Full text data of CSF2RA
CSF2RA
(CSF2R, CSF2RY)
[Confidence: high (a blood group or CD marker)]
Granulocyte-macrophage colony-stimulating factor receptor subunit alpha; GM-CSF-R-alpha; GMCSFR-alpha; GMR-alpha (CDw116; CD116; Flags: Precursor)
Granulocyte-macrophage colony-stimulating factor receptor subunit alpha; GM-CSF-R-alpha; GMCSFR-alpha; GMR-alpha (CDw116; CD116; Flags: Precursor)
UniProt
P15509
ID CSF2R_HUMAN Reviewed; 400 AA.
AC P15509; A7J003; A8KAM1; B4DW68; J3JS76; J3JS77; O00207; Q14429;
read moreAC Q14430; Q14431; Q16564;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-1990, sequence version 1.
DT 22-JAN-2014, entry version 150.
DE RecName: Full=Granulocyte-macrophage colony-stimulating factor receptor subunit alpha;
DE Short=GM-CSF-R-alpha;
DE Short=GMCSFR-alpha;
DE Short=GMR-alpha;
DE AltName: Full=CDw116;
DE AltName: CD_antigen=CD116;
DE Flags: Precursor;
GN Name=CSF2RA; Synonyms=CSF2R, CSF2RY;
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).
RC TISSUE=Placenta;
RX PubMed=2555171;
RA Gearing D.P., King J.A., Gough N.M., Nicola N.A.;
RT "Expression cloning of a receptor for human granulocyte-macrophage
RT colony-stimulating factor.";
RL EMBO J. 8:3667-3676(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RX PubMed=8144676;
RA Nakagawa Y., Kosugi H., Miyajima A., Arai K., Yokota T.;
RT "Structure of the gene encoding the alpha subunit of the human
RT granulocyte-macrophage colony stimulating factor receptor.
RT Implications for the evolution of the cytokine receptor superfamily.";
RL J. Biol. Chem. 269:10905-10912(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=1715577; DOI=10.1073/pnas.88.17.7744;
RA Crosier K.E., Wong G.G., Mathey-Prevot B., Nathan D.G., Sieff C.A.;
RT "A functional isoform of the human granulocyte/macrophage colony-
RT stimulating factor receptor has an unusual cytoplasmic domain.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:7744-7748(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Placenta;
RX PubMed=2148207; DOI=10.1093/nar/18.23.7178;
RA Ashworth A., Kraft A.;
RT "Cloning of a potentially soluble receptor for human GM-CSF.";
RL Nucleic Acids Res. 18:7178-7178(1990).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RX PubMed=1832774; DOI=10.1073/pnas.88.18.8203;
RA Raines M.A., Liu L., Quan S.G., Joe V., DiPersio J.F., Golde D.W.;
RT "Identification and molecular cloning of a soluble human granulocyte-
RT macrophage colony-stimulating factor receptor.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:8203-8207(1991).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 4 AND 5).
RC TISSUE=Blood;
RX PubMed=8086503; DOI=10.1016/0167-4889(94)90241-0;
RA Hu X., Emanuel P.D., Zuckerman K.S.;
RT "Cloning and sequencing of the cDNAs encoding two alternative
RT splicing-derived variants of the alpha subunit of the granulocyte-
RT macrophage colony-stimulating factor receptor.";
RL Biochim. Biophys. Acta 1223:306-308(1994).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 6).
RA Hu X., Zuckerman K.S.;
RT "Cloning and sequencing of the cDNA variant with 397 bp missing for
RT the GM-CSF receptor alpha subunit.";
RL Submitted (MAR-1997) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 7).
RX PubMed=17681666; DOI=10.1016/j.exphem.2007.06.008;
RA Pelley J.L., Nicholls C.D., Beattie T.L., Brown C.B.;
RT "Discovery and characterization of a novel splice variant of the GM-
RT CSF receptor alpha subunit.";
RL Exp. Hematol. 35:1483-1494(2007).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 8).
RC TISSUE=Synovium, and Uterus;
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 [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta, and Uterus;
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 [12]
RP NUCLEOTIDE SEQUENCE OF 376-400.
RX PubMed=1358805; DOI=10.1016/S0888-7543(05)80241-1;
RA Rappold G., Willson T.A., Henke A., Gough N.M.;
RT "Arrangement and localization of the human GM-CSF receptor alpha chain
RT gene CSF2RA within the X-Y pseudoautosomal region.";
RL Genomics 14:455-461(1992).
RN [13]
RP INVOLVEMENT IN SMDP4.
RX PubMed=18955567; DOI=10.1084/jem.20080759;
RA Martinez-Moczygemba M., Doan M.L., Elidemir O., Fan L.L., Cheung S.W.,
RA Lei J.T., Moore J.P., Tavana G., Lewis L.R., Zhu Y., Muzny D.M.,
RA Gibbs R.A., Huston D.P.;
RT "Pulmonary alveolar proteinosis caused by deletion of the GM-CSFRalpha
RT gene in the X chromosome pseudoautosomal region 1.";
RL J. Exp. Med. 205:2711-2716(2008).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 218-320 IN COMPLEX WITH
RP CSF2RB AND CSF2, SUBUNIT, AND GLYCOSYLATION AT ASN-229.
RX PubMed=18692472; DOI=10.1016/j.cell.2008.05.053;
RA Hansen G., Hercus T.R., McClure B.J., Stomski F.C., Dottore M.,
RA Powell J., Ramshaw H., Woodcock J.M., Xu Y., Guthridge M.,
RA McKinstry W.J., Lopez A.F., Parker M.W.;
RT "The structure of the GM-CSF receptor complex reveals a distinct mode
RT of cytokine receptor activation.";
RL Cell 134:496-507(2008).
RN [15]
RP VARIANT SMDP4 ARG-196.
RX PubMed=18955570; DOI=10.1084/jem.20080990;
RA Suzuki T., Sakagami T., Rubin B.K., Nogee L.M., Wood R.E.,
RA Zimmerman S.L., Smolarek T., Dishop M.K., Wert S.E., Whitsett J.A.,
RA Grabowski G., Carey B.C., Stevens C., van der Loo J.C., Trapnell B.C.;
RT "Familial pulmonary alveolar proteinosis caused by mutations in
RT CSF2RA.";
RL J. Exp. Med. 205:2703-2710(2008).
CC -!- FUNCTION: Low affinity receptor for granulocyte-macrophage colony-
CC stimulating factor. Transduces a signal that results in the
CC proliferation, differentiation, and functional activation of
CC hematopoietic cells.
CC -!- SUBUNIT: Heterodimer of an alpha and a beta subunit. The beta
CC subunit is common to the IL3, IL5 and GM-CSF receptors. The
CC signaling GM-CSF receptor complex is a dodecamer of two head-to-
CC head hexamers of two alpha, two beta, and two ligand subunits.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein.
CC -!- SUBCELLULAR LOCATION: Isoform 3: Secreted (Probable).
CC -!- SUBCELLULAR LOCATION: Isoform 4: Secreted (Probable).
CC -!- SUBCELLULAR LOCATION: Isoform 6: Secreted (Probable).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=8;
CC Name=1;
CC IsoId=P15509-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P15509-2; Sequence=VSP_001670;
CC Name=3;
CC IsoId=P15509-3; Sequence=VSP_001668, VSP_001669;
CC Name=4;
CC IsoId=P15509-4; Sequence=VSP_001665, VSP_001666;
CC Name=5;
CC IsoId=P15509-5; Sequence=VSP_001667;
CC Name=6;
CC IsoId=P15509-6; Sequence=VSP_001663, VSP_001664;
CC Name=7; Synonyms=Alu-GMRalpha;
CC IsoId=P15509-7; Sequence=VSP_043715;
CC Name=8;
CC IsoId=P15509-8; Sequence=VSP_044272;
CC -!- DOMAIN: The WSXWS motif appears to be necessary for proper protein
CC folding and thereby efficient intracellular transport and cell-
CC surface receptor binding.
CC -!- DOMAIN: The box 1 motif is required for JAK interaction and/or
CC activation.
CC -!- DISEASE: Pulmonary surfactant metabolism dysfunction 4 (SMDP4)
CC [MIM:300770]: A rare lung disorder due to impaired surfactant
CC homeostasis. It is characterized by alveolar filling with
CC floccular material that stains positive using the periodic acid-
CC Schiff method and is derived from surfactant phospholipids and
CC protein components. Excessive lipoproteins accumulation in the
CC alveoli results in severe respiratory distress. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: The gene coding for this protein is located in the
CC pseudoautosomal region 1 (PAR1) of X and Y chromosomes.
CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 5
CC subfamily.
CC -!- SIMILARITY: Contains 1 fibronectin type-III domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA60962.1; Type=Miscellaneous discrepancy;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; X17648; CAA35638.1; -; mRNA.
DR EMBL; D26628; BAA05656.1; -; Genomic_DNA.
DR EMBL; M64445; AAA35908.1; -; mRNA.
DR EMBL; X54935; CAA38697.1; -; mRNA.
DR EMBL; M73832; AAA35909.1; -; mRNA.
DR EMBL; L29348; AAA60961.1; -; mRNA.
DR EMBL; L29349; AAA60962.1; ALT_SEQ; mRNA.
DR EMBL; U93096; AAB51535.1; -; mRNA.
DR EMBL; DQ841258; ABI32309.1; -; mRNA.
DR EMBL; AK293086; BAF85775.1; -; mRNA.
DR EMBL; AK301395; BAG62930.1; -; mRNA.
DR EMBL; BX649553; CAI95727.1; -; Genomic_DNA.
DR EMBL; BC002635; AAH02635.1; -; mRNA.
DR EMBL; BC071835; AAH71835.1; -; mRNA.
DR PIR; S06945; S06945.
DR PIR; S13684; S13684.
DR PIR; S50039; S50039.
DR PIR; S50040; S50040.
DR RefSeq; NP_001155001.1; NM_001161529.1.
DR RefSeq; NP_001155002.1; NM_001161530.1.
DR RefSeq; NP_001155003.1; NM_001161531.1.
DR RefSeq; NP_001155004.1; NM_001161532.1.
DR RefSeq; NP_006131.2; NM_006140.4.
DR RefSeq; NP_758448.1; NM_172245.2.
DR RefSeq; NP_758449.1; NM_172246.2.
DR RefSeq; NP_758450.1; NM_172247.2.
DR RefSeq; NP_758452.1; NM_172249.2.
DR UniGene; Hs.520937; -.
DR PDB; 3CXE; X-ray; 3.30 A; C=218-320.
DR PDBsum; 3CXE; -.
DR ProteinModelPortal; P15509; -.
DR SMR; P15509; 12-316.
DR DIP; DIP-635N; -.
DR IntAct; P15509; 2.
DR MINT; MINT-7242386; -.
DR STRING; 9606.ENSP00000370935; -.
DR ChEMBL; CHEMBL2364169; -.
DR DrugBank; DB00020; Sargramostim.
DR GuidetoPHARMACOLOGY; 1707; -.
DR PhosphoSite; P15509; -.
DR DMDM; 121509; -.
DR PaxDb; P15509; -.
DR PRIDE; P15509; -.
DR DNASU; 1438; -.
DR Ensembl; ENST00000355432; ENSP00000347606; ENSG00000198223.
DR Ensembl; ENST00000355805; ENSP00000348058; ENSG00000198223.
DR Ensembl; ENST00000361536; ENSP00000354836; ENSG00000198223.
DR Ensembl; ENST00000381500; ENSP00000370911; ENSG00000198223.
DR Ensembl; ENST00000381509; ENSP00000370920; ENSG00000198223.
DR Ensembl; ENST00000381524; ENSP00000370935; ENSG00000198223.
DR Ensembl; ENST00000381529; ENSP00000370940; ENSG00000198223.
DR Ensembl; ENST00000417535; ENSP00000394227; ENSG00000198223.
DR Ensembl; ENST00000432318; ENSP00000416437; ENSG00000198223.
DR Ensembl; ENST00000501036; ENSP00000440491; ENSG00000198223.
DR GeneID; 1438; -.
DR KEGG; hsa:1438; -.
DR UCSC; uc004cpp.2; human.
DR CTD; 1438; -.
DR GeneCards; GC0XP001347; -.
DR HGNC; HGNC:2435; CSF2RA.
DR HPA; CAB016148; -.
DR MIM; 300770; phenotype.
DR MIM; 306250; gene.
DR MIM; 425000; gene.
DR neXtProt; NX_P15509; -.
DR Orphanet; 264675; Congenital pulmonary alveolar proteinosis.
DR PharmGKB; PA26938; -.
DR eggNOG; NOG74889; -.
DR HOGENOM; HOG000004539; -.
DR HOVERGEN; HBG103561; -.
DR KO; K05066; -.
DR OMA; NTTYLEC; -.
DR OrthoDB; EOG73BVCJ; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P15509; -.
DR EvolutionaryTrace; P15509; -.
DR GenomeRNAi; 1438; -.
DR NextBio; 35534741; -.
DR PRO; PR:P15509; -.
DR ArrayExpress; P15509; -.
DR Bgee; P15509; -.
DR CleanEx; HS_CSF2RA; -.
DR Genevestigator; P15509; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0004896; F:cytokine receptor activity; IEA:InterPro.
DR GO; GO:0004872; F:receptor activity; TAS:ProtInc.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IEA:GOC.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR015321; IL-6_rcpt_alpha-bd.
DR InterPro; IPR003532; Short_hematopoietin_rcpt_2_CS.
DR Pfam; PF09240; IL6Ra-bind; 1.
DR SMART; SM00060; FN3; 1.
DR SUPFAM; SSF49265; SSF49265; 2.
DR PROSITE; PS50853; FN3; 1.
DR PROSITE; PS01356; HEMATOPO_REC_S_F2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Complete proteome;
KW Disease mutation; Disulfide bond; Glycoprotein; Membrane; Receptor;
KW Reference proteome; Secreted; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1 22
FT CHAIN 23 400 Granulocyte-macrophage colony-stimulating
FT factor receptor subunit alpha.
FT /FTId=PRO_0000010872.
FT TOPO_DOM 23 320 Extracellular (Potential).
FT TRANSMEM 321 346 Helical; (Potential).
FT TOPO_DOM 347 400 Cytoplasmic (Potential).
FT DOMAIN 220 320 Fibronectin type-III.
FT MOTIF 306 310 WSXWS motif.
FT MOTIF 355 363 Box 1 motif.
FT CARBOHYD 46 46 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 54 54 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 99 99 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 123 123 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 135 135 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 182 182 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 195 195 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 223 223 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 229 229 N-linked (GlcNAc...).
FT CARBOHYD 272 272 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 305 305 N-linked (GlcNAc...) (Potential).
FT DISULFID 126 136 By similarity.
FT DISULFID 165 178 By similarity.
FT VAR_SEQ 1 133 Missing (in isoform 8).
FT /FTId=VSP_044272.
FT VAR_SEQ 216 233 ERFNPPSNVTVRCNTTHC -> GSLGYSGCSRQFHRSKTN
FT (in isoform 6).
FT /FTId=VSP_001663.
FT VAR_SEQ 234 400 Missing (in isoform 6).
FT /FTId=VSP_001664.
FT VAR_SEQ 271 286 INVSGDLENRYNFPSS -> VVLTTGTSALCTFMCS (in
FT isoform 4).
FT /FTId=VSP_001665.
FT VAR_SEQ 287 400 Missing (in isoform 4).
FT /FTId=VSP_001666.
FT VAR_SEQ 315 315 F -> FGSHSVTQAGVQWHNLGSLQPPSPRLKRFSCLRLP
FT (in isoform 7).
FT /FTId=VSP_043715.
FT VAR_SEQ 316 400 GSDDGNLGSVYIYVLLIVGTLVCGIVLGFLFKRFLRIQRLF
FT PPVPQIKDKLNDNHEVEDEIIWEEFTPEEGKGYREEVLTVK
FT EIT -> DHLGGIHPRGRERLPRRGLDREGNYLRPRGCRNG
FT MDISASATRGNCFLDDAVNLYIIFYVFI (in isoform
FT 5).
FT /FTId=VSP_001667.
FT VAR_SEQ 318 333 DDGNLGSVYIYVLLIV -> LGYSGCSRQFHRSKTN (in
FT isoform 3).
FT /FTId=VSP_001668.
FT VAR_SEQ 334 400 Missing (in isoform 3).
FT /FTId=VSP_001669.
FT VAR_SEQ 376 400 IIWEEFTPEEGKGYREEVLTVKEIT -> MGPQRHHRCGWN
FT LYPTPGPSPGSGSSPRLGSESSL (in isoform 2).
FT /FTId=VSP_001670.
FT VARIANT 196 196 G -> R (in SMDP4).
FT /FTId=VAR_058507.
FT STRAND 226 228
FT STRAND 230 235
FT STRAND 249 254
FT STRAND 269 271
FT STRAND 275 277
FT STRAND 295 300
SQ SEQUENCE 400 AA; 46207 MW; D9025B981E41311D CRC64;
MLLLVTSLLL CELPHPAFLL IPEKSDLRTV APASSLNVRF DSRTMNLSWD CQENTTFSKC
FLTDKKNRVV EPRLSNNECS CTFREICLHE GVTFEVHVNT SQRGFQQKLL YPNSGREGTA
AQNFSCFIYN ADLMNCTWAR GPTAPRDVQY FLYIRNSKRR REIRCPYYIQ DSGTHVGCHL
DNLSGLTSRN YFLVNGTSRE IGIQFFDSLL DTKKIERFNP PSNVTVRCNT THCLVRWKQP
RTYQKLSYLD FQYQLDVHRK NTQPGTENLL INVSGDLENR YNFPSSEPRA KHSVKIRAAD
VRILNWSSWS EAIEFGSDDG NLGSVYIYVL LIVGTLVCGI VLGFLFKRFL RIQRLFPPVP
QIKDKLNDNH EVEDEIIWEE FTPEEGKGYR EEVLTVKEIT
//
ID CSF2R_HUMAN Reviewed; 400 AA.
AC P15509; A7J003; A8KAM1; B4DW68; J3JS76; J3JS77; O00207; Q14429;
read moreAC Q14430; Q14431; Q16564;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-1990, sequence version 1.
DT 22-JAN-2014, entry version 150.
DE RecName: Full=Granulocyte-macrophage colony-stimulating factor receptor subunit alpha;
DE Short=GM-CSF-R-alpha;
DE Short=GMCSFR-alpha;
DE Short=GMR-alpha;
DE AltName: Full=CDw116;
DE AltName: CD_antigen=CD116;
DE Flags: Precursor;
GN Name=CSF2RA; Synonyms=CSF2R, CSF2RY;
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).
RC TISSUE=Placenta;
RX PubMed=2555171;
RA Gearing D.P., King J.A., Gough N.M., Nicola N.A.;
RT "Expression cloning of a receptor for human granulocyte-macrophage
RT colony-stimulating factor.";
RL EMBO J. 8:3667-3676(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RX PubMed=8144676;
RA Nakagawa Y., Kosugi H., Miyajima A., Arai K., Yokota T.;
RT "Structure of the gene encoding the alpha subunit of the human
RT granulocyte-macrophage colony stimulating factor receptor.
RT Implications for the evolution of the cytokine receptor superfamily.";
RL J. Biol. Chem. 269:10905-10912(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=1715577; DOI=10.1073/pnas.88.17.7744;
RA Crosier K.E., Wong G.G., Mathey-Prevot B., Nathan D.G., Sieff C.A.;
RT "A functional isoform of the human granulocyte/macrophage colony-
RT stimulating factor receptor has an unusual cytoplasmic domain.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:7744-7748(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Placenta;
RX PubMed=2148207; DOI=10.1093/nar/18.23.7178;
RA Ashworth A., Kraft A.;
RT "Cloning of a potentially soluble receptor for human GM-CSF.";
RL Nucleic Acids Res. 18:7178-7178(1990).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RX PubMed=1832774; DOI=10.1073/pnas.88.18.8203;
RA Raines M.A., Liu L., Quan S.G., Joe V., DiPersio J.F., Golde D.W.;
RT "Identification and molecular cloning of a soluble human granulocyte-
RT macrophage colony-stimulating factor receptor.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:8203-8207(1991).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 4 AND 5).
RC TISSUE=Blood;
RX PubMed=8086503; DOI=10.1016/0167-4889(94)90241-0;
RA Hu X., Emanuel P.D., Zuckerman K.S.;
RT "Cloning and sequencing of the cDNAs encoding two alternative
RT splicing-derived variants of the alpha subunit of the granulocyte-
RT macrophage colony-stimulating factor receptor.";
RL Biochim. Biophys. Acta 1223:306-308(1994).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 6).
RA Hu X., Zuckerman K.S.;
RT "Cloning and sequencing of the cDNA variant with 397 bp missing for
RT the GM-CSF receptor alpha subunit.";
RL Submitted (MAR-1997) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 7).
RX PubMed=17681666; DOI=10.1016/j.exphem.2007.06.008;
RA Pelley J.L., Nicholls C.D., Beattie T.L., Brown C.B.;
RT "Discovery and characterization of a novel splice variant of the GM-
RT CSF receptor alpha subunit.";
RL Exp. Hematol. 35:1483-1494(2007).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 8).
RC TISSUE=Synovium, and Uterus;
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 [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta, and Uterus;
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 [12]
RP NUCLEOTIDE SEQUENCE OF 376-400.
RX PubMed=1358805; DOI=10.1016/S0888-7543(05)80241-1;
RA Rappold G., Willson T.A., Henke A., Gough N.M.;
RT "Arrangement and localization of the human GM-CSF receptor alpha chain
RT gene CSF2RA within the X-Y pseudoautosomal region.";
RL Genomics 14:455-461(1992).
RN [13]
RP INVOLVEMENT IN SMDP4.
RX PubMed=18955567; DOI=10.1084/jem.20080759;
RA Martinez-Moczygemba M., Doan M.L., Elidemir O., Fan L.L., Cheung S.W.,
RA Lei J.T., Moore J.P., Tavana G., Lewis L.R., Zhu Y., Muzny D.M.,
RA Gibbs R.A., Huston D.P.;
RT "Pulmonary alveolar proteinosis caused by deletion of the GM-CSFRalpha
RT gene in the X chromosome pseudoautosomal region 1.";
RL J. Exp. Med. 205:2711-2716(2008).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 218-320 IN COMPLEX WITH
RP CSF2RB AND CSF2, SUBUNIT, AND GLYCOSYLATION AT ASN-229.
RX PubMed=18692472; DOI=10.1016/j.cell.2008.05.053;
RA Hansen G., Hercus T.R., McClure B.J., Stomski F.C., Dottore M.,
RA Powell J., Ramshaw H., Woodcock J.M., Xu Y., Guthridge M.,
RA McKinstry W.J., Lopez A.F., Parker M.W.;
RT "The structure of the GM-CSF receptor complex reveals a distinct mode
RT of cytokine receptor activation.";
RL Cell 134:496-507(2008).
RN [15]
RP VARIANT SMDP4 ARG-196.
RX PubMed=18955570; DOI=10.1084/jem.20080990;
RA Suzuki T., Sakagami T., Rubin B.K., Nogee L.M., Wood R.E.,
RA Zimmerman S.L., Smolarek T., Dishop M.K., Wert S.E., Whitsett J.A.,
RA Grabowski G., Carey B.C., Stevens C., van der Loo J.C., Trapnell B.C.;
RT "Familial pulmonary alveolar proteinosis caused by mutations in
RT CSF2RA.";
RL J. Exp. Med. 205:2703-2710(2008).
CC -!- FUNCTION: Low affinity receptor for granulocyte-macrophage colony-
CC stimulating factor. Transduces a signal that results in the
CC proliferation, differentiation, and functional activation of
CC hematopoietic cells.
CC -!- SUBUNIT: Heterodimer of an alpha and a beta subunit. The beta
CC subunit is common to the IL3, IL5 and GM-CSF receptors. The
CC signaling GM-CSF receptor complex is a dodecamer of two head-to-
CC head hexamers of two alpha, two beta, and two ligand subunits.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein.
CC -!- SUBCELLULAR LOCATION: Isoform 3: Secreted (Probable).
CC -!- SUBCELLULAR LOCATION: Isoform 4: Secreted (Probable).
CC -!- SUBCELLULAR LOCATION: Isoform 6: Secreted (Probable).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=8;
CC Name=1;
CC IsoId=P15509-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P15509-2; Sequence=VSP_001670;
CC Name=3;
CC IsoId=P15509-3; Sequence=VSP_001668, VSP_001669;
CC Name=4;
CC IsoId=P15509-4; Sequence=VSP_001665, VSP_001666;
CC Name=5;
CC IsoId=P15509-5; Sequence=VSP_001667;
CC Name=6;
CC IsoId=P15509-6; Sequence=VSP_001663, VSP_001664;
CC Name=7; Synonyms=Alu-GMRalpha;
CC IsoId=P15509-7; Sequence=VSP_043715;
CC Name=8;
CC IsoId=P15509-8; Sequence=VSP_044272;
CC -!- DOMAIN: The WSXWS motif appears to be necessary for proper protein
CC folding and thereby efficient intracellular transport and cell-
CC surface receptor binding.
CC -!- DOMAIN: The box 1 motif is required for JAK interaction and/or
CC activation.
CC -!- DISEASE: Pulmonary surfactant metabolism dysfunction 4 (SMDP4)
CC [MIM:300770]: A rare lung disorder due to impaired surfactant
CC homeostasis. It is characterized by alveolar filling with
CC floccular material that stains positive using the periodic acid-
CC Schiff method and is derived from surfactant phospholipids and
CC protein components. Excessive lipoproteins accumulation in the
CC alveoli results in severe respiratory distress. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: The gene coding for this protein is located in the
CC pseudoautosomal region 1 (PAR1) of X and Y chromosomes.
CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 5
CC subfamily.
CC -!- SIMILARITY: Contains 1 fibronectin type-III domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA60962.1; Type=Miscellaneous discrepancy;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; X17648; CAA35638.1; -; mRNA.
DR EMBL; D26628; BAA05656.1; -; Genomic_DNA.
DR EMBL; M64445; AAA35908.1; -; mRNA.
DR EMBL; X54935; CAA38697.1; -; mRNA.
DR EMBL; M73832; AAA35909.1; -; mRNA.
DR EMBL; L29348; AAA60961.1; -; mRNA.
DR EMBL; L29349; AAA60962.1; ALT_SEQ; mRNA.
DR EMBL; U93096; AAB51535.1; -; mRNA.
DR EMBL; DQ841258; ABI32309.1; -; mRNA.
DR EMBL; AK293086; BAF85775.1; -; mRNA.
DR EMBL; AK301395; BAG62930.1; -; mRNA.
DR EMBL; BX649553; CAI95727.1; -; Genomic_DNA.
DR EMBL; BC002635; AAH02635.1; -; mRNA.
DR EMBL; BC071835; AAH71835.1; -; mRNA.
DR PIR; S06945; S06945.
DR PIR; S13684; S13684.
DR PIR; S50039; S50039.
DR PIR; S50040; S50040.
DR RefSeq; NP_001155001.1; NM_001161529.1.
DR RefSeq; NP_001155002.1; NM_001161530.1.
DR RefSeq; NP_001155003.1; NM_001161531.1.
DR RefSeq; NP_001155004.1; NM_001161532.1.
DR RefSeq; NP_006131.2; NM_006140.4.
DR RefSeq; NP_758448.1; NM_172245.2.
DR RefSeq; NP_758449.1; NM_172246.2.
DR RefSeq; NP_758450.1; NM_172247.2.
DR RefSeq; NP_758452.1; NM_172249.2.
DR UniGene; Hs.520937; -.
DR PDB; 3CXE; X-ray; 3.30 A; C=218-320.
DR PDBsum; 3CXE; -.
DR ProteinModelPortal; P15509; -.
DR SMR; P15509; 12-316.
DR DIP; DIP-635N; -.
DR IntAct; P15509; 2.
DR MINT; MINT-7242386; -.
DR STRING; 9606.ENSP00000370935; -.
DR ChEMBL; CHEMBL2364169; -.
DR DrugBank; DB00020; Sargramostim.
DR GuidetoPHARMACOLOGY; 1707; -.
DR PhosphoSite; P15509; -.
DR DMDM; 121509; -.
DR PaxDb; P15509; -.
DR PRIDE; P15509; -.
DR DNASU; 1438; -.
DR Ensembl; ENST00000355432; ENSP00000347606; ENSG00000198223.
DR Ensembl; ENST00000355805; ENSP00000348058; ENSG00000198223.
DR Ensembl; ENST00000361536; ENSP00000354836; ENSG00000198223.
DR Ensembl; ENST00000381500; ENSP00000370911; ENSG00000198223.
DR Ensembl; ENST00000381509; ENSP00000370920; ENSG00000198223.
DR Ensembl; ENST00000381524; ENSP00000370935; ENSG00000198223.
DR Ensembl; ENST00000381529; ENSP00000370940; ENSG00000198223.
DR Ensembl; ENST00000417535; ENSP00000394227; ENSG00000198223.
DR Ensembl; ENST00000432318; ENSP00000416437; ENSG00000198223.
DR Ensembl; ENST00000501036; ENSP00000440491; ENSG00000198223.
DR GeneID; 1438; -.
DR KEGG; hsa:1438; -.
DR UCSC; uc004cpp.2; human.
DR CTD; 1438; -.
DR GeneCards; GC0XP001347; -.
DR HGNC; HGNC:2435; CSF2RA.
DR HPA; CAB016148; -.
DR MIM; 300770; phenotype.
DR MIM; 306250; gene.
DR MIM; 425000; gene.
DR neXtProt; NX_P15509; -.
DR Orphanet; 264675; Congenital pulmonary alveolar proteinosis.
DR PharmGKB; PA26938; -.
DR eggNOG; NOG74889; -.
DR HOGENOM; HOG000004539; -.
DR HOVERGEN; HBG103561; -.
DR KO; K05066; -.
DR OMA; NTTYLEC; -.
DR OrthoDB; EOG73BVCJ; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P15509; -.
DR EvolutionaryTrace; P15509; -.
DR GenomeRNAi; 1438; -.
DR NextBio; 35534741; -.
DR PRO; PR:P15509; -.
DR ArrayExpress; P15509; -.
DR Bgee; P15509; -.
DR CleanEx; HS_CSF2RA; -.
DR Genevestigator; P15509; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0004896; F:cytokine receptor activity; IEA:InterPro.
DR GO; GO:0004872; F:receptor activity; TAS:ProtInc.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IEA:GOC.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR015321; IL-6_rcpt_alpha-bd.
DR InterPro; IPR003532; Short_hematopoietin_rcpt_2_CS.
DR Pfam; PF09240; IL6Ra-bind; 1.
DR SMART; SM00060; FN3; 1.
DR SUPFAM; SSF49265; SSF49265; 2.
DR PROSITE; PS50853; FN3; 1.
DR PROSITE; PS01356; HEMATOPO_REC_S_F2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Complete proteome;
KW Disease mutation; Disulfide bond; Glycoprotein; Membrane; Receptor;
KW Reference proteome; Secreted; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1 22
FT CHAIN 23 400 Granulocyte-macrophage colony-stimulating
FT factor receptor subunit alpha.
FT /FTId=PRO_0000010872.
FT TOPO_DOM 23 320 Extracellular (Potential).
FT TRANSMEM 321 346 Helical; (Potential).
FT TOPO_DOM 347 400 Cytoplasmic (Potential).
FT DOMAIN 220 320 Fibronectin type-III.
FT MOTIF 306 310 WSXWS motif.
FT MOTIF 355 363 Box 1 motif.
FT CARBOHYD 46 46 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 54 54 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 99 99 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 123 123 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 135 135 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 182 182 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 195 195 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 223 223 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 229 229 N-linked (GlcNAc...).
FT CARBOHYD 272 272 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 305 305 N-linked (GlcNAc...) (Potential).
FT DISULFID 126 136 By similarity.
FT DISULFID 165 178 By similarity.
FT VAR_SEQ 1 133 Missing (in isoform 8).
FT /FTId=VSP_044272.
FT VAR_SEQ 216 233 ERFNPPSNVTVRCNTTHC -> GSLGYSGCSRQFHRSKTN
FT (in isoform 6).
FT /FTId=VSP_001663.
FT VAR_SEQ 234 400 Missing (in isoform 6).
FT /FTId=VSP_001664.
FT VAR_SEQ 271 286 INVSGDLENRYNFPSS -> VVLTTGTSALCTFMCS (in
FT isoform 4).
FT /FTId=VSP_001665.
FT VAR_SEQ 287 400 Missing (in isoform 4).
FT /FTId=VSP_001666.
FT VAR_SEQ 315 315 F -> FGSHSVTQAGVQWHNLGSLQPPSPRLKRFSCLRLP
FT (in isoform 7).
FT /FTId=VSP_043715.
FT VAR_SEQ 316 400 GSDDGNLGSVYIYVLLIVGTLVCGIVLGFLFKRFLRIQRLF
FT PPVPQIKDKLNDNHEVEDEIIWEEFTPEEGKGYREEVLTVK
FT EIT -> DHLGGIHPRGRERLPRRGLDREGNYLRPRGCRNG
FT MDISASATRGNCFLDDAVNLYIIFYVFI (in isoform
FT 5).
FT /FTId=VSP_001667.
FT VAR_SEQ 318 333 DDGNLGSVYIYVLLIV -> LGYSGCSRQFHRSKTN (in
FT isoform 3).
FT /FTId=VSP_001668.
FT VAR_SEQ 334 400 Missing (in isoform 3).
FT /FTId=VSP_001669.
FT VAR_SEQ 376 400 IIWEEFTPEEGKGYREEVLTVKEIT -> MGPQRHHRCGWN
FT LYPTPGPSPGSGSSPRLGSESSL (in isoform 2).
FT /FTId=VSP_001670.
FT VARIANT 196 196 G -> R (in SMDP4).
FT /FTId=VAR_058507.
FT STRAND 226 228
FT STRAND 230 235
FT STRAND 249 254
FT STRAND 269 271
FT STRAND 275 277
FT STRAND 295 300
SQ SEQUENCE 400 AA; 46207 MW; D9025B981E41311D CRC64;
MLLLVTSLLL CELPHPAFLL IPEKSDLRTV APASSLNVRF DSRTMNLSWD CQENTTFSKC
FLTDKKNRVV EPRLSNNECS CTFREICLHE GVTFEVHVNT SQRGFQQKLL YPNSGREGTA
AQNFSCFIYN ADLMNCTWAR GPTAPRDVQY FLYIRNSKRR REIRCPYYIQ DSGTHVGCHL
DNLSGLTSRN YFLVNGTSRE IGIQFFDSLL DTKKIERFNP PSNVTVRCNT THCLVRWKQP
RTYQKLSYLD FQYQLDVHRK NTQPGTENLL INVSGDLENR YNFPSSEPRA KHSVKIRAAD
VRILNWSSWS EAIEFGSDDG NLGSVYIYVL LIVGTLVCGI VLGFLFKRFL RIQRLFPPVP
QIKDKLNDNH EVEDEIIWEE FTPEEGKGYR EEVLTVKEIT
//
MIM
300770
*RECORD*
*FIELD* NO
300770
*FIELD* TI
#300770 SURFACTANT METABOLISM DYSFUNCTION, PULMONARY, 4; SMDP4
;;PULMONARY ALVEOLAR PROTEINOSIS, CONGENITAL, 4;;
read morePAP DUE TO CSF2RA DEFICIENCY;;
CSF2RA DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because pulmonary alveolar
proteinosis due to CSF2RA deficiency is caused by mutation in the CSF2RA
gene (306250).
DESCRIPTION
Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which
surfactant-derived lipoproteins accumulate excessively within pulmonary
alveoli, causing severe respiratory distress. Three forms of PAP have
been described: hereditary (usually congenital), secondary, and
acquired. Hereditary PAP is associated with mutations in the CSF2RA gene
or in genes encoding surfactant proteins. Secondary PAP develops in
conditions in which there are reduced numbers or functional impairment
of alveolar macrophages and is associated with inhalation of inorganic
dust (silica) or toxic fumes, hematologic malignancies, pharmacologic
immunosuppression, infections, and impaired CSF2RB (138960) expression.
Acquired PAP (610910), the most common form, usually occurs in adults
and is caused by neutralizing autoantibodies to CSF2 (138960)
(Martinez-Moczygemba et al., 2008).
For a general phenotypic description and a discussion of genetic
heterogeneity of congenital pulmonary surfactant metabolism dysfunction,
see SMDP1 (265120).
CLINICAL FEATURES
Martinez-Moczygemba et al. (2008) reported a 4-year-old female with
symptoms associated with Turner syndrome and respiratory insufficiency
who had been diagnosed with PAP at age 3 years. She had exhibited
respiratory failure caused by respiratory syncytial virus pneumonia in
the first month of life, with a diagnosis of reactive airways disease.
The patient presented with respiratory distress and hypoxemia, with a
'crazy paving' pattern on chest imaging. Open lung biopsy revealed
alveolar proteinaceous material without alveolar epithelial hyperplasia
or chronic interstitial changes, and bronchoalveolar lavage revealed
proteinaceous material and foamy macrophages. ELISA showed no anti-CSF2
antibodies and elevated baseline CSF2 serum levels. Exogenous CSF2
administration, which may be efficacious in some patients with acquired
PAP, resulted in no clinical improvement.
Suzuki et al. (2008) reported 2 sisters with PAP. The index patient
presented at age 6 years with a 2-year history of progressive tachypnea
and failure to thrive. Both parents were well developed and healthy with
no history of lung disease. Examination of the patient revealed moderate
tachypnea, mild tachycardia, and inspiratory crackles. Pulmonary
function testing showed severe restrictive impairment. Oxygen saturation
was 88% while breathing room air and decreased while talking or walking
a short distance. PAP diagnosis was suspected based on chest radiography
and confirmed by histopathologic examination of lung tissue. CSF2
autoantibodies were absent. Serum SPD (SFTPD; 178635) was increased in
the patient compared with her parents and controls. The patient's
8-year-old sister, who was thought to be healthy, also had increased
serum SPD. Subsequent clinical evaluation revealed that the sister had
poor growth, a diffusion capacity for carbon dioxide of 57% that
predicted, and mild patchy ground glass opacities throughout both lungs,
consistent with a diagnosis of PAP.
MAPPING
PAP due to CSF2RA deficiency results from mutation in the CSF2RA gene,
which maps to chromosome Xp22.33, within the X chromosome
pseudoautosomal region-1 (PAR1) (Martinez-Moczygemba et al., 2008).
MOLECULAR GENETICS
Using flow cytometry, Martinez-Moczygemba et al. (2008) found that
CSF2RA was absent on monocytes from the patient they reported with PAP.
The patient's mother expressed CSF2RA on all monocytes, whereas the
patient's father and sister expressed CSF2RA only on a subpopulation of
monocytes. Stimulation of granulocytes with CSF2 induced upregulation of
CD11B (ITGAM; 120980) in the mother, but not the patient. Karyotypic
analysis showed that the patient had 1 X chromosome of apparently normal
length and 1 X chromosome with a truncated Xp arm that did not hybridize
with a PAR1 probe. RT-PCR analysis detected expression of CSF2RA and
IL3RA (308385), which are located in PAR1, in leukocytes from the
patient's family members, but not in those from the patient. PCR
analysis of the 11 coding exons of the CSF2RA gene detected a deletion
of exons 5 through 13 (306250.0001), providing a genetic basis for the
absence of CSF2RA mRNA and protein. The authors noted that the deletion
affecting CSF2RA likely extends to IL3RA, but that impaired IL3 (147740)
responses do not result in PAP in mice and have not been associated with
PAP in humans.
Using flow cytometry, Suzuki et al. (2008) found that both CSF2RA and
CSF2RB were present on leukocytes from the 2 sisters they reported with
PAP, as well as all family members tested. However, Western blot
analysis showed that the affected sisters expressed only a truncated
form of CSF2RA, whereas their father was heterozygous for the normal and
truncated forms, and their mother expressed only normal CSF2RA. CSF2
binding and CSF2-dependent signaling were severely reduced, but not
abolished, in the sisters, and their CD11B stimulation test was
abnormal. Suzuki et al. (2008) identified a mutation in the CSF2RA gene
in the affected sisters that resulted in a gly174-to-arg (G174R;
306250.0002) substitution that altered 1 of 11 predicted N-glycosylation
sites. The father was heterozygous for the G174R mutation, but the
mother had only wildtype CSF2RA, suggesting a deletion of 1 maternal
CSF2RA allele. PCR analysis showed that CSF2RA copy number was reduced
in the sisters and their mother, but not in the father. FISH analysis
demonstrated a 1.6-Mb deletion of PAR1, including the CSF2RA gene, in 1
X chromosome of the sisters and mother. Transfection of CSF2RA with the
G174R mutation into 293 cells faithfully reproduced the CSF2 signaling
defect at physiologic CSF2 concentrations. At high CSF2 concentrations,
similar to those observed in the index patient, signaling was partially
rescued, thereby providing a molecular explanation for the slow disease
progression in the 2 sisters. Suzuki et al. (2008) concluded that PAP
may be caused by compound heterozygous abnormalities affecting the
CSF2RA gene, and that CSF2 signaling is critical for surfactant
homeostasis in humans.
CLINICAL MANAGEMENT
Martinez-Moczygemba et al. (2008) noted that diagnosing PAP due to
CSF2RA deficiency has important therapeutic implications, since bone
marrow transplantation from a healthy donor should result in CSF2RA
expression on leukocytes and thereby cure the impaired surfactant
homeostasis that underlies PAP. The patient they reported with PAP due
to CSF2RA deficiency underwent bone marrow transplantation, but she died
of an infectious respiratory complication 4 weeks after transplantation,
before the establishment of immune competency.
*FIELD* RF
1. Martinez-Moczygemba, M.; Doan, M. L.; Elidemir, O.; Fan, L. L.;
Cheung, S. W.; Lei, J. T.; Moore, J. P.; Tavana, G.; Lewis, L. R.;
Zhu, Y.; Muzny, D. M.; Gibbs, R. A.; Huston, D. P.: Pulmonary alveolar
proteinosis caused by deletion of the GM-CSFR-alpha gene in the X
chromosome pseudoautosomal region 1. J. Exp. Med. 205: 2711-2716,
2008.
2. Suzuki, T.; Sakagami, T.; Rubin, B. K.; Nogee, L. M.; Wood, R.
E.; Zimmerman, S. L.; Smolarek, T.; Dishop, M. K.; Wert, S. E.; Whitsett,
J. A.; Grabowski, G.; Carey, B. C.; Stevens, C.; van der Loo, J. C.
M.; Trapnell, B. C.: Familial pulmonary alveolar proteinosis caused
by mutations in CSF2RA. J. Exp. Med. 205: 2703-2710, 2008.
*FIELD* CN
Paul J. Converse - updated: 3/31/2009
*FIELD* CD
Matthew B. Gross: 3/30/2009
*FIELD* ED
ckniffin: 12/01/2011
terry: 4/28/2011
ckniffin: 4/27/2009
mgross: 3/31/2009
*RECORD*
*FIELD* NO
300770
*FIELD* TI
#300770 SURFACTANT METABOLISM DYSFUNCTION, PULMONARY, 4; SMDP4
;;PULMONARY ALVEOLAR PROTEINOSIS, CONGENITAL, 4;;
read morePAP DUE TO CSF2RA DEFICIENCY;;
CSF2RA DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because pulmonary alveolar
proteinosis due to CSF2RA deficiency is caused by mutation in the CSF2RA
gene (306250).
DESCRIPTION
Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which
surfactant-derived lipoproteins accumulate excessively within pulmonary
alveoli, causing severe respiratory distress. Three forms of PAP have
been described: hereditary (usually congenital), secondary, and
acquired. Hereditary PAP is associated with mutations in the CSF2RA gene
or in genes encoding surfactant proteins. Secondary PAP develops in
conditions in which there are reduced numbers or functional impairment
of alveolar macrophages and is associated with inhalation of inorganic
dust (silica) or toxic fumes, hematologic malignancies, pharmacologic
immunosuppression, infections, and impaired CSF2RB (138960) expression.
Acquired PAP (610910), the most common form, usually occurs in adults
and is caused by neutralizing autoantibodies to CSF2 (138960)
(Martinez-Moczygemba et al., 2008).
For a general phenotypic description and a discussion of genetic
heterogeneity of congenital pulmonary surfactant metabolism dysfunction,
see SMDP1 (265120).
CLINICAL FEATURES
Martinez-Moczygemba et al. (2008) reported a 4-year-old female with
symptoms associated with Turner syndrome and respiratory insufficiency
who had been diagnosed with PAP at age 3 years. She had exhibited
respiratory failure caused by respiratory syncytial virus pneumonia in
the first month of life, with a diagnosis of reactive airways disease.
The patient presented with respiratory distress and hypoxemia, with a
'crazy paving' pattern on chest imaging. Open lung biopsy revealed
alveolar proteinaceous material without alveolar epithelial hyperplasia
or chronic interstitial changes, and bronchoalveolar lavage revealed
proteinaceous material and foamy macrophages. ELISA showed no anti-CSF2
antibodies and elevated baseline CSF2 serum levels. Exogenous CSF2
administration, which may be efficacious in some patients with acquired
PAP, resulted in no clinical improvement.
Suzuki et al. (2008) reported 2 sisters with PAP. The index patient
presented at age 6 years with a 2-year history of progressive tachypnea
and failure to thrive. Both parents were well developed and healthy with
no history of lung disease. Examination of the patient revealed moderate
tachypnea, mild tachycardia, and inspiratory crackles. Pulmonary
function testing showed severe restrictive impairment. Oxygen saturation
was 88% while breathing room air and decreased while talking or walking
a short distance. PAP diagnosis was suspected based on chest radiography
and confirmed by histopathologic examination of lung tissue. CSF2
autoantibodies were absent. Serum SPD (SFTPD; 178635) was increased in
the patient compared with her parents and controls. The patient's
8-year-old sister, who was thought to be healthy, also had increased
serum SPD. Subsequent clinical evaluation revealed that the sister had
poor growth, a diffusion capacity for carbon dioxide of 57% that
predicted, and mild patchy ground glass opacities throughout both lungs,
consistent with a diagnosis of PAP.
MAPPING
PAP due to CSF2RA deficiency results from mutation in the CSF2RA gene,
which maps to chromosome Xp22.33, within the X chromosome
pseudoautosomal region-1 (PAR1) (Martinez-Moczygemba et al., 2008).
MOLECULAR GENETICS
Using flow cytometry, Martinez-Moczygemba et al. (2008) found that
CSF2RA was absent on monocytes from the patient they reported with PAP.
The patient's mother expressed CSF2RA on all monocytes, whereas the
patient's father and sister expressed CSF2RA only on a subpopulation of
monocytes. Stimulation of granulocytes with CSF2 induced upregulation of
CD11B (ITGAM; 120980) in the mother, but not the patient. Karyotypic
analysis showed that the patient had 1 X chromosome of apparently normal
length and 1 X chromosome with a truncated Xp arm that did not hybridize
with a PAR1 probe. RT-PCR analysis detected expression of CSF2RA and
IL3RA (308385), which are located in PAR1, in leukocytes from the
patient's family members, but not in those from the patient. PCR
analysis of the 11 coding exons of the CSF2RA gene detected a deletion
of exons 5 through 13 (306250.0001), providing a genetic basis for the
absence of CSF2RA mRNA and protein. The authors noted that the deletion
affecting CSF2RA likely extends to IL3RA, but that impaired IL3 (147740)
responses do not result in PAP in mice and have not been associated with
PAP in humans.
Using flow cytometry, Suzuki et al. (2008) found that both CSF2RA and
CSF2RB were present on leukocytes from the 2 sisters they reported with
PAP, as well as all family members tested. However, Western blot
analysis showed that the affected sisters expressed only a truncated
form of CSF2RA, whereas their father was heterozygous for the normal and
truncated forms, and their mother expressed only normal CSF2RA. CSF2
binding and CSF2-dependent signaling were severely reduced, but not
abolished, in the sisters, and their CD11B stimulation test was
abnormal. Suzuki et al. (2008) identified a mutation in the CSF2RA gene
in the affected sisters that resulted in a gly174-to-arg (G174R;
306250.0002) substitution that altered 1 of 11 predicted N-glycosylation
sites. The father was heterozygous for the G174R mutation, but the
mother had only wildtype CSF2RA, suggesting a deletion of 1 maternal
CSF2RA allele. PCR analysis showed that CSF2RA copy number was reduced
in the sisters and their mother, but not in the father. FISH analysis
demonstrated a 1.6-Mb deletion of PAR1, including the CSF2RA gene, in 1
X chromosome of the sisters and mother. Transfection of CSF2RA with the
G174R mutation into 293 cells faithfully reproduced the CSF2 signaling
defect at physiologic CSF2 concentrations. At high CSF2 concentrations,
similar to those observed in the index patient, signaling was partially
rescued, thereby providing a molecular explanation for the slow disease
progression in the 2 sisters. Suzuki et al. (2008) concluded that PAP
may be caused by compound heterozygous abnormalities affecting the
CSF2RA gene, and that CSF2 signaling is critical for surfactant
homeostasis in humans.
CLINICAL MANAGEMENT
Martinez-Moczygemba et al. (2008) noted that diagnosing PAP due to
CSF2RA deficiency has important therapeutic implications, since bone
marrow transplantation from a healthy donor should result in CSF2RA
expression on leukocytes and thereby cure the impaired surfactant
homeostasis that underlies PAP. The patient they reported with PAP due
to CSF2RA deficiency underwent bone marrow transplantation, but she died
of an infectious respiratory complication 4 weeks after transplantation,
before the establishment of immune competency.
*FIELD* RF
1. Martinez-Moczygemba, M.; Doan, M. L.; Elidemir, O.; Fan, L. L.;
Cheung, S. W.; Lei, J. T.; Moore, J. P.; Tavana, G.; Lewis, L. R.;
Zhu, Y.; Muzny, D. M.; Gibbs, R. A.; Huston, D. P.: Pulmonary alveolar
proteinosis caused by deletion of the GM-CSFR-alpha gene in the X
chromosome pseudoautosomal region 1. J. Exp. Med. 205: 2711-2716,
2008.
2. Suzuki, T.; Sakagami, T.; Rubin, B. K.; Nogee, L. M.; Wood, R.
E.; Zimmerman, S. L.; Smolarek, T.; Dishop, M. K.; Wert, S. E.; Whitsett,
J. A.; Grabowski, G.; Carey, B. C.; Stevens, C.; van der Loo, J. C.
M.; Trapnell, B. C.: Familial pulmonary alveolar proteinosis caused
by mutations in CSF2RA. J. Exp. Med. 205: 2703-2710, 2008.
*FIELD* CN
Paul J. Converse - updated: 3/31/2009
*FIELD* CD
Matthew B. Gross: 3/30/2009
*FIELD* ED
ckniffin: 12/01/2011
terry: 4/28/2011
ckniffin: 4/27/2009
mgross: 3/31/2009
MIM
306250
*RECORD*
*FIELD* NO
306250
*FIELD* TI
*306250 COLONY-STIMULATING FACTOR 2 RECEPTOR, ALPHA; CSF2RA
;;GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR RECEPTOR, LOW AFFINITY,
read moreALPHA SUBUNIT; GMCSFR
*FIELD* TX
DESCRIPTION
Granulocyte/macrophage colony-stimulating factor (GMCSF, or CSF2;
138960) activates STAT5 (601511) and other signaling pathways via
binding to a cell surface receptor composed of a ligand-binding alpha
subunit, encoded by CSF2RA, and a nonbinding affinity-enhancing beta
subunit, encoded by CSF2RB (138981) (Suzuki et al., 2008).
CLONING
Using an expression cloning strategy, Gearing et al. (1989) isolated a
cDNA encoding CSF2RA, which they called GMCSFR, from a human placenta
cDNA library. The deduced 400-amino acid precursor protein has a
22-amino acid signal peptide. The 378-amino acid mature protein has a
calculated molecular mass of 43.7 kD and contains a single transmembrane
domain, a glycosylated extracellular domain, and a short
intracytoplasmic tail. Northern blot analysis detected GMCSFR expression
in a variety of hemopoietic cells displaying GMCSF binding.
Raines et al. (1991) identified a truncated, soluble form of the
low-affinity GMCSF receptor in choriocarcinoma cells. Clones encoding
the soluble receptor were identical in sequence to the membrane-bound
form except for a 97-nucleotide deletion. The amino acid sequence of
this deleted cDNA predicted a protein that lacks the 84 C-terminal amino
acids of the membrane-bound receptor, including the transmembrane and
cytoplasmic domains, and contains 16 different amino acids at its C
terminus. RNase protection analysis indicated that this variant cDNA was
derived from a naturally occurring mRNA. Soluble receptors had been
identified for several other hematopoietin receptors and may be a
general feature of this class. It is likely that alternative mRNA
splicing is the mechanism by which the soluble counterparts are
generated.
GENE STRUCTURE
Rappold et al. (1992) found that the CSF2RA gene spans at least 45 kb.
MAPPING
By Southern blot analysis of a panel of mouse-human somatic cell
hybrids, Gough et al. (1990) demonstrated that the CSF2R gene is on the
X chromosome. The possibility that an allele also maps to the Y
chromosome was suggested by the observation that many DNA samples from
normal males carry 2 alleles of this gene. Among 65 normal persons, 23
females and 20 males were homozygous for an allele of fragment A,
whereas 8 females and 14 males were heterozygous. By in situ
hybridization, Gough et al. (1990) showed that the CSF2R gene maps to
the tip of the short arm of the X chromosome and the short arm of the Y
chromosome (see 425000), with the most likely localization being
Xpter-p21 and Ypter-p11.2. Although this information was consistent with
its location in the pseudoautosomal region (PAR), conclusive proof
required study of segregation of the locus with respect to sexual
phenotype. They found in a total of 14 informative male meioses, 3
recombination events; i.e., in 2 cases a daughter had inherited the
allele from the paternal Y chromosome, and in 1 instance a son had
inherited the allele from the paternal X chromosome. Thus, the CSF2R
locus is distal to the MIC2 locus (313470), which shows only about 2.5%
recombination and maps close to the PAR boundary. This was the first
localization of a gene of known function to this region, which
encompasses about 2,500 kb.
By pulsed field gel electrophoresis, Rappold et al. (1992) localized the
CSF2RA gene 1,180 to 1,300 kb from the telomere, in close proximity to
the CpG island B5. The gene showed abundant hypervariable sequences, and
a number of informative restriction fragment length polymorphisms were
defined. Rappold et al. (1992) suggested that these polymorphisms might
be useful in proving the pseudoautosomal inheritance of apparently
autosomal traits, as has been suggested for schizophrenia (Crow, 1988),
cerebral dominance (Crow, 1989), and Kabuki make-up syndrome (Niikawa et
al., 1988; 147920), among others.
Rappold (1993) discussed in detail the pseudoautosomal regions that
exist at the tips of the short and long arms of the X and Y chromosomes
and cover 2.6 and 0.4 Mb, respectively.
By both in situ hybridization and linkage analysis, Disteche et al.
(1992) found that the murine Csf2ra gene maps to chromosome 19.
GENE FUNCTION
DiPersio et al. (1988) studied the binding of GMCSF, over a wide range
of concentrations, to normal human peripheral blood cells, bone marrow,
acute and chronic myeloid leukemia cells, and a number of established
human myeloid and nonmyeloid cell lines; thereby, they defined the
receptors.
Gearing et al. (1989) found that transfection of GMCSFR cDNA into COS
cells directed expression of a GMCSF receptor showing a single class of
affinity and specificity for human GMCSF, but not interleukin-3 (IL3;
147740).
Hayashida et al. (1990) showed that the high-affinity GMCSF receptor is
composed of at least 2 components in a manner analogous to the IL2
receptor (see 147730). They proposed to designate the low-affinity GMCSF
receptor as the alpha subunit, and the 'new' protein that they
identified and called KH97 as the beta subunit (see 138981). The 2
subunits are approximately 80 and 120 kD, respectively.
Raines et al. (1991) found that expression of the variant cDNA encoding
the truncated, soluble CSF2R isoform produced a secreted protein that
retained its capacity to bind CSF2 in solution.
Kondo et al. (2000) showed that a clonogenic common lymphoid progenitor,
a bone marrow-resident cell that gives rise exclusively to lymphocytes
(T, B, and natural killer cells), can be redirected to the myeloid
lineage by stimulation through exogenously expressed interleukin-2
receptor (146710) and GMCSF receptor. Analysis of mutants of the
beta-chain of the IL2 receptor revealed that the granulocyte and
monocyte differentiation signals are triggered by different cytoplasmic
domains, showing that the signaling pathways responsible for these
unique developmental outcomes are separable. Finally, Kondo et al.
(2000) showed that the endogenous myelomonocytic cytokine receptors for
GMCSF and macrophage colony-stimulating factor (CSF1R; 164770) are
expressed at low to moderate levels on the more primitive hematopoietic
stem cells, are absent on common lymphoid progenitors, and are
upregulated after myeloid lineage induction by IL2 (147680). Kondo et
al. (2000) concluded that cytokine signaling can regulate cell fate
decisions and proposed that a critical step in lymphoid commitment is
downregulation of cytokine receptors that drive myeloid cell
development.
Loss of either the X or the Y chromosome is apparent in 25% of acute
myeloid leukemias of the M2 subtype (AML-M2), compared with only 1 to 6%
in other AML subtypes, suggesting the involvement of a 'recessive
oncogene' in the genesis of M2 AMLs. The presumed gene is likely to be
in the PAR, because if it were located in the portion of the X
chromosome not shared with the Y, then similar loss of the Y chromosome
would not be predicted, and vice versa. Gough et al. (1990) suggested
that CSF2R may be the gene in question. Loss or inactivation of both
copies of the gene in a myeloid progenitor cell would be expected to
result in a clone of cells unable to respond to GMCSF, and hence in the
relatively undifferentiated phenotype of the M2 form of leukemia.
MOLECULAR GENETICS
Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which
surfactant-derived lipoproteins accumulate excessively within pulmonary
alveoli, causing severe respiratory distress. It is a disorder of
surfactant metabolism. The importance of CSF2 in the pathogenesis of PAP
has been confirmed in humans and mice, wherein CSF2 signaling is
required for pulmonary alveolar macrophage catabolism of surfactant.
Using flow cytometry, Martinez-Moczygemba et al. (2008) found that
CSF2RA was absent on monocytes from a 4-year-old girl with PAP due to
pulmonary surfactant metabolism dysfunction (SMDP4; 300770). The
patient's mother expressed CSF2RA on all monocytes, whereas the
patient's father and sister expressed CSF2RA only on a subpopulation of
monocytes. Stimulation of granulocytes with CSF2 induced upregulation of
CD11B (ITGAM; 120980) in the mother, but not the patient. Karyotypic
analysis showed that the patient had 1 X chromosome of apparently normal
length and 1 X chromosome with a truncated Xp arm that did not hybridize
with a PAR1 probe. RT-PCR analysis detected expression of CSF2RA in
leukocytes from the patient's family members, but not in those from the
patient. PCR analysis of the 11 coding exons of the CSF2RA gene revealed
a deletion of exons 5 through 13 (306250.0001) in the patient's DNA,
providing a genetic basis for the absence of CSF2RA mRNA and protein.
Using flow cytometry, Suzuki et al. (2008) found that both CSF2RA and
CSF2RB were present on leukocytes from 2 sisters with PAP, as well as
all family members tested. However, Western blot analysis showed that
the affected sisters expressed only a truncated form of CSF2RA, whereas
their father was heterozygous for the normal and truncated forms, and
their mother expressed only normal CSF2RA. CSF2 binding and
CSF2-dependent signaling were severely reduced, but not abolished, in
the sisters, and their CD11B stimulation test was abnormal. Suzuki et
al. (2008) identified a mutation in the CSF2RA gene in the affected
sisters that resulted in a gly174-to-arg (G174R; 306250.0002)
substitution. The father was heterozygous for the G174R mutation, but
the mother had only wildtype CSF2RA. PCR analysis showed that CSF2RA
copy number was reduced in the sisters and their mother, but not in the
father. FISH analysis demonstrated a 1.6-Mb deletion of PAR1, including
the CSF2RA gene, in 1 X chromosome of the sisters and mother. Suzuki et
al. (2008) concluded that PAP may be caused by compound heterozygous
abnormalities affecting the CSF2RA gene, and that CSF2 signaling is
critical for surfactant homeostasis in humans.
ANIMAL MODEL
Schweizerhof et al. (2009) presented evidence that GCSF (CSF3; 138970)
and GMCSF mediate bone cancer pain and tumor-nerve interactions.
Increased levels of both factors were detected in bone marrow lysates
and adjoining connective tissue in a mouse sarcoma model of bone
tumor-induced pain compared to controls. The functional receptors GCSFR
(CSF3R; 138971) and GMCSFR were expressed on peripheral nerves in the
bone matrix and in dorsal root ganglia. GMCSF sensitized nerves to
mechanical stimuli in vitro and in vivo, potentiated CGRP (114130)
release, and caused sprouting of sensory nerve endings in the skin. RNA
interference of GCSF and GMCSF signaling in the mouse sarcoma model led
to reduced tumor growth and nerve remodeling, and abrogated bone cancer
pain.
*FIELD* AV
.0001
SURFACTANT METABOLISM DYSFUNCTION, PULMONARY, 4
CSF2RA, EX5-13 DEL
In a 4-year-old girl with pulmonary alveolar proteinosis (300770),
Martinez-Moczygemba et al. (2008) identified a deletion of exons 5
through 13 in the CSF2RA gene. Karyotypic analysis showed that the
patient's other X chromosome had a truncated Xp arm that did not
hybridize with a probe for pseudoautosomal region-1, which contains
CSF2RA. The patient's mother expressed CSF2RA on all monocytes, whereas
the patient's father and sister expressed CSF2RA only on a subpopulation
of monocytes. Stimulation of granulocytes with CSF2 (1389060) induced
upregulation of CD11B (ITGAM; 120980) in the mother, but not the
patient. RT-PCR analysis detected expression of CSF2RA in leukocytes
from the patient's family members, but not in those from the patient.
.0002
SURFACTANT METABOLISM DYSFUNCTION, PULMONARY, 4
CSF2RA, GLY174ARG
Suzuki et al. (2008) identified a G-to-A transition in exon 7 of the
CSF2RA gene in genomic DNA from 2 sisters with pulmonary alveolar
proteinosis (300770), one 6 years of age and the other 8 years of age.
The mutation resulted in a gly174-to-arg (G174R) substitution that
altered 1 of 11 potential N-glycosylation sites in the CSF2RA protein.
Western blot analysis showed that the affected sisters expressed only a
truncated form of CSF2RA, whereas their father was heterozygous for the
normal and truncated forms, and their mother expressed only normal
CSF2RA. CSF2 (138960) binding and CSF2-dependent signaling were severely
reduced, but not abolished, in the sisters, and their CD11B (120980)
stimulation test was abnormal. The father was heterozygous for the G174R
mutation, but the mother had only wildtype CSF2RA. PCR analysis showed
that CSF2RA copy number was reduced in the sisters and their mother, but
not in the father. FISH analysis demonstrated a 1.6-Mb deletion of
pseudoautosomal region-1, including the CSF2RA gene, in 1 X chromosome
of the sisters and mother. Transfection of CSF2RA with the G174R
mutation into 293 cells reproduced the CSF2 signaling defect at
physiologic CSF2 concentrations. At high CSF2 concentrations, similar to
those observed in the index patient, signaling was partially rescued,
thereby providing a molecular explanation for the slow disease
progression in the 2 sisters.
*FIELD* RF
1. Crow, T. J.: Sex chromosomes and psychosis: the case for a pseudoautosomal
locus. Brit. J. Psychiat. 153: 675-683, 1988.
2. Crow, T. J.: Pseudoautosomal locus for the cerebral dominance
gene. (Letter) Lancet 334: 339-340, 1989. Note: Originally Volume
II.
3. DiPersio, J.; Billing, P.; Kaufman, S.; Eghtesady, P.; Williams,
R. E.; Gasson, J. C.: Characterization of the human granulocyte-macrophage
colony-stimulating factor receptor. J. Biol. Chem. 263: 1834-1841,
1988.
4. Disteche, C. M.; Brannan, C. I.; Larsen, A.; Adler, D. A.; Schorderet,
D. F.; Gearing, D.; Copeland, N. G.; Jenkins, N. A.; Park, L. S.:
The human pseudoautosomal GM-CSF receptor alpha subunit gene is autosomal
in mouse. Nature Genet. 1: 333-336, 1992.
5. Gearing, D. P.; King, J. A.; Gough, N. M.; Nicola, N. A.: Expression
cloning of a receptor for granulocyte-macrophage colony-stimulating
factor. EMBO J. 8: 3667-3676, 1989.
6. Gough, N. M.; Gearing, D. P.; Nicola, N. A.; Baker, E.; Pritchard,
M.; Callen, D. F.; Sutherland, G. R.: Localization of the human GM-CSF
receptor gene to the X-Y pseudoautosomal region. Nature 345: 734-736,
1990.
7. Hayashida, K.; Kitamura, T.; Gorman, D. M.; Arai, K.; Yokota, T.;
Miyajima, A.: Molecular cloning of a second subunit of the receptor
for human granulocyte-macrophage colony-stimulating factor (GM-CSF):
reconstitution of a high-affinity GM-CSF receptor. Proc. Nat. Acad.
Sci. 87: 9655-9659, 1990.
8. Kondo, M.; Scherer, D. C.; Miyamoto, T.; King, A. G.; Akashi, K.;
Sugamura, K.; Weissman, I. L.: Cell-fate conversion of lymphoid-committed
progenitors by instructive actions of cytokines. Nature 407: 383-386,
2000.
9. Martinez-Moczygemba, M.; Doan, M. L.; Elidemir, O.; Fan, L. L.;
Cheung, S. W.; Lei, J. T.; Moore, J. P.; Tavana, G.; Lewis, L. R.;
Zhu, Y.; Muzny, D. M.; Gibbs, R. A.; Huston, D. P.: Pulmonary alveolar
proteinosis caused by deletion of the GM-CSFR-alpha gene in the X
chromosome pseudoautosomal region 1. J. Exp. Med. 205: 2711-2716,
2008.
10. Niikawa, N.; Kuroki, Y.; Kajii, T.; Matsuura, N.; Ishikiriyama,
S.; Tonoki, H.; Ishikawa, N.; Yamada, Y.; Fujita, M.; Umemoto, H.;
Iwama, Y.; Kondoh, I.; and 34 others: Kabuki make-up (Niikawa-Kuroki)
syndrome: a study of 62 patients. Am. J. Med. Genet. 31: 565-589,
1988.
11. Raines, M. A.; Liu, L.; Quan, S. G.; Joe, V.; DiPersio, J. F.;
Golde, D. W.: Identification and molecular cloning of a soluble human
granulocyte-macrophage colony-stimulating factor receptor. Proc.
Nat. Acad. Sci. 88: 8203-8207, 1991.
12. Rappold, G.; Willson, T. A.; Henke, A.; Gough, N. M.: Arrangement
and localization of the human GM-CSF receptor alpha chain gene CSF2RA
within the X-Y pseudoautosomal region. Genomics 14: 455-461, 1992.
13. Rappold, G. A.: The pseudoautosomal regions of the human sex
chromosomes. Hum. Genet. 92: 315-324, 1993.
14. Schweizerhof, M.; Stosser, S.; Kurejova, M.; Njoo, C.; Gangadharan,
V.; Agarwal, N.; Schmelz, M.; Bali, K. K.; Michalski, C. W.; Brugger,
S.; Dickenson, A.; Simone, D. A.; Kuner, R.: Hematopoietic colony-stimulating
factors mediate tumor-nerve interactions and bone cancer pain. (Letter) Nature
Med. 15: 802-807, 2009.
15. Suzuki, T.; Sakagami, T.; Rubin, B. K.; Nogee, L. M.; Wood, R.
E.; Zimmerman, S. L.; Smolarek, T.; Dishop, M. K.; Wert, S. E.; Whitsett,
J. A.; Grabowski, G.; Carey, B. C.; Stevens, C.; van der Loo, J. C.
M.; Trapnell, B. C.: Familial pulmonary alveolar proteinosis caused
by mutations in CSF2RA. J. Exp. Med. 205: 2703-2710, 2008.
*FIELD* CN
Cassandra L. Kniffin - updated: 8/18/2009
Matthew B. Gross - updated: 3/31/2009
Paul J. Converse - updated: 3/27/2009
Ada Hamosh - updated: 9/20/2000
*FIELD* CD
Victor A. McKusick: 8/14/1990
*FIELD* ED
carol: 05/24/2011
wwang: 9/8/2009
ckniffin: 8/18/2009
ckniffin: 4/27/2009
mgross: 3/31/2009
terry: 3/27/2009
alopez: 11/6/2003
alopez: 9/20/2000
dkim: 10/12/1998
alopez: 7/18/1997
davew: 8/18/1994
carol: 4/27/1994
terry: 4/21/1994
mimadm: 4/12/1994
warfield: 3/30/1994
carol: 12/16/1993
*RECORD*
*FIELD* NO
306250
*FIELD* TI
*306250 COLONY-STIMULATING FACTOR 2 RECEPTOR, ALPHA; CSF2RA
;;GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR RECEPTOR, LOW AFFINITY,
read moreALPHA SUBUNIT; GMCSFR
*FIELD* TX
DESCRIPTION
Granulocyte/macrophage colony-stimulating factor (GMCSF, or CSF2;
138960) activates STAT5 (601511) and other signaling pathways via
binding to a cell surface receptor composed of a ligand-binding alpha
subunit, encoded by CSF2RA, and a nonbinding affinity-enhancing beta
subunit, encoded by CSF2RB (138981) (Suzuki et al., 2008).
CLONING
Using an expression cloning strategy, Gearing et al. (1989) isolated a
cDNA encoding CSF2RA, which they called GMCSFR, from a human placenta
cDNA library. The deduced 400-amino acid precursor protein has a
22-amino acid signal peptide. The 378-amino acid mature protein has a
calculated molecular mass of 43.7 kD and contains a single transmembrane
domain, a glycosylated extracellular domain, and a short
intracytoplasmic tail. Northern blot analysis detected GMCSFR expression
in a variety of hemopoietic cells displaying GMCSF binding.
Raines et al. (1991) identified a truncated, soluble form of the
low-affinity GMCSF receptor in choriocarcinoma cells. Clones encoding
the soluble receptor were identical in sequence to the membrane-bound
form except for a 97-nucleotide deletion. The amino acid sequence of
this deleted cDNA predicted a protein that lacks the 84 C-terminal amino
acids of the membrane-bound receptor, including the transmembrane and
cytoplasmic domains, and contains 16 different amino acids at its C
terminus. RNase protection analysis indicated that this variant cDNA was
derived from a naturally occurring mRNA. Soluble receptors had been
identified for several other hematopoietin receptors and may be a
general feature of this class. It is likely that alternative mRNA
splicing is the mechanism by which the soluble counterparts are
generated.
GENE STRUCTURE
Rappold et al. (1992) found that the CSF2RA gene spans at least 45 kb.
MAPPING
By Southern blot analysis of a panel of mouse-human somatic cell
hybrids, Gough et al. (1990) demonstrated that the CSF2R gene is on the
X chromosome. The possibility that an allele also maps to the Y
chromosome was suggested by the observation that many DNA samples from
normal males carry 2 alleles of this gene. Among 65 normal persons, 23
females and 20 males were homozygous for an allele of fragment A,
whereas 8 females and 14 males were heterozygous. By in situ
hybridization, Gough et al. (1990) showed that the CSF2R gene maps to
the tip of the short arm of the X chromosome and the short arm of the Y
chromosome (see 425000), with the most likely localization being
Xpter-p21 and Ypter-p11.2. Although this information was consistent with
its location in the pseudoautosomal region (PAR), conclusive proof
required study of segregation of the locus with respect to sexual
phenotype. They found in a total of 14 informative male meioses, 3
recombination events; i.e., in 2 cases a daughter had inherited the
allele from the paternal Y chromosome, and in 1 instance a son had
inherited the allele from the paternal X chromosome. Thus, the CSF2R
locus is distal to the MIC2 locus (313470), which shows only about 2.5%
recombination and maps close to the PAR boundary. This was the first
localization of a gene of known function to this region, which
encompasses about 2,500 kb.
By pulsed field gel electrophoresis, Rappold et al. (1992) localized the
CSF2RA gene 1,180 to 1,300 kb from the telomere, in close proximity to
the CpG island B5. The gene showed abundant hypervariable sequences, and
a number of informative restriction fragment length polymorphisms were
defined. Rappold et al. (1992) suggested that these polymorphisms might
be useful in proving the pseudoautosomal inheritance of apparently
autosomal traits, as has been suggested for schizophrenia (Crow, 1988),
cerebral dominance (Crow, 1989), and Kabuki make-up syndrome (Niikawa et
al., 1988; 147920), among others.
Rappold (1993) discussed in detail the pseudoautosomal regions that
exist at the tips of the short and long arms of the X and Y chromosomes
and cover 2.6 and 0.4 Mb, respectively.
By both in situ hybridization and linkage analysis, Disteche et al.
(1992) found that the murine Csf2ra gene maps to chromosome 19.
GENE FUNCTION
DiPersio et al. (1988) studied the binding of GMCSF, over a wide range
of concentrations, to normal human peripheral blood cells, bone marrow,
acute and chronic myeloid leukemia cells, and a number of established
human myeloid and nonmyeloid cell lines; thereby, they defined the
receptors.
Gearing et al. (1989) found that transfection of GMCSFR cDNA into COS
cells directed expression of a GMCSF receptor showing a single class of
affinity and specificity for human GMCSF, but not interleukin-3 (IL3;
147740).
Hayashida et al. (1990) showed that the high-affinity GMCSF receptor is
composed of at least 2 components in a manner analogous to the IL2
receptor (see 147730). They proposed to designate the low-affinity GMCSF
receptor as the alpha subunit, and the 'new' protein that they
identified and called KH97 as the beta subunit (see 138981). The 2
subunits are approximately 80 and 120 kD, respectively.
Raines et al. (1991) found that expression of the variant cDNA encoding
the truncated, soluble CSF2R isoform produced a secreted protein that
retained its capacity to bind CSF2 in solution.
Kondo et al. (2000) showed that a clonogenic common lymphoid progenitor,
a bone marrow-resident cell that gives rise exclusively to lymphocytes
(T, B, and natural killer cells), can be redirected to the myeloid
lineage by stimulation through exogenously expressed interleukin-2
receptor (146710) and GMCSF receptor. Analysis of mutants of the
beta-chain of the IL2 receptor revealed that the granulocyte and
monocyte differentiation signals are triggered by different cytoplasmic
domains, showing that the signaling pathways responsible for these
unique developmental outcomes are separable. Finally, Kondo et al.
(2000) showed that the endogenous myelomonocytic cytokine receptors for
GMCSF and macrophage colony-stimulating factor (CSF1R; 164770) are
expressed at low to moderate levels on the more primitive hematopoietic
stem cells, are absent on common lymphoid progenitors, and are
upregulated after myeloid lineage induction by IL2 (147680). Kondo et
al. (2000) concluded that cytokine signaling can regulate cell fate
decisions and proposed that a critical step in lymphoid commitment is
downregulation of cytokine receptors that drive myeloid cell
development.
Loss of either the X or the Y chromosome is apparent in 25% of acute
myeloid leukemias of the M2 subtype (AML-M2), compared with only 1 to 6%
in other AML subtypes, suggesting the involvement of a 'recessive
oncogene' in the genesis of M2 AMLs. The presumed gene is likely to be
in the PAR, because if it were located in the portion of the X
chromosome not shared with the Y, then similar loss of the Y chromosome
would not be predicted, and vice versa. Gough et al. (1990) suggested
that CSF2R may be the gene in question. Loss or inactivation of both
copies of the gene in a myeloid progenitor cell would be expected to
result in a clone of cells unable to respond to GMCSF, and hence in the
relatively undifferentiated phenotype of the M2 form of leukemia.
MOLECULAR GENETICS
Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which
surfactant-derived lipoproteins accumulate excessively within pulmonary
alveoli, causing severe respiratory distress. It is a disorder of
surfactant metabolism. The importance of CSF2 in the pathogenesis of PAP
has been confirmed in humans and mice, wherein CSF2 signaling is
required for pulmonary alveolar macrophage catabolism of surfactant.
Using flow cytometry, Martinez-Moczygemba et al. (2008) found that
CSF2RA was absent on monocytes from a 4-year-old girl with PAP due to
pulmonary surfactant metabolism dysfunction (SMDP4; 300770). The
patient's mother expressed CSF2RA on all monocytes, whereas the
patient's father and sister expressed CSF2RA only on a subpopulation of
monocytes. Stimulation of granulocytes with CSF2 induced upregulation of
CD11B (ITGAM; 120980) in the mother, but not the patient. Karyotypic
analysis showed that the patient had 1 X chromosome of apparently normal
length and 1 X chromosome with a truncated Xp arm that did not hybridize
with a PAR1 probe. RT-PCR analysis detected expression of CSF2RA in
leukocytes from the patient's family members, but not in those from the
patient. PCR analysis of the 11 coding exons of the CSF2RA gene revealed
a deletion of exons 5 through 13 (306250.0001) in the patient's DNA,
providing a genetic basis for the absence of CSF2RA mRNA and protein.
Using flow cytometry, Suzuki et al. (2008) found that both CSF2RA and
CSF2RB were present on leukocytes from 2 sisters with PAP, as well as
all family members tested. However, Western blot analysis showed that
the affected sisters expressed only a truncated form of CSF2RA, whereas
their father was heterozygous for the normal and truncated forms, and
their mother expressed only normal CSF2RA. CSF2 binding and
CSF2-dependent signaling were severely reduced, but not abolished, in
the sisters, and their CD11B stimulation test was abnormal. Suzuki et
al. (2008) identified a mutation in the CSF2RA gene in the affected
sisters that resulted in a gly174-to-arg (G174R; 306250.0002)
substitution. The father was heterozygous for the G174R mutation, but
the mother had only wildtype CSF2RA. PCR analysis showed that CSF2RA
copy number was reduced in the sisters and their mother, but not in the
father. FISH analysis demonstrated a 1.6-Mb deletion of PAR1, including
the CSF2RA gene, in 1 X chromosome of the sisters and mother. Suzuki et
al. (2008) concluded that PAP may be caused by compound heterozygous
abnormalities affecting the CSF2RA gene, and that CSF2 signaling is
critical for surfactant homeostasis in humans.
ANIMAL MODEL
Schweizerhof et al. (2009) presented evidence that GCSF (CSF3; 138970)
and GMCSF mediate bone cancer pain and tumor-nerve interactions.
Increased levels of both factors were detected in bone marrow lysates
and adjoining connective tissue in a mouse sarcoma model of bone
tumor-induced pain compared to controls. The functional receptors GCSFR
(CSF3R; 138971) and GMCSFR were expressed on peripheral nerves in the
bone matrix and in dorsal root ganglia. GMCSF sensitized nerves to
mechanical stimuli in vitro and in vivo, potentiated CGRP (114130)
release, and caused sprouting of sensory nerve endings in the skin. RNA
interference of GCSF and GMCSF signaling in the mouse sarcoma model led
to reduced tumor growth and nerve remodeling, and abrogated bone cancer
pain.
*FIELD* AV
.0001
SURFACTANT METABOLISM DYSFUNCTION, PULMONARY, 4
CSF2RA, EX5-13 DEL
In a 4-year-old girl with pulmonary alveolar proteinosis (300770),
Martinez-Moczygemba et al. (2008) identified a deletion of exons 5
through 13 in the CSF2RA gene. Karyotypic analysis showed that the
patient's other X chromosome had a truncated Xp arm that did not
hybridize with a probe for pseudoautosomal region-1, which contains
CSF2RA. The patient's mother expressed CSF2RA on all monocytes, whereas
the patient's father and sister expressed CSF2RA only on a subpopulation
of monocytes. Stimulation of granulocytes with CSF2 (1389060) induced
upregulation of CD11B (ITGAM; 120980) in the mother, but not the
patient. RT-PCR analysis detected expression of CSF2RA in leukocytes
from the patient's family members, but not in those from the patient.
.0002
SURFACTANT METABOLISM DYSFUNCTION, PULMONARY, 4
CSF2RA, GLY174ARG
Suzuki et al. (2008) identified a G-to-A transition in exon 7 of the
CSF2RA gene in genomic DNA from 2 sisters with pulmonary alveolar
proteinosis (300770), one 6 years of age and the other 8 years of age.
The mutation resulted in a gly174-to-arg (G174R) substitution that
altered 1 of 11 potential N-glycosylation sites in the CSF2RA protein.
Western blot analysis showed that the affected sisters expressed only a
truncated form of CSF2RA, whereas their father was heterozygous for the
normal and truncated forms, and their mother expressed only normal
CSF2RA. CSF2 (138960) binding and CSF2-dependent signaling were severely
reduced, but not abolished, in the sisters, and their CD11B (120980)
stimulation test was abnormal. The father was heterozygous for the G174R
mutation, but the mother had only wildtype CSF2RA. PCR analysis showed
that CSF2RA copy number was reduced in the sisters and their mother, but
not in the father. FISH analysis demonstrated a 1.6-Mb deletion of
pseudoautosomal region-1, including the CSF2RA gene, in 1 X chromosome
of the sisters and mother. Transfection of CSF2RA with the G174R
mutation into 293 cells reproduced the CSF2 signaling defect at
physiologic CSF2 concentrations. At high CSF2 concentrations, similar to
those observed in the index patient, signaling was partially rescued,
thereby providing a molecular explanation for the slow disease
progression in the 2 sisters.
*FIELD* RF
1. Crow, T. J.: Sex chromosomes and psychosis: the case for a pseudoautosomal
locus. Brit. J. Psychiat. 153: 675-683, 1988.
2. Crow, T. J.: Pseudoautosomal locus for the cerebral dominance
gene. (Letter) Lancet 334: 339-340, 1989. Note: Originally Volume
II.
3. DiPersio, J.; Billing, P.; Kaufman, S.; Eghtesady, P.; Williams,
R. E.; Gasson, J. C.: Characterization of the human granulocyte-macrophage
colony-stimulating factor receptor. J. Biol. Chem. 263: 1834-1841,
1988.
4. Disteche, C. M.; Brannan, C. I.; Larsen, A.; Adler, D. A.; Schorderet,
D. F.; Gearing, D.; Copeland, N. G.; Jenkins, N. A.; Park, L. S.:
The human pseudoautosomal GM-CSF receptor alpha subunit gene is autosomal
in mouse. Nature Genet. 1: 333-336, 1992.
5. Gearing, D. P.; King, J. A.; Gough, N. M.; Nicola, N. A.: Expression
cloning of a receptor for granulocyte-macrophage colony-stimulating
factor. EMBO J. 8: 3667-3676, 1989.
6. Gough, N. M.; Gearing, D. P.; Nicola, N. A.; Baker, E.; Pritchard,
M.; Callen, D. F.; Sutherland, G. R.: Localization of the human GM-CSF
receptor gene to the X-Y pseudoautosomal region. Nature 345: 734-736,
1990.
7. Hayashida, K.; Kitamura, T.; Gorman, D. M.; Arai, K.; Yokota, T.;
Miyajima, A.: Molecular cloning of a second subunit of the receptor
for human granulocyte-macrophage colony-stimulating factor (GM-CSF):
reconstitution of a high-affinity GM-CSF receptor. Proc. Nat. Acad.
Sci. 87: 9655-9659, 1990.
8. Kondo, M.; Scherer, D. C.; Miyamoto, T.; King, A. G.; Akashi, K.;
Sugamura, K.; Weissman, I. L.: Cell-fate conversion of lymphoid-committed
progenitors by instructive actions of cytokines. Nature 407: 383-386,
2000.
9. Martinez-Moczygemba, M.; Doan, M. L.; Elidemir, O.; Fan, L. L.;
Cheung, S. W.; Lei, J. T.; Moore, J. P.; Tavana, G.; Lewis, L. R.;
Zhu, Y.; Muzny, D. M.; Gibbs, R. A.; Huston, D. P.: Pulmonary alveolar
proteinosis caused by deletion of the GM-CSFR-alpha gene in the X
chromosome pseudoautosomal region 1. J. Exp. Med. 205: 2711-2716,
2008.
10. Niikawa, N.; Kuroki, Y.; Kajii, T.; Matsuura, N.; Ishikiriyama,
S.; Tonoki, H.; Ishikawa, N.; Yamada, Y.; Fujita, M.; Umemoto, H.;
Iwama, Y.; Kondoh, I.; and 34 others: Kabuki make-up (Niikawa-Kuroki)
syndrome: a study of 62 patients. Am. J. Med. Genet. 31: 565-589,
1988.
11. Raines, M. A.; Liu, L.; Quan, S. G.; Joe, V.; DiPersio, J. F.;
Golde, D. W.: Identification and molecular cloning of a soluble human
granulocyte-macrophage colony-stimulating factor receptor. Proc.
Nat. Acad. Sci. 88: 8203-8207, 1991.
12. Rappold, G.; Willson, T. A.; Henke, A.; Gough, N. M.: Arrangement
and localization of the human GM-CSF receptor alpha chain gene CSF2RA
within the X-Y pseudoautosomal region. Genomics 14: 455-461, 1992.
13. Rappold, G. A.: The pseudoautosomal regions of the human sex
chromosomes. Hum. Genet. 92: 315-324, 1993.
14. Schweizerhof, M.; Stosser, S.; Kurejova, M.; Njoo, C.; Gangadharan,
V.; Agarwal, N.; Schmelz, M.; Bali, K. K.; Michalski, C. W.; Brugger,
S.; Dickenson, A.; Simone, D. A.; Kuner, R.: Hematopoietic colony-stimulating
factors mediate tumor-nerve interactions and bone cancer pain. (Letter) Nature
Med. 15: 802-807, 2009.
15. Suzuki, T.; Sakagami, T.; Rubin, B. K.; Nogee, L. M.; Wood, R.
E.; Zimmerman, S. L.; Smolarek, T.; Dishop, M. K.; Wert, S. E.; Whitsett,
J. A.; Grabowski, G.; Carey, B. C.; Stevens, C.; van der Loo, J. C.
M.; Trapnell, B. C.: Familial pulmonary alveolar proteinosis caused
by mutations in CSF2RA. J. Exp. Med. 205: 2703-2710, 2008.
*FIELD* CN
Cassandra L. Kniffin - updated: 8/18/2009
Matthew B. Gross - updated: 3/31/2009
Paul J. Converse - updated: 3/27/2009
Ada Hamosh - updated: 9/20/2000
*FIELD* CD
Victor A. McKusick: 8/14/1990
*FIELD* ED
carol: 05/24/2011
wwang: 9/8/2009
ckniffin: 8/18/2009
ckniffin: 4/27/2009
mgross: 3/31/2009
terry: 3/27/2009
alopez: 11/6/2003
alopez: 9/20/2000
dkim: 10/12/1998
alopez: 7/18/1997
davew: 8/18/1994
carol: 4/27/1994
terry: 4/21/1994
mimadm: 4/12/1994
warfield: 3/30/1994
carol: 12/16/1993
MIM
425000
*RECORD*
*FIELD* NO
425000
*FIELD* TI
*425000 GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR RECEPTOR, ALPHA SUBUNIT,
Y-CHROMOSOMAL; CSF2RY
read more*FIELD* TX
By in situ hybridization, Gough et al. (1990) showed that the gene for
the alpha subunit of the granulocyte-macrophage colony-stimulating
factor (CSF2R) maps to the tip of the short arm of the X chromosome and
to the short arm of the Y chromosome, with the most likely location
being Xpter-p21 (306250) and Ypter-p11.2. Although this information was
consistent with the location of the gene in the pseudoautosomal region
(PAR), conclusive proof required study of segregation of the locus with
respect to its actual phenotype. In a total of 14 informative male
meioses, they found 3 recombination events, i.e., in 2 cases, a daughter
had inherited the allele from the paternal Y chromosome, and in 1 case,
a son had inherited the allele from the paternal X chromosome. Thus, the
CSF2R locus is distal to the MIC2 locus (313470, 450000), which shows
only about 2.5% recombination with the sexual phenotype and maps close
to the PAR boundary. CSF2R was the first gene of known function to be
mapped to the PAR, which encompasses about 2,500 kb. Loss of either the
X or the Y chromosome is apparent in 25% of acute myeloid leukemias of
the M2 subtype (AML-M2), compared with only 1 to 6% of other AML
subtypes, suggesting the involvement of a 'recessive oncogene' in the
genesis of M2 AMLs. The presumed gene is likely to be in the PAR,
because if it were located in the portion of the X chromosome not shared
with the Y, then similar loss of the Y chromosome would not be predicted
and vice versa. Gough et al. (1990) suggested that CSF2R may be the gene
in question. Loss or inactivation of both copies of the gene in a
myeloid progenitor cell would be expected to result in a clone of cells
unable to respond to GM-CSF, and hence in the relatively
undifferentiated phenotype of the M2 form of leukemia.
*FIELD* RF
1. Gough, N. M.; Gearing, D. P.; Nicola, N. A.; Baker, E.; Pritchard,
M.; Callen, D. F.; Sutherland, G. R.: Localization of the human GM-CSF
receptor gene to the X-Y pseudoautosomal region. Nature 345: 734-736,
1990.
*FIELD* CD
Victor A. McKusick: 9/14/1992
*FIELD* ED
mimadm: 3/11/1994
carol: 9/22/1992
carol: 9/14/1992
*RECORD*
*FIELD* NO
425000
*FIELD* TI
*425000 GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR RECEPTOR, ALPHA SUBUNIT,
Y-CHROMOSOMAL; CSF2RY
read more*FIELD* TX
By in situ hybridization, Gough et al. (1990) showed that the gene for
the alpha subunit of the granulocyte-macrophage colony-stimulating
factor (CSF2R) maps to the tip of the short arm of the X chromosome and
to the short arm of the Y chromosome, with the most likely location
being Xpter-p21 (306250) and Ypter-p11.2. Although this information was
consistent with the location of the gene in the pseudoautosomal region
(PAR), conclusive proof required study of segregation of the locus with
respect to its actual phenotype. In a total of 14 informative male
meioses, they found 3 recombination events, i.e., in 2 cases, a daughter
had inherited the allele from the paternal Y chromosome, and in 1 case,
a son had inherited the allele from the paternal X chromosome. Thus, the
CSF2R locus is distal to the MIC2 locus (313470, 450000), which shows
only about 2.5% recombination with the sexual phenotype and maps close
to the PAR boundary. CSF2R was the first gene of known function to be
mapped to the PAR, which encompasses about 2,500 kb. Loss of either the
X or the Y chromosome is apparent in 25% of acute myeloid leukemias of
the M2 subtype (AML-M2), compared with only 1 to 6% of other AML
subtypes, suggesting the involvement of a 'recessive oncogene' in the
genesis of M2 AMLs. The presumed gene is likely to be in the PAR,
because if it were located in the portion of the X chromosome not shared
with the Y, then similar loss of the Y chromosome would not be predicted
and vice versa. Gough et al. (1990) suggested that CSF2R may be the gene
in question. Loss or inactivation of both copies of the gene in a
myeloid progenitor cell would be expected to result in a clone of cells
unable to respond to GM-CSF, and hence in the relatively
undifferentiated phenotype of the M2 form of leukemia.
*FIELD* RF
1. Gough, N. M.; Gearing, D. P.; Nicola, N. A.; Baker, E.; Pritchard,
M.; Callen, D. F.; Sutherland, G. R.: Localization of the human GM-CSF
receptor gene to the X-Y pseudoautosomal region. Nature 345: 734-736,
1990.
*FIELD* CD
Victor A. McKusick: 9/14/1992
*FIELD* ED
mimadm: 3/11/1994
carol: 9/22/1992
carol: 9/14/1992