Direct protein sequencing; Disease mutation; Glycoprotein; Membrane;
KW Reference proteome; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 409 Ammonium transporter Rh type A.
FT /FTId=PRO_0000168199.
FT TOPO_DOM 1 2 Cytoplasmic (Potential).
FT TRANSMEM 3 23 Helical; (Potential).
FT TOPO_DOM 24 51 Extracellular (Potential).
FT TRANSMEM 52 72 Helical; (Potential).
FT TOPO_DOM 73 79 Cytoplasmic (Potential).
FT TRANSMEM 80 100 Helical; (Potential).
FT TOPO_DOM 101 113 Extracellular (Potential).
FT TRANSMEM 114 134 Helical; (Potential).
FT TOPO_DOM 135 142 Cytoplasmic (Potential).
FT TRANSMEM 143 163 Helical; (Potential).
FT TOPO_DOM 164 167 Extracellular (Potential).
FT TRANSMEM 168 188 Helical; (Potential).
FT TOPO_DOM 189 208 Cytoplasmic (Potential).
FT TRANSMEM 209 229 Helical; (Potential).
FT TOPO_DOM 230 239 Extracellular (Potential).
FT TRANSMEM 240 260 Helical; (Potential).
FT TOPO_DOM 261 268 Cytoplasmic (Potential).
FT TRANSMEM 269 291 Helical; (Potential).
FT TOPO_DOM 292 295 Extracellular (Potential).
FT TRANSMEM 296 318 Helical; (Potential).
FT TOPO_DOM 319 332 Cytoplasmic (Potential).
FT TRANSMEM 333 353 Helical; (Potential).
FT TOPO_DOM 354 362 Extracellular (Potential).
FT TRANSMEM 363 383 Helical; (Potential).
FT TOPO_DOM 384 409 Cytoplasmic (Potential).
FT CARBOHYD 37 37 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 355 355 N-linked (GlcNAc...) (Potential).
FT VAR_SEQ 316 351 PLFTTKLRIHDTCGVHNLHGLPGVVGGLAGIVAVAM -> V
FT YGHAGSCTGFLYRNSSCWRSDDRFNSKVASLGTAI (in
FT isoform 2).
FT /FTId=VSP_047629.
FT VAR_SEQ 352 409 Missing (in isoform 2).
FT /FTId=VSP_047630.
FT VARIANT 79 79 S -> N (in RHN).
FT /FTId=VAR_006921.
FT VARIANT 242 242 N -> D (in dbSNP:rs1058063).
FT /FTId=VAR_047999.
FT VARIANT 270 270 V -> I (in RHN; dbSNP:rs16879498).
FT /FTId=VAR_015855.
FT VARIANT 279 279 G -> E (in RHN; dbSNP:rs28933991).
FT /FTId=VAR_015856.
FT VARIANT 280 280 G -> R (in RHN).
FT /FTId=VAR_015857.
FT VARIANT 380 380 G -> V (in RHN).
FT /FTId=VAR_015858.
FT CONFLICT 2 2 R -> C (in Ref. 7; AA sequence).
FT CONFLICT 37 37 N -> P (in Ref. 7; AA sequence).
SQ SEQUENCE 409 AA; 44198 MW; F6F024399CC0C88D CRC64;
MRFTFPLMAI VLEIAMIVLF GLFVEYETDQ TVLEQLNITK PTDMGIFFEL YPLFQDVHVM
IFVGFGFLMT FLKKYGFSSV GINLLVAALG LQWGTIVQGI LQSQGQKFNI GIKNMINADF
SAATVLISFG AVLGKTSPTQ MLIMTILEIV FFAHNEYLVS EIFKASDIGA SMTIHAFGAY
FGLAVAGILY RSGLRKGHEN EESAYYSDLF AMIGTLFLWM FWPSFNSAIA EPGDKQCRAI
VNTYFSLAAC VLTAFAFSSL VEHRGKLNMV HIQNATLAGG VAVGTCADMA IHPFGSMIIG
SIAGMVSVLG YKFLTPLFTT KLRIHDTCGV HNLHGLPGVV GGLAGIVAVA MGASNTSMAM
QAAALGSSIG TAVVGGLMTG LILKLPLWGQ PSDQNCYDDS VYWKVPKTR
//
ID RHAG_HUMAN Reviewed; 409 AA.
AC Q02094; B2R8T8; O43514; O43515; Q7L8L3; Q9H454;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-DEC-2008, sequence version 2.
DT 22-JAN-2014, entry version 118.
DE RecName: Full=Ammonium transporter Rh type A;
DE AltName: Full=Erythrocyte membrane glycoprotein Rh50;
DE AltName: Full=Erythrocyte plasma membrane 50 kDa glycoprotein;
DE Short=Rh50A;
DE AltName: Full=Rhesus blood group family type A glycoprotein;
DE Short=Rh family type A glycoprotein;
DE Short=Rh type A glycoprotein;
DE AltName: Full=Rhesus blood group-associated ammonia channel;
DE AltName: Full=Rhesus blood group-associated glycoprotein;
DE AltName: CD_antigen=CD241;
GN Name=RHAG; Synonyms=RH50;
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 ASP-242.
RC TISSUE=Bone marrow, and Liver;
RX PubMed=1417776;
RA Ridgwell K., Spurr N.K., Laguda B., Macgeoch C., Avent N.D.,
RA Tanner M.J.A.;
RT "Isolation of cDNA clones for a 50 kDa glycoprotein of the human
RT erythrocyte membrane associated with Rh (rhesus) blood-group antigen
RT expression.";
RL Biochem. J. 287:223-228(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2).
RX PubMed=9442063; DOI=10.1074/jbc.273.4.2207;
RA Huang C.-H.;
RT "The human Rh50 glycoprotein gene. Structural organization and
RT associated splicing defect resulting in Rh(null) disease.";
RL J. Biol. Chem. 273:2207-2213(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP ILE-270.
RC TISSUE=Heart;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E.,
RA Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S.,
RA Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J.,
RA Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P.,
RA Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E.,
RA Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A.,
RA Frankland J., French L., Garner P., Garnett J., Ghori M.J.,
RA Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M.,
RA Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S.,
RA Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R.,
RA Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E.,
RA Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A.,
RA Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M.,
RA Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K.,
RA McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T.,
RA Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R.,
RA Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W.,
RA Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M.,
RA Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L.,
RA Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J.,
RA Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L.,
RA Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W.,
RA Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A.,
RA Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-52, AND TISSUE SPECIFICITY.
RX PubMed=9473510; DOI=10.1006/bbrc.1997.8023;
RA Iwamoto S., Omi T., Yamasaki M., Okuda H., Kawano M., Kajii E.;
RT "Identification of 5' flanking sequence of RH50 gene and the core
RT region for erythroid-specific expression.";
RL Biochem. Biophys. Res. Commun. 243:233-240(1998).
RN [7]
RP PROTEIN SEQUENCE OF 1-39.
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 [8]
RP FUNCTION.
RX PubMed=11062476; DOI=10.1038/81656;
RA Marini A.-M., Matassi G., Raynal V., Andre B., Cartron J.-P.,
RA Cherif-Zahar B.;
RT "The human Rhesus-associated RhAG protein and a kidney homologue
RT promote ammonium transport in yeast.";
RL Nat. Genet. 26:341-344(2000).
RN [9]
RP FUNCTION.
RX PubMed=11861637; DOI=10.1074/jbc.C200060200;
RA Westhoff C.M., Ferreri-Jacobia M., Mak D.-O.D., Foskett J.K.;
RT "Identification of the erythrocyte Rh blood group glycoprotein as a
RT mammalian ammonium transporter.";
RL J. Biol. Chem. 277:12499-12502(2002).
RN [10]
RP CHARACTERIZATION.
RX PubMed=14966114; DOI=10.1074/jbc.M311853200;
RA Westhoff C.M., Siegel D.L., Burd C.G., Foskett J.K.;
RT "Mechanism of genetic complementation of ammonium transport in yeast
RT by human erythrocyte Rh-associated glycoprotein.";
RL J. Biol. Chem. 279:17443-17448(2004).
RN [11]
RP VARIANT RHN ASN-79.
RX PubMed=8563755; DOI=10.1038/ng0296-168;
RA Cherif-Zahar B., Raynal V., Gane P., Mattei M.-G., Bailly P.,
RA Gibbs B., Colin Y., Cartron J.-P.;
RT "Candidate gene acting as a suppressor of the RH locus in most cases
RT of Rh-deficiency.";
RL Nat. Genet. 12:168-173(1996).
RN [12]
RP VARIANT RHN GLU-279.
RX PubMed=9454778;
RA Hyland C.A., Cherif-Zahar B., Cowley N., Raynal V., Parkes J.,
RA Saul A., Cartron J.-P.;
RT "A novel single missense mutation identified along the RH50 gene in a
RT composite heterozygous Rhnull blood donor of the regulator type.";
RL Blood 91:1458-1463(1998).
RN [13]
RP VARIANT RHN GLU-279.
RX PubMed=9716608;
RA Huang C.-H., Liu Z., Cheng G., Chen Y.;
RT "Rh50 glycoprotein gene and rhnull disease: a silent splice donor is
RT trans to a Gly279-->Glu missense mutation in the conserved
RT transmembrane segment.";
RL Blood 92:1776-1784(1998).
RN [14]
RP VARIANTS RHN ILE-270; ARG-280 AND VAL-380.
RX PubMed=10467273;
RX DOI=10.1002/(SICI)1096-8652(199909)62:1<25::AID-AJH5>3.0.CO;2-K;
RA Huang C.-H., Cheng G., Liu Z., Chen Y., Reid M.E., Halverson G.,
RA Okubo Y.;
RT "Molecular basis for Rh(null) syndrome: identification of three new
RT missense mutations in the Rh50 glycoprotein gene.";
RL Am. J. Hematol. 62:25-32(1999).
CC -!- FUNCTION: Associated with rhesus blood group antigen expression.
CC May be part of an oligomeric complex which is likely to have a
CC transport or channel function in the erythrocyte membrane.
CC -!- SUBUNIT: Heterotetramer.
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q02094-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q02094-2; Sequence=VSP_047629, VSP_047630;
CC -!- TISSUE SPECIFICITY: Erythrocytes.
CC -!- DISEASE: Regulator type Rh-null hemolytic anemia (RHN)
CC [MIM:268150]: Form of chronic hemolytic anemia in which the red
CC blood cells have a stomatocytosis and spherocytosis morphology, an
CC increased osmotic fragility, an altered ion transport system, and
CC abnormal membrane phospholipid organization. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the ammonium transporter (TC 2.A.49)
CC family. Rh subfamily.
CC -----------------------------------------------------------------------
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DR EMBL; X64594; CAA45883.1; -; mRNA.
DR EMBL; AF031548; AAC04247.1; -; mRNA.
DR EMBL; AF031549; AAC04248.1; -; mRNA.
DR EMBL; AF237387; AAF78209.1; -; Genomic_DNA.
DR EMBL; AF237382; AAF78209.1; JOINED; Genomic_DNA.
DR EMBL; AF237383; AAF78209.1; JOINED; Genomic_DNA.
DR EMBL; AF237384; AAF78209.1; JOINED; Genomic_DNA.
DR EMBL; AF237385; AAF78209.1; JOINED; Genomic_DNA.
DR EMBL; AF237386; AAF78209.1; JOINED; Genomic_DNA.
DR EMBL; AK313505; BAG36285.1; -; mRNA.
DR EMBL; AL121950; CAC10519.2; -; Genomic_DNA.
DR EMBL; AL590244; CAC10519.2; JOINED; Genomic_DNA.
DR EMBL; AL590244; CAI13085.1; -; Genomic_DNA.
DR EMBL; AL121950; CAI13085.1; JOINED; Genomic_DNA.
DR EMBL; CH471081; EAX04337.1; -; Genomic_DNA.
DR EMBL; CH471081; EAX04338.1; -; Genomic_DNA.
DR PIR; S29124; S29124.
DR RefSeq; NP_000315.2; NM_000324.2.
DR UniGene; Hs.120950; -.
DR ProteinModelPortal; Q02094; -.
DR SMR; Q02094; 1-407.
DR STRING; 9606.ENSP00000360217; -.
DR GuidetoPHARMACOLOGY; 1198; -.
DR TCDB; 1.A.11.4.3; the ammonia transporter channel (amt) family.
DR PhosphoSite; Q02094; -.
DR DMDM; 218511807; -.
DR PaxDb; Q02094; -.
DR PRIDE; Q02094; -.
DR DNASU; 6005; -.
DR Ensembl; ENST00000229810; ENSP00000229810; ENSG00000112077.
DR Ensembl; ENST00000371175; ENSP00000360217; ENSG00000112077.
DR GeneID; 6005; -.
DR KEGG; hsa:6005; -.
DR UCSC; uc010jzm.3; human.
DR CTD; 6005; -.
DR GeneCards; GC06M049619; -.
DR H-InvDB; HIX0005947; -.
DR HGNC; HGNC:10006; RHAG.
DR HPA; HPA055331; -.
DR MIM; 180297; gene.
DR MIM; 268150; phenotype.
DR neXtProt; NX_Q02094; -.
DR Orphanet; 3203; Overhydrated hereditary stomatocytosis.
DR Orphanet; 71275; Rh deficiency syndrome.
DR PharmGKB; PA34381; -.
DR eggNOG; NOG276393; -.
DR HOGENOM; HOG000007656; -.
DR HOVERGEN; HBG004374; -.
DR InParanoid; Q02094; -.
DR KO; K06580; -.
DR OMA; NEESAYY; -.
DR OrthoDB; EOG73NG3C; -.
DR PhylomeDB; Q02094; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_20679; Amine compound SLC transporters.
DR GeneWiki; RHAG; -.
DR GenomeRNAi; 6005; -.
DR NextBio; 23423; -.
DR PRO; PR:Q02094; -.
DR ArrayExpress; Q02094; -.
DR Bgee; Q02094; -.
DR CleanEx; HS_RHAG; -.
DR Genevestigator; Q02094; -.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0051739; F:ammonia transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0008519; F:ammonium transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0015701; P:bicarbonate transport; TAS:Reactome.
DR GO; GO:0015670; P:carbon dioxide transport; IDA:UniProtKB.
DR GO; GO:0006873; P:cellular ion homeostasis; IDA:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
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; Ammonia transport; Complete proteome;
KW Direct protein sequencing; Disease mutation; Glycoprotein; Membrane;
KW Reference proteome; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 409 Ammonium transporter Rh type A.
FT /FTId=PRO_0000168199.
FT TOPO_DOM 1 2 Cytoplasmic (Potential).
FT TRANSMEM 3 23 Helical; (Potential).
FT TOPO_DOM 24 51 Extracellular (Potential).
FT TRANSMEM 52 72 Helical; (Potential).
FT TOPO_DOM 73 79 Cytoplasmic (Potential).
FT TRANSMEM 80 100 Helical; (Potential).
FT TOPO_DOM 101 113 Extracellular (Potential).
FT TRANSMEM 114 134 Helical; (Potential).
FT TOPO_DOM 135 142 Cytoplasmic (Potential).
FT TRANSMEM 143 163 Helical; (Potential).
FT TOPO_DOM 164 167 Extracellular (Potential).
FT TRANSMEM 168 188 Helical; (Potential).
FT TOPO_DOM 189 208 Cytoplasmic (Potential).
FT TRANSMEM 209 229 Helical; (Potential).
FT TOPO_DOM 230 239 Extracellular (Potential).
FT TRANSMEM 240 260 Helical; (Potential).
FT TOPO_DOM 261 268 Cytoplasmic (Potential).
FT TRANSMEM 269 291 Helical; (Potential).
FT TOPO_DOM 292 295 Extracellular (Potential).
FT TRANSMEM 296 318 Helical; (Potential).
FT TOPO_DOM 319 332 Cytoplasmic (Potential).
FT TRANSMEM 333 353 Helical; (Potential).
FT TOPO_DOM 354 362 Extracellular (Potential).
FT TRANSMEM 363 383 Helical; (Potential).
FT TOPO_DOM 384 409 Cytoplasmic (Potential).
FT CARBOHYD 37 37 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 355 355 N-linked (GlcNAc...) (Potential).
FT VAR_SEQ 316 351 PLFTTKLRIHDTCGVHNLHGLPGVVGGLAGIVAVAM -> V
FT YGHAGSCTGFLYRNSSCWRSDDRFNSKVASLGTAI (in
FT isoform 2).
FT /FTId=VSP_047629.
FT VAR_SEQ 352 409 Missing (in isoform 2).
FT /FTId=VSP_047630.
FT VARIANT 79 79 S -> N (in RHN).
FT /FTId=VAR_006921.
FT VARIANT 242 242 N -> D (in dbSNP:rs1058063).
FT /FTId=VAR_047999.
FT VARIANT 270 270 V -> I (in RHN; dbSNP:rs16879498).
FT /FTId=VAR_015855.
FT VARIANT 279 279 G -> E (in RHN; dbSNP:rs28933991).
FT /FTId=VAR_015856.
FT VARIANT 280 280 G -> R (in RHN).
FT /FTId=VAR_015857.
FT VARIANT 380 380 G -> V (in RHN).
FT /FTId=VAR_015858.
FT CONFLICT 2 2 R -> C (in Ref. 7; AA sequence).
FT CONFLICT 37 37 N -> P (in Ref. 7; AA sequence).
SQ SEQUENCE 409 AA; 44198 MW; F6F024399CC0C88D CRC64;
MRFTFPLMAI VLEIAMIVLF GLFVEYETDQ TVLEQLNITK PTDMGIFFEL YPLFQDVHVM
IFVGFGFLMT FLKKYGFSSV GINLLVAALG LQWGTIVQGI LQSQGQKFNI GIKNMINADF
SAATVLISFG AVLGKTSPTQ MLIMTILEIV FFAHNEYLVS EIFKASDIGA SMTIHAFGAY
FGLAVAGILY RSGLRKGHEN EESAYYSDLF AMIGTLFLWM FWPSFNSAIA EPGDKQCRAI
VNTYFSLAAC VLTAFAFSSL VEHRGKLNMV HIQNATLAGG VAVGTCADMA IHPFGSMIIG
SIAGMVSVLG YKFLTPLFTT KLRIHDTCGV HNLHGLPGVV GGLAGIVAVA MGASNTSMAM
QAAALGSSIG TAVVGGLMTG LILKLPLWGQ PSDQNCYDDS VYWKVPKTR
//
MIM
180297
*RECORD*
*FIELD* NO
180297
*FIELD* TI
*180297 RHESUS BLOOD GROUP-ASSOCIATED GLYCOPROTEIN; RHAG
;;RHESUS ASSOCIATED POLYPEPTIDE, 50-KD; RH50A;;
read moreRH2
*FIELD* TX
DESCRIPTION
The Rh blood group antigens (111700) are associated with human
erythrocyte membrane proteins of approximately 30 kD, the so-called Rh30
polypeptides. Heterogeneously glycosylated membrane proteins of 50 and
45 kD, the Rh50 glycoproteins, are coprecipitated with the Rh30
polypeptides on immunoprecipitation with anti-Rh-specific mono- and
polyclonal antibodies. The Rh antigens appear to exist as a multisubunit
complex of CD47 (601028), LW (111250), and glycophorin B (111740), and
play a critical role in the Rh50 glycoprotein.
CLONING
Ridgwell et al. (1992) isolated cDNA clones representing a member of the
Rh50 glycoprotein family, the Rh50A glycoprotein. They used PCR with
degenerate primers based on the N-terminal amino acid sequence of the
Rh50 glycoproteins and human genomic DNA as a template. The cDNA clones
containing the full coding sequence of the Rh50A glycoprotein predicted
a 409-amino acid N-glycosylated membrane protein with up to 12
transmembrane domains. It showed clear similarity to the Rh30A protein
in both amino acid sequence and predicted topology. The findings were
considered consistent with the possibility that the Rh30 and Rh50 groups
of proteins are different subunits of an oligomeric complex which is
likely to have a transport or channel function in the erythrocyte
membrane.
GENE STRUCTURE
Huang (1998) determined the intron/exon structure of the Rh50 gene. The
structure of the Rh50 gene is nearly identical to that of the Rh30 gene.
Of the 10 exons assigned, conservation of size and sequence was confined
mainly to the region from exons 2 to 9, suggesting that RH50 and RH30
were formed as 2 separate genetic loci from a common ancestor via a
transchromosomal insertion event.
GENE FUNCTION
The absence of the RhAG and Rh proteins in Rh(null) individuals leads to
morphologic and functional abnormalities of erythrocytes, known as the
Rh-deficiency syndrome. The RhAG and Rh polypeptides are
erythroid-specific transmembrane proteins belonging to the same family
(36% identity). Marini et al. (1997) and Matassi et al. (1998) found
significant sequence similarity between the Rh family proteins,
especially RhAG, and Mep/Amt ammonium transporters. Marini et al. (2000)
showed that RhAG and also RhGK (605381), a human homolog expressed in
kidney cells only, function as ammonium transport proteins when
expressed in yeast. Both specifically complement the growth defect of a
yeast mutant deficient in ammonium uptake. Moreover, ammonium efflux
assays and growth tests in the presence of toxic concentrations of the
analog methylammonium indicated that RhAG and RhGK also promote ammonium
export. The results provided the first experimental evidence for a
direct role of RhAG and RhGK in ammonium transport and were of high
interest, because no specific ammonium transport system had been
previously characterized in human.
Westhoff et al. (2002) used the Xenopus oocyte expression system to
determine the function of Rh and RhAG proteins. They demonstrated
expression of fully glycosylated RhAG protein and provided the first
direct evidence for RhAG-mediated ammonium uptake.
Ripoche et al. (2004) assayed transport in red blood cells and ghosts
from human and mouse genetic variants with defects in RhAG or other
components of the Rh complex. They found that the rate constant for
methylammonium or ammonium transport directly correlated with the amount
of functional RhAG and was unaffected by the amount of Rh, CD47, or LW.
BIOCHEMICAL FEATURES
- Crystal Structure
Khademi et al. (2004) determined the crystal structure of the ammonia
channel from the Amt/MEP/Rh protein superfamily at 1.35-angstrom
resolution. The channel spans the membrane 11 times. Two structurally
similar halves span the membrane with opposite polarity. Structures with
and without ammonia or methyl ammonia show a vestibule that recruits
NH4+/NH3, a binding site for NH4+, and a 20-angstrom-long hydrophobic
channel that lowers the NH4+ pKa to below 6 and conducts NH3. Favorable
interactions for NH3 were seen within the channel and used conserved
histidines. Khademi et al. (2004) concluded that reconstitution of AmtB
into vesicles shows that AmtB conducts uncharged ammonia.
MAPPING
By analysis of somatic cell hybrids, Ridgwell et al. (1992) mapped the
Rh50A gene to 6p21-qter, indicating that genetic differences in the
genes for the Rh30 polypeptide, rather than the Rh50 genes, specify the
major polymorphic forms of the Rh antigens, because the Rh blood group
maps to chromosome 1, not chromosome 6. Cherif-Zahar et al. (1996)
carried out 5 regional assignments of the Rh50 gene by isotopic in situ
hybridization and concluded that it maps to 6p21.1-p11, probably 6p12.
MOLECULAR GENETICS
The Rh(null) types, Rh(null) regulator and Rh(mod) (in which trace
amounts of Rh antigens are found), exhibit the same clinical
abnormalities associated with chronic hemolytic anemia, stomatocytosis
and spherocytosis, reduced osmotic fragility, and increased cation
permeability. In addition, Rh(null) membranes characteristically have
hyperactive membrane ATPases and reduced red cell cation and water
content. Cherif-Zahar et al. (1996) proposed that mutant alleles of Rh50
are suppressors of the RH locus and account for most cases of
Rh-deficiency. They analyzed the genes and transcripts encoding Rh,
CD47, and Rh50 proteins in 5 unrelated Rh(null) cases and identified 3
types of Rh50 mutations in the transcripts and genomic DNA from them.
The first mutation was observed in homozygous state in 2 apparently
unrelated individuals originating from South Africa and involved a 2-bp
transversion and a 2-bp deletion, introducing a frameshift after the
codon for tyrosine-51 (180297.0001). They stated that, since the Rh50
glycoprotein was not detectable by flow cytometry or Western blot
analysis on the red cells of these 2 individuals, it is likely that the
predicted truncated Rh50 polypeptide (107 residues instead of 409) from
these variants was degraded and not inserted into the membrane. The
second mutation consisted of a single base deletion at nucleotide 1086,
resulting in a frameshift after the codon for alanine-362 (180297.0002).
The deduced Rh50 protein was 376 amino acids long (instead of 409) and
included 14 novel residues at its C terminus. Surprisingly, this
mutation was found in the heterozygous state by RFLP analysis. Attempts
to amplify the product of the second Rh50 allele were unsuccessful,
strongly suggesting that this transcript was either absent or poorly
represented in reticulocytes. Cherif-Zahar et al. (1996) assumed that
this allele was transcriptionally silent and that the subjects
erythrocytes should carry half the normal dose of a truncated Rh50
protein. Interestingly, flow cytometry and Western blot analysis
indicated a complete absence of the protein. They noted that RH and Rh50
proteins interact with each other and suggested that the C terminus of
Rh50 may stabilize this interaction or may represent a site of
protein-protein interaction critical for cell surface expression. The
third Rh50 mutation identified by Cherif-Zahar et al. (1996) was a
missense mutation caused by a G236A transition (180297.0003). Flow
cytometry and Western blot analysis indicated that the mutant protein
was expressed at the cell surface at only 20% of the wildtype level.
Cherif-Zahar et al. (1996) provided a diagram of the implication of the
3 mutations in 4 patients with the Rh(null) phenotype of the regulator
type. In the fifth subject with Rh(null) phenotype studied by
Cherif-Zahar et al. (1996), all attempts to amplify the Rh50 transcript
were unsuccessful, although Rh, CD47, and LW sequences were easily
amplified and sequenced from reticulocyte RNAs. This suggested that the
Rh50 gene was transcriptionally silent in this variant, as had been
observed in 1 allele of the subject with the deletion of nucleotide
1086. Findings in these cases indicated to the authors that Rh antigens
are significantly expressed only when Rh50 proteins are present.
Cherif-Zahar et al. (1996) stated, however, that the converse is not
true; a small amount of Rh50 may reach the cell surface in the absence
of Rh proteins as indicated by the Rh(null) variant of the silent type.
The identification of different Rh50 mutations may account for the well
known heterogeneity of Rh(null) individuals classified as regulator and
Rh(mod) types.
Huang et al. (1998) described compound heterozygosity for 2 mutations in
the Rh50 glycoprotein gene. An 836G-A mutation in exon 6 resulted in a
gly279-to-glu substitution, changing a central amino acid of the
transmembrane segment 9. While cDNA analysis showed expression of the
836A allele only, genomic studies showed the presence of both 836A and
836G alleles. A detailed analysis of gene organization led to the
identification in the 836G allele of a defective donor splice site,
caused by a G-to-A mutation in the invariant GT element of the splice
donor site of intron 1.
The Rh(mod) syndrome is a rare genetic disorder thought to result from
mutations at a 'modifier' separate from the suppressor underlying the
regulator type of Rh(null) disease, i.e., the RHAG gene. Huang et al.
(1999) studied this disorder in a Jewish family with a consanguineous
background and analyzed RH and RHAG, the 2 loci that control Rh-antigen
expression and Rh-complex assembly. Despite the presence of a d
(D-negative) haplotype, no other gross alteration was found at the RH
locus, and cDNA sequencing showed a normal structure of D, Ce, and ce Rh
transcripts in family members. However, analysis of the RHAG transcript
identified a single G-to-T transversion in the initiation codon, causing
a missense amino acid change: ATG (met) to ATT (ile) (180297.0007).
EVOLUTION
Heitman and Agre (2000) diagrammed the phylogenetic tree of multiple
sequences from human Rh blood group antigens, human Rh glycoproteins,
nonhuman sequences with Rh homology, and ammonium transporters from
yeast, bacteria, plants, and worms.
*FIELD* AV
.0001
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, CCTC-TO-GA, NT154
In 2 apparently unrelated subjects originating from South Africa and
showing the Rh(null) phenotype of the regulator type (268150),
Cherif-Zahar et al. (1996) found that nucleotide 154-157 was changed
from CCTC to GA (a 2-bp transversion and a 2-bp deletion), introducing a
frameshift after the codon for tyrosine-51 and resulting in a premature
stop codon at codon 107.
.0002
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, 1-BP DEL, 1086A
In a subject with Rh(null) of the regulator type (268150), Cherif-Zahar
et al. (1996) found heterozygosity for a deletion of adenine-1086 which
introduced a frameshift after the codon for alanine-362 and resulted in
a premature stop codon at codon 376.
.0003
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, SER79ASN
In a subject with Rh(null) of the 'mod' type (268150), Cherif-Zahar et
al. (1996) found a missense mutation, ser79 to asn, caused by a G-to-A
transition at nucleotide 236. The other allele was apparently silent.
.0004
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, GLY279GLU
Hyland et al. (1998) reported molecular findings in the case of an
Rh(null) (268150) individual, Y.T., for whom the regulator or amorph
type had never been formally documented, although the donor's cells were
used in several biochemical studies. Preliminary family studies showed
that functional D and C antigens were transmitted from Y.T. to 3
children, suggesting that Y.T. belonged to the regulator type. Molecular
studies showed that Y.T. inherited the mutation from her mother and was
a compound heterozygote (composite heterozygote in the terminology of
Hyland et al., 1998), carrying 1 mutant Rh50 allele and 1
transcriptionally silent Rh50 allele. The Rh50 mRNA was found to contain
an 836G-A transition yielding a missense and nonconservative
gly279-to-glu (G279E) amino acid substitution within a predicted
hydrophobic domain of the membrane protein. Y.T. was found by study of
genomic DNA to be carrying both an 836A allele and an 836G allele but
only the 836A sequence was represented in cDNA, indicating that the 836G
allele was silent.
Huang et al. (1998) demonstrated compound heterozygosity of the Rh50
gene as the basis of the Rh(null) phenotype. One mutation was an 836G-A
mutation resulting in a missense change, gly279 to glu, in exon 6. The
other mutation was a change of the invariant GT element of the splice
donor site of intron 1 to AT. The blood sample in this case was from a
female proband (Y.T.) of Australian origin. Serologic tests confirmed
the null status of Rh antigens (D-C-E-c-e- and Rh17-).
.0005
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, IVS1, G-A, +1
See 180297.0004 and Huang et al. (1998). The same mutation was found by
Cherif-Zahar et al. (1998) in homozygous state in a patient in
California with Rh(null) of the regulator type (268150).
.0006
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, IVS6, G-A, -1
Cherif-Zahar et al. (1998) described splicing mutations in the Rh50 gene
in 2 unrelated patients with the 'typical Rh(null) syndrome' (268150).
The first mutation affected the invariant G residue of the 3-prime
acceptor splice site of intron 6, causing the skipping of the downstream
exon and the premature termination of translation. The second mutation
occurred at the first base of the 5-prime donor splice site of intron 1
(180297.0005). Both of these mutations were found in homozygous state.
.0007
RH-MOD SYNDROME
RHAG, MET1ILE
In a Jewish family of Russian origin with a consanguineous background,
Huang et al. (1999) found that the basis of the Rh(mod) syndrome was a
met-to-ile mutation in the initiation codon of the RHAG transcript. This
point mutation occurred in the genomic region spanning exon 1 of RHAG.
The presence of the mutation in the mother and 2 children was confirmed
by SSCP analysis. Although blood typing showed a very weak expression of
Rh antigens, immunoblotting barely detected the Rh proteins in Rh(mod)
membrane. In vitro transcription-coupled translation assays showed that
the initiator mutants of Rh(mod), but not those of the wildtype, could
be translated from ATG codons downstream. The findings pointed to
incomplete penetrance of the Rh(mod) mutation, in the form of 'leaky'
translation, leading to some posttranslational defects affecting the
structure, interaction, and processing of Rh50 glycoprotein. The mother
in this pedigree (S.M.) and her brother (S.S.) were first described as
cases of Rh(null). S.M. had a well-compensated hemolytic anemia, whereas
S.S. had a normal hematologic count with numerous spherocytes and
stomatocytes after splenectomy. S.M. was found to be homozygous for the
mutation; SS was deceased at the time of study. The 2 children of S.M.
were heterozygotes.
.0008
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, IVS7, G-A, +1
In 1 patient with Rh-null disease of the regulator type (268150), Huang
(1998) detected a shortened Rh50 transcript lacking the sequence of exon
7. They identified a G-to-A transition at the +1 site of IVS7 in
homozygosity in this patient. This splicing mutation caused not only a
total skipping of exon 7 but also a frameshift and premature chain
termination. Thus, the deduced translation product contained 351 instead
of 409 amino acids, with an entirely different C-terminal sequence
following thr315.
.0009
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, VAL270ILE AND GLY280ARG
Huang et al. (1999) demonstrated that a Japanese patient with Rh-null
hemolytic anemia of the regulator type (268150) was homozygous for 2 cis
mutations in the RHAG gene: in exon 6, G-to-A transitions, GTT to ATT
and GGA to AGA, which caused val270-to-ile and gly280-to-arg
substitutions, respectively.
.0010
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, GLY380VAL
In a Japanese patient with Rh-null hemolytic anemia of the regulator
type (268150), Huang et al. (1999) identified a G-to-T transversion in
exon 9 of the RHAG gene, converting GGT (gly) to GTT (val) at codon 380
in the transmembrane-12 segment. The transversion, which was located at
the +1 position of exon 9, had also affected pre-mRNA splicing and
caused partial exon skipping. Despite a structurally normal Rh antigen
locus, hemagglutination and immunoblotting showed no expression of Rh
antigens or proteins.
*FIELD* RF
1. Cherif-Zahar, B.; Matassi, G.; Raynal, V.; Gane, P.; Delaunay,
J.; Arrizabalaga, B.; Cartron, J.-P.: Rh-deficiency of the regulator
type caused by splicing mutations in the human RH50 gene. Blood 92:
2535-2540, 1998.
2. Cherif-Zahar, B.; Raynal, V.; Gane, P.; Mattei, M.-G.; Bailly,
P.; Gibbs, B.; Colin, Y.; Cartron, J.-P.: Candidate gene acting as
a suppressor of the RH locus in most cases of Rh-deficiency. Nature
Genet. 12: 168-173, 1996.
3. Heitman, J.; Agre, P.: A new face of the rhesus antigen. Nature
Genet. 26: 258-259, 2000.
4. Huang, C.-H.: The human Rh50 glycoprotein gene: structural organization
and associated splicing defect resulting in Rh-null disease. J. Biol.
Chem. 273: 2207-2213, 1998.
5. Huang, C.-H.; Cheng, G.; Liu, Z.; Chen, Y.; Reid, M. E.; Halverson,
G.; Okubo, Y.: Molecular basis for Rh-null syndrome: identification
of three new missense mutations in the Rh50 glycoprotein gene. Am.
J. Hemat. 62: 25-32, 1999.
6. Huang, C.-H.; Cheng, G.-J.; Reid, M. E.; Chen, Y.: Rh(mod) syndrome:
a family study of the translation-initiator mutation in the Rh50 glycoprotein
gene. Am. J. Hum. Genet. 64: 108-117, 1999.
7. Huang, C.-H.; Liu, Z.; Cheng, G.; Chen, Y.: Rh50 glycoprotein
gene and Rh(null) disease: a silent splice donor is trans to a gly279-to-glu
missense mutation in the conserved transmembrane segment. Blood 92:
1776-1784, 1998.
8. Hyland, C. A.; Cherif-Zahar, B.; Cowley, N.; Raynal, V.; Parkes,
J.; Saul, A.; Cartron, J. P.: A novel single missense mutation identified
along the RH50 gene in a composite heterozygous Rh(null) blood donor
of the regulator type. Blood 91: 1458-1463, 1998.
9. Khademi, S.; O'Connell, J., III; Remis, J.; Robles-Colmenares,
Y.; Miercke, L. J. W.; Stroud, R. M.: Mechanism of ammonia transport
by Amt/MEP/Rh: Structure of AmtB at 1.35 A. Science 305: 1587-1594,
2004.
10. Marini, A.-M.; Matassi, G.; Raynal, V.; Andre, B.; Cartron, J.-P.;
Cherif-Zahar, B.: The human Rhesus-associated RhAG protein and a
kidney homologue promote ammonium transport in yeast. Nature Genet. 26:
341-344, 2000.
11. Marini, A. M.; Urrestarazu, A.; Beauwens, R.; Andre, B.: The
Rh (rhesus) blood polypeptides are related to NH4+ transporters. Trends
Biochem. Sci. 22: 460-461, 1997.
12. Matassi, G.; Cherif-Zahar, B.; Raynal, V.; Rouger, P.; Cartron,
J. P.: Organization of the human RH50A gene (RHAG) and evolution
of base composition of the RH gene family. Genomics 47: 286-293,
1998.
13. Ridgwell, K.; Spurr, N. K.; Laguda, B.; MacGeoch, C.; Avent, N.
D.; Tanner, M. J.: Isolation of cDNA clones for a 50 kDa glycoprotein
of the human erythrocyte membrane associated with Rh (rhesus) blood-group
antigen expression. Biochem. J. 287: 223-228, 1992.
14. Ripoche, P.; Bertrand, O.; Gane, P.; Birkenmeier, C.; Colin, Y.;
Cartron, J.-P.: Human Rhesus-associated glycoprotein mediates facilitated
transport of NH3 into red blood cells. Proc. Nat. Acad. Sci. 101:
17222-17227, 2004.
15. Westhoff, C. M.; Ferreri-Jacobia, M.; Mak, D.-O. D.; Foskett,
J. K.: Identification of the erythrocyte Rh blood group glycoprotein
as a mammalian ammonium transporter. J. Biol. Chem. 277: 12499-12502,
2002.
*FIELD* CN
Patricia A. Hartz - updated: 2/17/2005
Ada Hamosh - updated: 9/28/2004
Victor A. McKusick - updated: 5/13/2002
Victor A. McKusick - updated: 12/4/2000
Victor A. McKusick - updated: 10/27/2000
Ada Hamosh - updated: 9/25/2000
Victor A. McKusick - updated: 2/9/1999
Victor A. McKusick - updated: 11/13/1998
Victor A. McKusick - updated: 10/13/1998
Victor A. McKusick - updated: 3/31/1998
*FIELD* CD
Victor A. McKusick: 9/16/1993
*FIELD* ED
carol: 07/14/2011
mgross: 2/17/2005
alopez: 10/4/2004
tkritzer: 9/28/2004
alopez: 10/21/2002
alopez: 5/21/2002
terry: 5/13/2002
mcapotos: 12/19/2000
mcapotos: 12/15/2000
terry: 12/4/2000
joanna: 11/1/2000
alopez: 10/31/2000
terry: 10/27/2000
alopez: 10/3/2000
terry: 9/25/2000
carol: 2/14/1999
terry: 2/9/1999
carol: 11/13/1998
terry: 11/13/1998
carol: 10/18/1998
terry: 10/13/1998
dkim: 7/30/1998
alopez: 3/31/1998
terry: 3/24/1998
mark: 9/1/1997
mark: 2/1/1996
terry: 1/30/1996
mark: 10/10/1995
mimadm: 3/25/1995
carol: 10/21/1993
carol: 9/21/1993
carol: 9/16/1993
*RECORD*
*FIELD* NO
180297
*FIELD* TI
*180297 RHESUS BLOOD GROUP-ASSOCIATED GLYCOPROTEIN; RHAG
;;RHESUS ASSOCIATED POLYPEPTIDE, 50-KD; RH50A;;
read moreRH2
*FIELD* TX
DESCRIPTION
The Rh blood group antigens (111700) are associated with human
erythrocyte membrane proteins of approximately 30 kD, the so-called Rh30
polypeptides. Heterogeneously glycosylated membrane proteins of 50 and
45 kD, the Rh50 glycoproteins, are coprecipitated with the Rh30
polypeptides on immunoprecipitation with anti-Rh-specific mono- and
polyclonal antibodies. The Rh antigens appear to exist as a multisubunit
complex of CD47 (601028), LW (111250), and glycophorin B (111740), and
play a critical role in the Rh50 glycoprotein.
CLONING
Ridgwell et al. (1992) isolated cDNA clones representing a member of the
Rh50 glycoprotein family, the Rh50A glycoprotein. They used PCR with
degenerate primers based on the N-terminal amino acid sequence of the
Rh50 glycoproteins and human genomic DNA as a template. The cDNA clones
containing the full coding sequence of the Rh50A glycoprotein predicted
a 409-amino acid N-glycosylated membrane protein with up to 12
transmembrane domains. It showed clear similarity to the Rh30A protein
in both amino acid sequence and predicted topology. The findings were
considered consistent with the possibility that the Rh30 and Rh50 groups
of proteins are different subunits of an oligomeric complex which is
likely to have a transport or channel function in the erythrocyte
membrane.
GENE STRUCTURE
Huang (1998) determined the intron/exon structure of the Rh50 gene. The
structure of the Rh50 gene is nearly identical to that of the Rh30 gene.
Of the 10 exons assigned, conservation of size and sequence was confined
mainly to the region from exons 2 to 9, suggesting that RH50 and RH30
were formed as 2 separate genetic loci from a common ancestor via a
transchromosomal insertion event.
GENE FUNCTION
The absence of the RhAG and Rh proteins in Rh(null) individuals leads to
morphologic and functional abnormalities of erythrocytes, known as the
Rh-deficiency syndrome. The RhAG and Rh polypeptides are
erythroid-specific transmembrane proteins belonging to the same family
(36% identity). Marini et al. (1997) and Matassi et al. (1998) found
significant sequence similarity between the Rh family proteins,
especially RhAG, and Mep/Amt ammonium transporters. Marini et al. (2000)
showed that RhAG and also RhGK (605381), a human homolog expressed in
kidney cells only, function as ammonium transport proteins when
expressed in yeast. Both specifically complement the growth defect of a
yeast mutant deficient in ammonium uptake. Moreover, ammonium efflux
assays and growth tests in the presence of toxic concentrations of the
analog methylammonium indicated that RhAG and RhGK also promote ammonium
export. The results provided the first experimental evidence for a
direct role of RhAG and RhGK in ammonium transport and were of high
interest, because no specific ammonium transport system had been
previously characterized in human.
Westhoff et al. (2002) used the Xenopus oocyte expression system to
determine the function of Rh and RhAG proteins. They demonstrated
expression of fully glycosylated RhAG protein and provided the first
direct evidence for RhAG-mediated ammonium uptake.
Ripoche et al. (2004) assayed transport in red blood cells and ghosts
from human and mouse genetic variants with defects in RhAG or other
components of the Rh complex. They found that the rate constant for
methylammonium or ammonium transport directly correlated with the amount
of functional RhAG and was unaffected by the amount of Rh, CD47, or LW.
BIOCHEMICAL FEATURES
- Crystal Structure
Khademi et al. (2004) determined the crystal structure of the ammonia
channel from the Amt/MEP/Rh protein superfamily at 1.35-angstrom
resolution. The channel spans the membrane 11 times. Two structurally
similar halves span the membrane with opposite polarity. Structures with
and without ammonia or methyl ammonia show a vestibule that recruits
NH4+/NH3, a binding site for NH4+, and a 20-angstrom-long hydrophobic
channel that lowers the NH4+ pKa to below 6 and conducts NH3. Favorable
interactions for NH3 were seen within the channel and used conserved
histidines. Khademi et al. (2004) concluded that reconstitution of AmtB
into vesicles shows that AmtB conducts uncharged ammonia.
MAPPING
By analysis of somatic cell hybrids, Ridgwell et al. (1992) mapped the
Rh50A gene to 6p21-qter, indicating that genetic differences in the
genes for the Rh30 polypeptide, rather than the Rh50 genes, specify the
major polymorphic forms of the Rh antigens, because the Rh blood group
maps to chromosome 1, not chromosome 6. Cherif-Zahar et al. (1996)
carried out 5 regional assignments of the Rh50 gene by isotopic in situ
hybridization and concluded that it maps to 6p21.1-p11, probably 6p12.
MOLECULAR GENETICS
The Rh(null) types, Rh(null) regulator and Rh(mod) (in which trace
amounts of Rh antigens are found), exhibit the same clinical
abnormalities associated with chronic hemolytic anemia, stomatocytosis
and spherocytosis, reduced osmotic fragility, and increased cation
permeability. In addition, Rh(null) membranes characteristically have
hyperactive membrane ATPases and reduced red cell cation and water
content. Cherif-Zahar et al. (1996) proposed that mutant alleles of Rh50
are suppressors of the RH locus and account for most cases of
Rh-deficiency. They analyzed the genes and transcripts encoding Rh,
CD47, and Rh50 proteins in 5 unrelated Rh(null) cases and identified 3
types of Rh50 mutations in the transcripts and genomic DNA from them.
The first mutation was observed in homozygous state in 2 apparently
unrelated individuals originating from South Africa and involved a 2-bp
transversion and a 2-bp deletion, introducing a frameshift after the
codon for tyrosine-51 (180297.0001). They stated that, since the Rh50
glycoprotein was not detectable by flow cytometry or Western blot
analysis on the red cells of these 2 individuals, it is likely that the
predicted truncated Rh50 polypeptide (107 residues instead of 409) from
these variants was degraded and not inserted into the membrane. The
second mutation consisted of a single base deletion at nucleotide 1086,
resulting in a frameshift after the codon for alanine-362 (180297.0002).
The deduced Rh50 protein was 376 amino acids long (instead of 409) and
included 14 novel residues at its C terminus. Surprisingly, this
mutation was found in the heterozygous state by RFLP analysis. Attempts
to amplify the product of the second Rh50 allele were unsuccessful,
strongly suggesting that this transcript was either absent or poorly
represented in reticulocytes. Cherif-Zahar et al. (1996) assumed that
this allele was transcriptionally silent and that the subjects
erythrocytes should carry half the normal dose of a truncated Rh50
protein. Interestingly, flow cytometry and Western blot analysis
indicated a complete absence of the protein. They noted that RH and Rh50
proteins interact with each other and suggested that the C terminus of
Rh50 may stabilize this interaction or may represent a site of
protein-protein interaction critical for cell surface expression. The
third Rh50 mutation identified by Cherif-Zahar et al. (1996) was a
missense mutation caused by a G236A transition (180297.0003). Flow
cytometry and Western blot analysis indicated that the mutant protein
was expressed at the cell surface at only 20% of the wildtype level.
Cherif-Zahar et al. (1996) provided a diagram of the implication of the
3 mutations in 4 patients with the Rh(null) phenotype of the regulator
type. In the fifth subject with Rh(null) phenotype studied by
Cherif-Zahar et al. (1996), all attempts to amplify the Rh50 transcript
were unsuccessful, although Rh, CD47, and LW sequences were easily
amplified and sequenced from reticulocyte RNAs. This suggested that the
Rh50 gene was transcriptionally silent in this variant, as had been
observed in 1 allele of the subject with the deletion of nucleotide
1086. Findings in these cases indicated to the authors that Rh antigens
are significantly expressed only when Rh50 proteins are present.
Cherif-Zahar et al. (1996) stated, however, that the converse is not
true; a small amount of Rh50 may reach the cell surface in the absence
of Rh proteins as indicated by the Rh(null) variant of the silent type.
The identification of different Rh50 mutations may account for the well
known heterogeneity of Rh(null) individuals classified as regulator and
Rh(mod) types.
Huang et al. (1998) described compound heterozygosity for 2 mutations in
the Rh50 glycoprotein gene. An 836G-A mutation in exon 6 resulted in a
gly279-to-glu substitution, changing a central amino acid of the
transmembrane segment 9. While cDNA analysis showed expression of the
836A allele only, genomic studies showed the presence of both 836A and
836G alleles. A detailed analysis of gene organization led to the
identification in the 836G allele of a defective donor splice site,
caused by a G-to-A mutation in the invariant GT element of the splice
donor site of intron 1.
The Rh(mod) syndrome is a rare genetic disorder thought to result from
mutations at a 'modifier' separate from the suppressor underlying the
regulator type of Rh(null) disease, i.e., the RHAG gene. Huang et al.
(1999) studied this disorder in a Jewish family with a consanguineous
background and analyzed RH and RHAG, the 2 loci that control Rh-antigen
expression and Rh-complex assembly. Despite the presence of a d
(D-negative) haplotype, no other gross alteration was found at the RH
locus, and cDNA sequencing showed a normal structure of D, Ce, and ce Rh
transcripts in family members. However, analysis of the RHAG transcript
identified a single G-to-T transversion in the initiation codon, causing
a missense amino acid change: ATG (met) to ATT (ile) (180297.0007).
EVOLUTION
Heitman and Agre (2000) diagrammed the phylogenetic tree of multiple
sequences from human Rh blood group antigens, human Rh glycoproteins,
nonhuman sequences with Rh homology, and ammonium transporters from
yeast, bacteria, plants, and worms.
*FIELD* AV
.0001
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, CCTC-TO-GA, NT154
In 2 apparently unrelated subjects originating from South Africa and
showing the Rh(null) phenotype of the regulator type (268150),
Cherif-Zahar et al. (1996) found that nucleotide 154-157 was changed
from CCTC to GA (a 2-bp transversion and a 2-bp deletion), introducing a
frameshift after the codon for tyrosine-51 and resulting in a premature
stop codon at codon 107.
.0002
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, 1-BP DEL, 1086A
In a subject with Rh(null) of the regulator type (268150), Cherif-Zahar
et al. (1996) found heterozygosity for a deletion of adenine-1086 which
introduced a frameshift after the codon for alanine-362 and resulted in
a premature stop codon at codon 376.
.0003
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, SER79ASN
In a subject with Rh(null) of the 'mod' type (268150), Cherif-Zahar et
al. (1996) found a missense mutation, ser79 to asn, caused by a G-to-A
transition at nucleotide 236. The other allele was apparently silent.
.0004
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, GLY279GLU
Hyland et al. (1998) reported molecular findings in the case of an
Rh(null) (268150) individual, Y.T., for whom the regulator or amorph
type had never been formally documented, although the donor's cells were
used in several biochemical studies. Preliminary family studies showed
that functional D and C antigens were transmitted from Y.T. to 3
children, suggesting that Y.T. belonged to the regulator type. Molecular
studies showed that Y.T. inherited the mutation from her mother and was
a compound heterozygote (composite heterozygote in the terminology of
Hyland et al., 1998), carrying 1 mutant Rh50 allele and 1
transcriptionally silent Rh50 allele. The Rh50 mRNA was found to contain
an 836G-A transition yielding a missense and nonconservative
gly279-to-glu (G279E) amino acid substitution within a predicted
hydrophobic domain of the membrane protein. Y.T. was found by study of
genomic DNA to be carrying both an 836A allele and an 836G allele but
only the 836A sequence was represented in cDNA, indicating that the 836G
allele was silent.
Huang et al. (1998) demonstrated compound heterozygosity of the Rh50
gene as the basis of the Rh(null) phenotype. One mutation was an 836G-A
mutation resulting in a missense change, gly279 to glu, in exon 6. The
other mutation was a change of the invariant GT element of the splice
donor site of intron 1 to AT. The blood sample in this case was from a
female proband (Y.T.) of Australian origin. Serologic tests confirmed
the null status of Rh antigens (D-C-E-c-e- and Rh17-).
.0005
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, IVS1, G-A, +1
See 180297.0004 and Huang et al. (1998). The same mutation was found by
Cherif-Zahar et al. (1998) in homozygous state in a patient in
California with Rh(null) of the regulator type (268150).
.0006
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, IVS6, G-A, -1
Cherif-Zahar et al. (1998) described splicing mutations in the Rh50 gene
in 2 unrelated patients with the 'typical Rh(null) syndrome' (268150).
The first mutation affected the invariant G residue of the 3-prime
acceptor splice site of intron 6, causing the skipping of the downstream
exon and the premature termination of translation. The second mutation
occurred at the first base of the 5-prime donor splice site of intron 1
(180297.0005). Both of these mutations were found in homozygous state.
.0007
RH-MOD SYNDROME
RHAG, MET1ILE
In a Jewish family of Russian origin with a consanguineous background,
Huang et al. (1999) found that the basis of the Rh(mod) syndrome was a
met-to-ile mutation in the initiation codon of the RHAG transcript. This
point mutation occurred in the genomic region spanning exon 1 of RHAG.
The presence of the mutation in the mother and 2 children was confirmed
by SSCP analysis. Although blood typing showed a very weak expression of
Rh antigens, immunoblotting barely detected the Rh proteins in Rh(mod)
membrane. In vitro transcription-coupled translation assays showed that
the initiator mutants of Rh(mod), but not those of the wildtype, could
be translated from ATG codons downstream. The findings pointed to
incomplete penetrance of the Rh(mod) mutation, in the form of 'leaky'
translation, leading to some posttranslational defects affecting the
structure, interaction, and processing of Rh50 glycoprotein. The mother
in this pedigree (S.M.) and her brother (S.S.) were first described as
cases of Rh(null). S.M. had a well-compensated hemolytic anemia, whereas
S.S. had a normal hematologic count with numerous spherocytes and
stomatocytes after splenectomy. S.M. was found to be homozygous for the
mutation; SS was deceased at the time of study. The 2 children of S.M.
were heterozygotes.
.0008
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, IVS7, G-A, +1
In 1 patient with Rh-null disease of the regulator type (268150), Huang
(1998) detected a shortened Rh50 transcript lacking the sequence of exon
7. They identified a G-to-A transition at the +1 site of IVS7 in
homozygosity in this patient. This splicing mutation caused not only a
total skipping of exon 7 but also a frameshift and premature chain
termination. Thus, the deduced translation product contained 351 instead
of 409 amino acids, with an entirely different C-terminal sequence
following thr315.
.0009
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, VAL270ILE AND GLY280ARG
Huang et al. (1999) demonstrated that a Japanese patient with Rh-null
hemolytic anemia of the regulator type (268150) was homozygous for 2 cis
mutations in the RHAG gene: in exon 6, G-to-A transitions, GTT to ATT
and GGA to AGA, which caused val270-to-ile and gly280-to-arg
substitutions, respectively.
.0010
RH-NULL HEMOLYTIC ANEMIA, REGULATOR TYPE
RHAG, GLY380VAL
In a Japanese patient with Rh-null hemolytic anemia of the regulator
type (268150), Huang et al. (1999) identified a G-to-T transversion in
exon 9 of the RHAG gene, converting GGT (gly) to GTT (val) at codon 380
in the transmembrane-12 segment. The transversion, which was located at
the +1 position of exon 9, had also affected pre-mRNA splicing and
caused partial exon skipping. Despite a structurally normal Rh antigen
locus, hemagglutination and immunoblotting showed no expression of Rh
antigens or proteins.
*FIELD* RF
1. Cherif-Zahar, B.; Matassi, G.; Raynal, V.; Gane, P.; Delaunay,
J.; Arrizabalaga, B.; Cartron, J.-P.: Rh-deficiency of the regulator
type caused by splicing mutations in the human RH50 gene. Blood 92:
2535-2540, 1998.
2. Cherif-Zahar, B.; Raynal, V.; Gane, P.; Mattei, M.-G.; Bailly,
P.; Gibbs, B.; Colin, Y.; Cartron, J.-P.: Candidate gene acting as
a suppressor of the RH locus in most cases of Rh-deficiency. Nature
Genet. 12: 168-173, 1996.
3. Heitman, J.; Agre, P.: A new face of the rhesus antigen. Nature
Genet. 26: 258-259, 2000.
4. Huang, C.-H.: The human Rh50 glycoprotein gene: structural organization
and associated splicing defect resulting in Rh-null disease. J. Biol.
Chem. 273: 2207-2213, 1998.
5. Huang, C.-H.; Cheng, G.; Liu, Z.; Chen, Y.; Reid, M. E.; Halverson,
G.; Okubo, Y.: Molecular basis for Rh-null syndrome: identification
of three new missense mutations in the Rh50 glycoprotein gene. Am.
J. Hemat. 62: 25-32, 1999.
6. Huang, C.-H.; Cheng, G.-J.; Reid, M. E.; Chen, Y.: Rh(mod) syndrome:
a family study of the translation-initiator mutation in the Rh50 glycoprotein
gene. Am. J. Hum. Genet. 64: 108-117, 1999.
7. Huang, C.-H.; Liu, Z.; Cheng, G.; Chen, Y.: Rh50 glycoprotein
gene and Rh(null) disease: a silent splice donor is trans to a gly279-to-glu
missense mutation in the conserved transmembrane segment. Blood 92:
1776-1784, 1998.
8. Hyland, C. A.; Cherif-Zahar, B.; Cowley, N.; Raynal, V.; Parkes,
J.; Saul, A.; Cartron, J. P.: A novel single missense mutation identified
along the RH50 gene in a composite heterozygous Rh(null) blood donor
of the regulator type. Blood 91: 1458-1463, 1998.
9. Khademi, S.; O'Connell, J., III; Remis, J.; Robles-Colmenares,
Y.; Miercke, L. J. W.; Stroud, R. M.: Mechanism of ammonia transport
by Amt/MEP/Rh: Structure of AmtB at 1.35 A. Science 305: 1587-1594,
2004.
10. Marini, A.-M.; Matassi, G.; Raynal, V.; Andre, B.; Cartron, J.-P.;
Cherif-Zahar, B.: The human Rhesus-associated RhAG protein and a
kidney homologue promote ammonium transport in yeast. Nature Genet. 26:
341-344, 2000.
11. Marini, A. M.; Urrestarazu, A.; Beauwens, R.; Andre, B.: The
Rh (rhesus) blood polypeptides are related to NH4+ transporters. Trends
Biochem. Sci. 22: 460-461, 1997.
12. Matassi, G.; Cherif-Zahar, B.; Raynal, V.; Rouger, P.; Cartron,
J. P.: Organization of the human RH50A gene (RHAG) and evolution
of base composition of the RH gene family. Genomics 47: 286-293,
1998.
13. Ridgwell, K.; Spurr, N. K.; Laguda, B.; MacGeoch, C.; Avent, N.
D.; Tanner, M. J.: Isolation of cDNA clones for a 50 kDa glycoprotein
of the human erythrocyte membrane associated with Rh (rhesus) blood-group
antigen expression. Biochem. J. 287: 223-228, 1992.
14. Ripoche, P.; Bertrand, O.; Gane, P.; Birkenmeier, C.; Colin, Y.;
Cartron, J.-P.: Human Rhesus-associated glycoprotein mediates facilitated
transport of NH3 into red blood cells. Proc. Nat. Acad. Sci. 101:
17222-17227, 2004.
15. Westhoff, C. M.; Ferreri-Jacobia, M.; Mak, D.-O. D.; Foskett,
J. K.: Identification of the erythrocyte Rh blood group glycoprotein
as a mammalian ammonium transporter. J. Biol. Chem. 277: 12499-12502,
2002.
*FIELD* CN
Patricia A. Hartz - updated: 2/17/2005
Ada Hamosh - updated: 9/28/2004
Victor A. McKusick - updated: 5/13/2002
Victor A. McKusick - updated: 12/4/2000
Victor A. McKusick - updated: 10/27/2000
Ada Hamosh - updated: 9/25/2000
Victor A. McKusick - updated: 2/9/1999
Victor A. McKusick - updated: 11/13/1998
Victor A. McKusick - updated: 10/13/1998
Victor A. McKusick - updated: 3/31/1998
*FIELD* CD
Victor A. McKusick: 9/16/1993
*FIELD* ED
carol: 07/14/2011
mgross: 2/17/2005
alopez: 10/4/2004
tkritzer: 9/28/2004
alopez: 10/21/2002
alopez: 5/21/2002
terry: 5/13/2002
mcapotos: 12/19/2000
mcapotos: 12/15/2000
terry: 12/4/2000
joanna: 11/1/2000
alopez: 10/31/2000
terry: 10/27/2000
alopez: 10/3/2000
terry: 9/25/2000
carol: 2/14/1999
terry: 2/9/1999
carol: 11/13/1998
terry: 11/13/1998
carol: 10/18/1998
terry: 10/13/1998
dkim: 7/30/1998
alopez: 3/31/1998
terry: 3/24/1998
mark: 9/1/1997
mark: 2/1/1996
terry: 1/30/1996
mark: 10/10/1995
mimadm: 3/25/1995
carol: 10/21/1993
carol: 9/21/1993
carol: 9/16/1993
MIM
268150
*RECORD*
*FIELD* NO
268150
*FIELD* TI
#268150 RH-NULL, REGULATOR TYPE; RHN
RH DEFICIENCY SYNDROME, INCLUDED;;
RH-NULL DISEASE, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
Rh deficiency syndrome is caused by mutations in the Rh50 gene (180297).
Red cells lacking Rh blood group antigens were first described by Vos et
al. (1961). Rh-null, no Rh antigen on the red cells, exists in two
forms. One is probably due to homozygosity for an amorph allele at the
Rh locus (111700). The other is due to homozygosity for a mutation at a
locus independent of the Rh locus. The latter form, called the regulator
type, is analogous to the Bombay type (211100). Race and Sanger (1975)
pointed out that the regulator cannot be part of the Rh complex: in a
family with consanguineous parents, both CDe-cde, one Rh-null sib had to
be genetically CDe-cde, because of her children's Rh blood types. Had
the regulator been part of, or closely linked to, the Rh locus, she
would have been either CDe-CDe or cde-cde. There is apparently
heterogeneity in the regulator type of Rh-null. Chown et al. (1972)
described a genetic modifier for the Rh blood groups. Heterozygotes
showed weakening of reaction of all Rh antigens. A homozygote also had a
weak reaction with anti-U and anti-S, compensated hemolytic anemia, and
unconjugated hyperbilirubinemia. The modifier was clearly not linked
with the Rh locus. The authors compared this 'modified' phenotype
(Rh-mod) with the Rh-null phenotypes that have been described. When
homozygous, both the suppressor gene and the Rh amorphic gene (Rh null)
result in anemia, shortened red cell survival, increased fragility,
stomatocytes, and increased fetal hemoglobin. Rh antigens constitute
part of the red cell membrane. Nash and Shojania (1987) restudied the
woman reported by Chown et al. (1972). The b(51)Cr red cell survival
studies showed the spleen to be the preferential site of red cell
destruction, and splenectomy produced a dramatic improvement in red cell
survival. Her parents were third cousins. Nash and Shojania (1987) found
reports of 32 cases of Rh-null and 10 cases of Rh-mod. The incidence of
the Rh-null phenotype was quoted as being about 1 in 6 million. In most
instances the propositi are the offspring of consanguineous marriages.
The term 'Rh deficiency syndrome' takes in both the Rh-null and the
Rh-mod phenotypes when they are associated with hemolytic anemia. By
testing hybrids containing various deletions of chromosome 3, Miller et
al. (1987) described an IgM monoclonal antibody, 1D8, that recognizes an
antigen coded by a gene that is located in the region 3cen-q22. The
monoclonal antibody has been designated MER6.
In a comprehensive review of the molecular genetics of the Rh blood
group antigens, Cartron (1994) indicated that all Rh-null phenotypes
that had been investigated appeared to result from transcriptional
regulatory mechanisms that were not yet understood. In addition to Rh
proteins, several other glycoproteins, such as CD47, glycophorin B,
Duffy, and LW, are absent or severely decreased on these cells. These
findings suggested that the Rh proteins are assembled into a multimeric
complex with these glycoproteins.
Cherif-Zahar et al. (1996) showed that the Rh-null phenotype, which is
unlinked to the Rh locus, is caused by mutations in the RH50A gene
(180297), located on chromosome 6p. The cell-surface antigen encoded by
3q and not expressed in Rh(null) cells probably has no significance to
the pathogenesis of the Rh deficiency syndrome. They noted that a number
of components of the multi-subunit complex composed of Rh polypeptides
and associated glycoproteins are absent in Rh(null) cells.
*FIELD* SA
Bhatia et al. (1974); Chown et al. (1971); Schmidt and Vos (1967);
Sistonen et al. (1985); Sturgeon (1970)
*FIELD* RF
1. Bhatia, H. M.; Sathe, M.; Gandhi, S.; Mehta, B. C.; Levine, P.
: Differences between Bombay and Rh null phenotypes. Vox Sang. 26:
272-275, 1974.
2. Cartron, J.-P.: Defining the Rh blood group antigens: biochemistry
and molecular genetics. Blood Rev. 8: 199-212, 1994.
3. Cherif-Zahar, B.; Raynal, V.; Gane, P.; Mattei, M.-G.; Bailly,
P.; Gibbs, B.; Colin, Y.; Cartron, J.-P.: Candidate gene acting as
a suppressor of the RH locus in most cases of Rh-deficiency. Nature
Genet. 12: 168-173, 1996.
4. Chown, B.; Lewis, M.; Kaita, H.; Lowen, B.: A new cause of haemolytic
anaemia? (Letter) Lancet 297: 396 only, 1971. Note: Originally Volume
I.
5. Chown, B.; Lewis, M.; Kaita, H.; Lowen, B.: An unlinked modifier
of Rh blood groups: effects when heterozygous and when homozygous. Am.
J. Hum. Genet. 24: 623-637, 1972.
6. Miller, Y. E.; Daniels, G. L.; Jones, C.; Palmer, D. K.: Identification
of a cell-surface antigen produced by a gene on human chromosome 3
(cen-q22) and not expressed by Rh(null) cells. Am. J. Hum. Genet. 41:
1061-1070, 1987.
7. Nash, R.; Shojania, A. M.: Hematological aspect of Rh deficiency
syndrome: a case report and a review of the literature. Am. J. Hemat. 24:
267-275, 1987.
8. Race, R. R.; Sanger, R.: Blood Groups in Man. Oxford: Blackwell
(pub.) (6th ed.): 1975. Pp. 220-227.
9. Schmidt, P. J.; Vos, G. H.: Multiple phenotypic abnormalities
associated with Rh-null. Vox Sang. 13: 18-20, 1967.
10. Sistonen, P.; Palosuo, T.; Snellman, A.: Identical twins with
the Rh(null) phenotype of the regulator type in a Finnish Lapp family. Vox
Sang. 48: 174-177, 1985.
11. Sturgeon, P.: Hematological observations on the anemia associated
with the blood type Rh null. Blood 36: 310-320, 1970.
12. Vos, G. H.; Vos, D.; Kirk, R. L.; Sanger, R.: A sample of blood
with no detectable Rh antigens. Lancet 277: 14-15, 1961. Note: Originally
Volume I.
*FIELD* CS
Heme:
Hemolytic anemia;
Rh-null
Skin:
Jaundice
Lab:
No red cell Rh blood group antigens;
Weak reaction with anti-U and anti-S;
Unconjugated hyperbilirubinemia;
Shortened red cell survival;
Increased red cell fragility,;
Stomatocytosis;
Increased fetal hemoglobin
Inheritance:
Autosomal recessive;
a suppressor gene form and the Rh amorphic gene (Rh null) form
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
terry: 03/25/2009
terry: 8/26/2008
mark: 2/1/1996
terry: 1/30/1996
carol: 2/13/1995
davew: 8/19/1994
warfield: 4/4/1994
mimadm: 3/12/1994
carol: 12/2/1992
supermim: 3/17/1992
*RECORD*
*FIELD* NO
268150
*FIELD* TI
#268150 RH-NULL, REGULATOR TYPE; RHN
RH DEFICIENCY SYNDROME, INCLUDED;;
RH-NULL DISEASE, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
Rh deficiency syndrome is caused by mutations in the Rh50 gene (180297).
Red cells lacking Rh blood group antigens were first described by Vos et
al. (1961). Rh-null, no Rh antigen on the red cells, exists in two
forms. One is probably due to homozygosity for an amorph allele at the
Rh locus (111700). The other is due to homozygosity for a mutation at a
locus independent of the Rh locus. The latter form, called the regulator
type, is analogous to the Bombay type (211100). Race and Sanger (1975)
pointed out that the regulator cannot be part of the Rh complex: in a
family with consanguineous parents, both CDe-cde, one Rh-null sib had to
be genetically CDe-cde, because of her children's Rh blood types. Had
the regulator been part of, or closely linked to, the Rh locus, she
would have been either CDe-CDe or cde-cde. There is apparently
heterogeneity in the regulator type of Rh-null. Chown et al. (1972)
described a genetic modifier for the Rh blood groups. Heterozygotes
showed weakening of reaction of all Rh antigens. A homozygote also had a
weak reaction with anti-U and anti-S, compensated hemolytic anemia, and
unconjugated hyperbilirubinemia. The modifier was clearly not linked
with the Rh locus. The authors compared this 'modified' phenotype
(Rh-mod) with the Rh-null phenotypes that have been described. When
homozygous, both the suppressor gene and the Rh amorphic gene (Rh null)
result in anemia, shortened red cell survival, increased fragility,
stomatocytes, and increased fetal hemoglobin. Rh antigens constitute
part of the red cell membrane. Nash and Shojania (1987) restudied the
woman reported by Chown et al. (1972). The b(51)Cr red cell survival
studies showed the spleen to be the preferential site of red cell
destruction, and splenectomy produced a dramatic improvement in red cell
survival. Her parents were third cousins. Nash and Shojania (1987) found
reports of 32 cases of Rh-null and 10 cases of Rh-mod. The incidence of
the Rh-null phenotype was quoted as being about 1 in 6 million. In most
instances the propositi are the offspring of consanguineous marriages.
The term 'Rh deficiency syndrome' takes in both the Rh-null and the
Rh-mod phenotypes when they are associated with hemolytic anemia. By
testing hybrids containing various deletions of chromosome 3, Miller et
al. (1987) described an IgM monoclonal antibody, 1D8, that recognizes an
antigen coded by a gene that is located in the region 3cen-q22. The
monoclonal antibody has been designated MER6.
In a comprehensive review of the molecular genetics of the Rh blood
group antigens, Cartron (1994) indicated that all Rh-null phenotypes
that had been investigated appeared to result from transcriptional
regulatory mechanisms that were not yet understood. In addition to Rh
proteins, several other glycoproteins, such as CD47, glycophorin B,
Duffy, and LW, are absent or severely decreased on these cells. These
findings suggested that the Rh proteins are assembled into a multimeric
complex with these glycoproteins.
Cherif-Zahar et al. (1996) showed that the Rh-null phenotype, which is
unlinked to the Rh locus, is caused by mutations in the RH50A gene
(180297), located on chromosome 6p. The cell-surface antigen encoded by
3q and not expressed in Rh(null) cells probably has no significance to
the pathogenesis of the Rh deficiency syndrome. They noted that a number
of components of the multi-subunit complex composed of Rh polypeptides
and associated glycoproteins are absent in Rh(null) cells.
*FIELD* SA
Bhatia et al. (1974); Chown et al. (1971); Schmidt and Vos (1967);
Sistonen et al. (1985); Sturgeon (1970)
*FIELD* RF
1. Bhatia, H. M.; Sathe, M.; Gandhi, S.; Mehta, B. C.; Levine, P.
: Differences between Bombay and Rh null phenotypes. Vox Sang. 26:
272-275, 1974.
2. Cartron, J.-P.: Defining the Rh blood group antigens: biochemistry
and molecular genetics. Blood Rev. 8: 199-212, 1994.
3. Cherif-Zahar, B.; Raynal, V.; Gane, P.; Mattei, M.-G.; Bailly,
P.; Gibbs, B.; Colin, Y.; Cartron, J.-P.: Candidate gene acting as
a suppressor of the RH locus in most cases of Rh-deficiency. Nature
Genet. 12: 168-173, 1996.
4. Chown, B.; Lewis, M.; Kaita, H.; Lowen, B.: A new cause of haemolytic
anaemia? (Letter) Lancet 297: 396 only, 1971. Note: Originally Volume
I.
5. Chown, B.; Lewis, M.; Kaita, H.; Lowen, B.: An unlinked modifier
of Rh blood groups: effects when heterozygous and when homozygous. Am.
J. Hum. Genet. 24: 623-637, 1972.
6. Miller, Y. E.; Daniels, G. L.; Jones, C.; Palmer, D. K.: Identification
of a cell-surface antigen produced by a gene on human chromosome 3
(cen-q22) and not expressed by Rh(null) cells. Am. J. Hum. Genet. 41:
1061-1070, 1987.
7. Nash, R.; Shojania, A. M.: Hematological aspect of Rh deficiency
syndrome: a case report and a review of the literature. Am. J. Hemat. 24:
267-275, 1987.
8. Race, R. R.; Sanger, R.: Blood Groups in Man. Oxford: Blackwell
(pub.) (6th ed.): 1975. Pp. 220-227.
9. Schmidt, P. J.; Vos, G. H.: Multiple phenotypic abnormalities
associated with Rh-null. Vox Sang. 13: 18-20, 1967.
10. Sistonen, P.; Palosuo, T.; Snellman, A.: Identical twins with
the Rh(null) phenotype of the regulator type in a Finnish Lapp family. Vox
Sang. 48: 174-177, 1985.
11. Sturgeon, P.: Hematological observations on the anemia associated
with the blood type Rh null. Blood 36: 310-320, 1970.
12. Vos, G. H.; Vos, D.; Kirk, R. L.; Sanger, R.: A sample of blood
with no detectable Rh antigens. Lancet 277: 14-15, 1961. Note: Originally
Volume I.
*FIELD* CS
Heme:
Hemolytic anemia;
Rh-null
Skin:
Jaundice
Lab:
No red cell Rh blood group antigens;
Weak reaction with anti-U and anti-S;
Unconjugated hyperbilirubinemia;
Shortened red cell survival;
Increased red cell fragility,;
Stomatocytosis;
Increased fetal hemoglobin
Inheritance:
Autosomal recessive;
a suppressor gene form and the Rh amorphic gene (Rh null) form
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
terry: 03/25/2009
terry: 8/26/2008
mark: 2/1/1996
terry: 1/30/1996
carol: 2/13/1995
davew: 8/19/1994
warfield: 4/4/1994
mimadm: 3/12/1994
carol: 12/2/1992
supermim: 3/17/1992