RBCC

Full text data of CSF3R

CSF3R (GCSFR) [Confidence: high (a blood group or CD marker)]
Granulocyte colony-stimulating factor receptor; G-CSF receptor; G-CSF-R (CD114; Flags: Precursor)

UniProt Q99062
ID CSF3R_HUMAN Reviewed; 836 AA.
AC Q99062;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1995, sequence version 1.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Granulocyte colony-stimulating factor receptor;
DE Short=G-CSF receptor;
DE Short=G-CSF-R;
DE AltName: CD_antigen=CD114;
DE Flags: Precursor;
GN Name=CSF3R; Synonyms=GCSFR;
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] (ISOFORMS 1 AND 4).
RC TISSUE=Placenta;
RX PubMed=2147944; DOI=10.1084/jem.172.6.1559;
RA Larsen A., Davis T., Curtis B.M., Gimpel S., Sims J.E., Cosman D.,
RA Park L., Sorensen E., March C.J., Smith C.A.;
RT "Expression cloning of a human granulocyte colony-stimulating factor
RT receptor: a structural mosaic of hematopoietin receptor,
RT immunoglobulin, and fibronectin domains.";
RL J. Exp. Med. 172:1559-1570(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3).
RC TISSUE=Placenta;
RX PubMed=1701053; DOI=10.1073/pnas.87.22.8702;
RA Fukunaga R., Seto Y., Mizushima S., Nagata S.;
RT "Three different mRNAs encoding human granulocyte colony-stimulating
RT factor receptor.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:8702-8706(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1530796;
RA Seto Y., Fukunaga R., Nagata S.;
RT "Chromosomal gene organization of the human granulocyte colony-
RT stimulating factor receptor.";
RL J. Immunol. 148:259-266(1992).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-231; ASN-320;
RP ARG-346; LYS-405; GLN-440; HIS-510; HIS-562 AND CYS-583.
RG SeattleSNPs variation discovery resource;
RL Submitted (SEP-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Blood;
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 [6]
RP PROTEIN SEQUENCE OF 234-269.
RX PubMed=8554326; DOI=10.1006/abbi.1995.0047;
RA Haniu M., Horan T., Arakawa T., Le J., Katta V., Rohde M.F.;
RT "Extracellular domain of granulocyte-colony stimulating factor
RT receptor. Interaction with its ligand and identification of a domain
RT in close proximity of ligand-binding region.";
RL Arch. Biochem. Biophys. 324:344-356(1995).
RN [7]
RP DOMAINS.
RX PubMed=1717255;
RA Fukunaga R., Ishizaka-Ikeda E., Pan C.-X., Seto Y., Nagata S.;
RT "Functional domains of the granulocyte colony-stimulating factor
RT receptor.";
RL EMBO J. 10:2855-2865(1991).
RN [8]
RP FUNCTION, AND POSSIBLE ASSOCIATION WITH SCN.
RX PubMed=7514305; DOI=10.1073/pnas.91.10.4480;
RA Dong F., Hoefsloot L.H., Schelen A.M., Broeders C.A., Meijer Y.,
RA Veerman A.J., Touw I.P., Lowenberg B.;
RT "Identification of a nonsense mutation in the granulocyte-colony-
RT stimulating factor receptor in severe congenital neutropenia.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:4480-4484(1994).
RN [9]
RP REVIEW.
RX PubMed=17127321; DOI=10.2741/2103;
RA Touw I.P., van de Geijn G.J.;
RT "Granulocyte colony-stimulating factor and its receptor in normal
RT myeloid cell development, leukemia and related blood cell disorders.";
RL Front. Biosci. 12:800-815(2007).
RN [10]
RP POSSIBLE ASSOCIATION WITH SCN.
RX PubMed=19120359; DOI=10.1111/j.1365-2141.2008.07425.x;
RA Zeidler C., Germeshausen M., Klein C., Welte K.;
RT "Clinical implications of ELA2-, HAX1-, and G-CSF-receptor (CSF3R)
RT mutations in severe congenital neutropenia.";
RL Br. J. Haematol. 144:459-467(2009).
RN [11]
RP STRUCTURE BY NMR OF 227-334.
RX PubMed=9187659; DOI=10.1038/nsb0697-498;
RA Yamasaki K., Naito S., Anaguchi H., Ohkubo T., Ota Y.;
RT "Solution structure of an extracellular domain containing the WSxWS
RT motif of the granulocyte colony-stimulating factor receptor and its
RT interaction with ligand.";
RL Nat. Struct. Biol. 4:498-504(1997).
RN [12]
RP 3D-STRUCTURE MODELING OF 125-331.
RX PubMed=9368043; DOI=10.1074/jbc.272.47.29735;
RA Layton J.E., Iaria J., Smith D.K., Treutlein H.R.;
RT "Identification of a ligand-binding site on the granulocyte colony-
RT stimulating factor receptor by molecular modeling and mutagenesis.";
RL J. Biol. Chem. 272:29735-29741(1997).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 25-333 IN COMPLEX WITH CSF3,
RP GLYCOSYLATION AT ASN-134, DISULFIDE BONDS, AND SUBUNIT.
RX PubMed=16492764; DOI=10.1073/pnas.0511264103;
RA Tamada T., Honjo E., Maeda Y., Okamoto T., Ishibashi M., Tokunaga M.,
RA Kuroki R.;
RT "Homodimeric cross-over structure of the human granulocyte colony-
RT stimulating factor (GCSF) receptor signaling complex.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:3135-3140(2006).
RN [14]
RP VARIANT HIS-229, CHARACTERIZATION OF VARIANT HIS-229, AND POSSIBLE
RP ASSOCIATION WITH SCN.
RX PubMed=10449521; DOI=10.1084/jem.190.4.497;
RA Ward A.C., van Aesch Y.M., Gits J., Schelen A.M., de Koning J.P.,
RA van Leeuwen D., Freedman M.H., Touw I.P.;
RT "Novel point mutation in the extracellular domain of the granulocyte
RT colony-stimulating factor (G-CSF) receptor in a case of severe
RT congenital neutropenia hyporesponsive to G-CSF treatment.";
RL J. Exp. Med. 190:497-507(1999).
RN [15]
RP VARIANT NEUTROPHILIA ASN-640.
RX PubMed=19620628; DOI=10.1084/jem.20090693;
RA Plo I., Zhang Y., Le Couedic J.P., Nakatake M., Boulet J.M., Itaya M.,
RA Smith S.O., Debili N., Constantinescu S.N., Vainchenker W.,
RA Louache F., de Botton S.;
RT "An activating mutation in the CSF3R gene induces a hereditary chronic
RT neutrophilia.";
RL J. Exp. Med. 206:1701-1707(2009).
CC -!- FUNCTION: Receptor for granulocyte colony-stimulating factor
CC (CSF3), essential for granulocytic maturation. Plays a crucial
CC role in the proliferation, differientation and survival of cells
CC along the neutrophilic lineage. In addition it may function in
CC some adhesion or recognition events at the cell surface.
CC -!- SUBUNIT: Homodimer. The dimeric receptor binds two CSF3 molecules.
CC -!- INTERACTION:
CC P40763:STAT3; NbExp=4; IntAct=EBI-7331284, EBI-518675;
CC P0CG48:UBC; NbExp=2; IntAct=EBI-7331284, EBI-3390054;
CC -!- SUBCELLULAR LOCATION: Isoform 2: Secreted (Probable).
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Comment=Additional isoforms seem to exist. Experimental
CC confirmation may be lacking for some isoforms;
CC Name=1; Synonyms=GCSFR-1;
CC IsoId=Q99062-1; Sequence=Displayed;
CC Name=2; Synonyms=GCSFR-2;
CC IsoId=Q99062-2; Sequence=VSP_001674;
CC Name=3; Synonyms=GCSFR-3;
CC IsoId=Q99062-3; Sequence=VSP_001673;
CC Name=4; Synonyms=GCSFR-4, D7;
CC IsoId=Q99062-4; Sequence=VSP_001671, VSP_001672;
CC -!- TISSUE SPECIFICITY: One or several isoforms have been found in
CC myelogenous leukemia cell line KG-1, leukemia U-937 cell line, in
CC bone marrow cells, placenta, and peripheral blood granulocytes.
CC Isoform GCSFR-2 is found only in leukemia U-937 cells. Isoform
CC GCSFR-3 is highly expressed in placenta.
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: Hereditary neutrophilia (NEUTROPHILIA) [MIM:162830]: A
CC form of lifelong, persistent neutrophilia, a condition
CC characterized by an increase in the number of neutrophils in the
CC blood. Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- MISCELLANEOUS: Mutations in CSF3R acquired in multipotent
CC hematopoietic progenitor cells and resulting in truncated hyper-
CC responsive forms of the receptor, have been identified in most
CC cases of severe congenital neutropenia (SCN). Patients carrying
CC these mutations are at risk for developing myelodysplastic
CC syndromes and/or acute myeloid leukemia. Constitutive mutations
CC leading to hyporesponsive forms of the receptor are responsible
CC for the refractoriness to CSF3 treatment observed in some SCN
CC patients.
CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 2
CC subfamily.
CC -!- SIMILARITY: Contains 5 fibronectin type-III domains.
CC -!- SIMILARITY: Contains 1 Ig-like C2-type (immunoglobulin-like)
CC domain.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/csf3r/";
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DR EMBL; X55721; CAA39253.1; -; mRNA.
DR EMBL; X55720; CAA39252.1; -; mRNA.
DR EMBL; M59818; AAA63176.1; -; mRNA.
DR EMBL; M59819; AAA63177.1; -; mRNA.
DR EMBL; M59820; AAA63178.1; -; mRNA.
DR EMBL; S71484; AAB20660.1; -; Genomic_DNA.
DR EMBL; AY148100; AAN05790.1; -; Genomic_DNA.
DR EMBL; BC053585; AAH53585.1; -; mRNA.
DR PIR; B38252; B38252.
DR PIR; C38252; C38252.
DR PIR; JH0329; JH0329.
DR RefSeq; NP_000751.1; NM_000760.3.
DR RefSeq; NP_724781.1; NM_156039.3.
DR RefSeq; NP_758519.1; NM_172313.2.
DR RefSeq; XP_005270551.1; XM_005270494.1.
DR UniGene; Hs.524517; -.
DR PDB; 1AZ7; Model; -; A=125-331.
DR PDB; 2D9Q; X-ray; 2.80 A; B=25-333.
DR PDBsum; 1AZ7; -.
DR PDBsum; 2D9Q; -.
DR ProteinModelPortal; Q99062; -.
DR SMR; Q99062; 23-618.
DR DIP; DIP-5788N; -.
DR IntAct; Q99062; 2.
DR MINT; MINT-4787360; -.
DR STRING; 9606.ENSP00000342623; -.
DR BindingDB; Q99062; -.
DR ChEMBL; CHEMBL1996; -.
DR DrugBank; DB00099; Filgrastim.
DR DrugBank; DB00019; Pegfilgrastim.
DR GuidetoPHARMACOLOGY; 1719; -.
DR PhosphoSite; Q99062; -.
DR DMDM; 729564; -.
DR PaxDb; Q99062; -.
DR PRIDE; Q99062; -.
DR Ensembl; ENST00000331941; ENSP00000332180; ENSG00000119535.
DR Ensembl; ENST00000361632; ENSP00000355406; ENSG00000119535.
DR Ensembl; ENST00000373103; ENSP00000362195; ENSG00000119535.
DR Ensembl; ENST00000373104; ENSP00000362196; ENSG00000119535.
DR Ensembl; ENST00000373106; ENSP00000362198; ENSG00000119535.
DR Ensembl; ENST00000418048; ENSP00000401588; ENSG00000119535.
DR Ensembl; ENST00000440588; ENSP00000397568; ENSG00000119535.
DR GeneID; 1441; -.
DR KEGG; hsa:1441; -.
DR UCSC; uc001caw.2; human.
DR CTD; 1441; -.
DR GeneCards; GC01M036931; -.
DR HGNC; HGNC:2439; CSF3R.
DR HPA; CAB017116; -.
DR MIM; 138971; gene.
DR MIM; 162830; phenotype.
DR neXtProt; NX_Q99062; -.
DR Orphanet; 98824; Atypical chronic myeloid leukemia.
DR Orphanet; 86829; Chronic neutrophilic leukemia.
DR Orphanet; 279943; Hereditary neutrophilia.
DR PharmGKB; PA26942; -.
DR eggNOG; NOG29566; -.
DR HOGENOM; HOG000231142; -.
DR HOVERGEN; HBG051130; -.
DR KO; K05061; -.
DR OMA; YLRCDST; -.
DR OrthoDB; EOG7FXZXN; -.
DR SignaLink; Q99062; -.
DR ChiTaRS; CSF3R; human.
DR EvolutionaryTrace; Q99062; -.
DR GeneWiki; Granulocyte_colony-stimulating_factor_receptor; -.
DR GenomeRNAi; 1441; -.
DR NextBio; 5901; -.
DR PRO; PR:Q99062; -.
DR ArrayExpress; Q99062; -.
DR Bgee; Q99062; -.
DR CleanEx; HS_CSF3R; -.
DR Genevestigator; Q99062; -.
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:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IEA:GOC.
DR GO; GO:0006952; P:defense response; TAS:ProtInc.
DR GO; GO:0030593; P:neutrophil chemotaxis; IEA:Ensembl.
DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IEA:Ensembl.
DR Gene3D; 2.60.40.10; -; 6.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR003529; Hematopoietin_rcpt_Gp130_CS.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR010457; IgC2-like_lig-bd.
DR Pfam; PF00041; fn3; 1.
DR Pfam; PF06328; Lep_receptor_Ig; 1.
DR SMART; SM00060; FN3; 5.
DR SUPFAM; SSF49265; SSF49265; 4.
DR PROSITE; PS50853; FN3; 5.
DR PROSITE; PS01353; HEMATOPO_REC_L_F2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell adhesion; Cell membrane;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW Disulfide bond; Glycoprotein; Immunoglobulin domain; Membrane;
KW Polymorphism; Receptor; Reference proteome; Repeat; Secreted; Signal;
KW Transmembrane; Transmembrane helix.
FT SIGNAL 1 24
FT CHAIN 25 836 Granulocyte colony-stimulating factor
FT receptor.
FT /FTId=PRO_0000010874.
FT TOPO_DOM 25 627 Extracellular (Potential).
FT TRANSMEM 628 650 Helical; (Potential).
FT TOPO_DOM 651 836 Cytoplasmic (Potential).
FT DOMAIN 25 117 Ig-like C2-type.
FT DOMAIN 125 230 Fibronectin type-III 1.
FT DOMAIN 233 332 Fibronectin type-III 2.
FT DOMAIN 334 430 Fibronectin type-III 3.
FT DOMAIN 431 528 Fibronectin type-III 4.
FT DOMAIN 530 623 Fibronectin type-III 5.
FT MOTIF 318 322 WSXWS motif.
FT MOTIF 658 666 Box 1 motif.
FT CARBOHYD 51 51 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 93 93 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 128 128 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 134 134 N-linked (GlcNAc...).
FT CARBOHYD 389 389 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 474 474 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 579 579 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 610 610 N-linked (GlcNAc...) (Potential).
FT DISULFID 26 52
FT DISULFID 46 101
FT DISULFID 131 142
FT DISULFID 167 218
FT DISULFID 177 186
FT DISULFID 248 295
FT DISULFID 266 309
FT VAR_SEQ 622 836 EGSELHIILGLFGLLLLLTCLCGTAWLCCSPNRKNPLWPSV
FT PDPAHSSLGSWVPTIMEEDAFQLPGLGTPPITKLTVLEEDE
FT KKPVPWESHNSSETCGLPTLVQTYVLQGDPRAVSTQPQSQS
FT GTSDQVLYGQLLGSPTSPGPGHYLRCDSTQPLLAGLTPSPK
FT SYENLWFQASPLGTLVTPAPSQEDDCVFGPLLNFPLLQGIR
FT VHGMEALGSF -> APTGRIPSGQVSQTQLTAAWAPGCPQS
FT WRRMPSSCPALARHPSPSSQCWRRMKRSRCPGSPITAQRPV
FT ASPLWSRPMCSRGTQEQFPPSPNPSLAPAIRSFMGSCWAAP
FT QAQGQGTISAVTPLSPSWRASPPAPSPMRTSGSRPAPWGPW
FT (in isoform 2).
FT /FTId=VSP_001674.
FT VAR_SEQ 680 680 E -> ELPGPRQGQWLGQTSEMSRALTPHPCVQ (in
FT isoform 3).
FT /FTId=VSP_001673.
FT VAR_SEQ 750 783 VLYGQLLGSPTSPGPGHYLRCDSTQPLLAGLTPS -> AGP
FT PRRSAYFKDQIMLHPAPPNGLLCLFPITSVL (in
FT isoform 4).
FT /FTId=VSP_001671.
FT VAR_SEQ 784 836 Missing (in isoform 4).
FT /FTId=VSP_001672.
FT VARIANT 229 229 P -> H (in a patient with severe
FT congenital neutropenia hyporesponsive to
FT CSF3 treatment; affects CSF3 mediated
FT proliferation and survival of myeloid
FT cells; abrogates receptor signaling by
FT altering ligand binding).
FT /FTId=VAR_062517.
FT VARIANT 231 231 M -> T (in dbSNP:rs3917973).
FT /FTId=VAR_014325.
FT VARIANT 320 320 D -> N (in dbSNP:rs3918018).
FT /FTId=VAR_014326.
FT VARIANT 346 346 Q -> R (in dbSNP:rs3917974).
FT /FTId=VAR_014327.
FT VARIANT 405 405 E -> K (in dbSNP:rs3918019).
FT /FTId=VAR_014328.
FT VARIANT 440 440 R -> Q (in dbSNP:rs3918020).
FT /FTId=VAR_014329.
FT VARIANT 510 510 D -> H (in dbSNP:rs3917991).
FT /FTId=VAR_014330.
FT VARIANT 562 562 Y -> H (in dbSNP:rs3917996).
FT /FTId=VAR_014331.
FT VARIANT 583 583 R -> C (in dbSNP:rs3917997).
FT /FTId=VAR_014332.
FT VARIANT 640 640 T -> N (in neutrophilia;
FT dbSNP:rs121918426).
FT /FTId=VAR_063065.
FT STRAND 29 32
FT STRAND 34 36
FT STRAND 42 46
FT STRAND 62 67
FT STRAND 79 81
FT STRAND 85 90
FT STRAND 94 119
FT STRAND 127 134
FT TURN 135 138
FT STRAND 139 145
FT STRAND 155 162
FT STRAND 174 177
FT STRAND 184 189
FT HELIX 190 192
FT STRAND 195 197
FT STRAND 199 207
FT STRAND 210 213
FT STRAND 217 219
FT HELIX 221 224
FT STRAND 231 234
FT STRAND 249 254
FT HELIX 257 259
FT STRAND 264 275
FT STRAND 280 285
FT STRAND 289 294
FT STRAND 303 311
FT STRAND 325 327
SQ SEQUENCE 836 AA; 92156 MW; 3531ADDC979D4BC3 CRC64;
MARLGNCSLT WAALIILLLP GSLEECGHIS VSAPIVHLGD PITASCIIKQ NCSHLDPEPQ
ILWRLGAELQ PGGRQQRLSD GTQESIITLP HLNHTQAFLS CCLNWGNSLQ ILDQVELRAG
YPPAIPHNLS CLMNLTTSSL ICQWEPGPET HLPTSFTLKS FKSRGNCQTQ GDSILDCVPK
DGQSHCCIPR KHLLLYQNMG IWVQAENALG TSMSPQLCLD PMDVVKLEPP MLRTMDPSPE
AAPPQAGCLQ LCWEPWQPGL HINQKCELRH KPQRGEASWA LVGPLPLEAL QYELCGLLPA
TAYTLQIRCI RWPLPGHWSD WSPSLELRTT ERAPTVRLDT WWRQRQLDPR TVQLFWKPVP
LEEDSGRIQG YVVSWRPSGQ AGAILPLCNT TELSCTFHLP SEAQEVALVA YNSAGTSRPT
PVVFSESRGP ALTRLHAMAR DPHSLWVGWE PPNPWPQGYV IEWGLGPPSA SNSNKTWRME
QNGRATGFLL KENIRPFQLY EIIVTPLYQD TMGPSQHVYA YSQEMAPSHA PELHLKHIGK
TWAQLEWVPE PPELGKSPLT HYTIFWTNAQ NQSFSAILNA SSRGFVLHGL EPASLYHIHL
MAASQAGATN STVLTLMTLT PEGSELHIIL GLFGLLLLLT CLCGTAWLCC SPNRKNPLWP
SVPDPAHSSL GSWVPTIMEE DAFQLPGLGT PPITKLTVLE EDEKKPVPWE SHNSSETCGL
PTLVQTYVLQ GDPRAVSTQP QSQSGTSDQV LYGQLLGSPT SPGPGHYLRC DSTQPLLAGL
TPSPKSYENL WFQASPLGTL VTPAPSQEDD CVFGPLLNFP LLQGIRVHGM EALGSF
//

MIM 138971
*RECORD*
*FIELD* NO
138971
*FIELD* TI
*138971 COLONY-STIMULATING FACTOR 3 RECEPTOR, GRANULOCYTE; CSF3R
;;GRANULOCYTE COLONY-STIMULATING FACTOR RECEPTOR; GCSFR
read more*FIELD* TX

CLONING

Granulocyte colony-stimulating factor or CSF3 (138970), is a
glycoprotein of MW 20,000-25,000 that is produced by macrophages
stimulated with endotoxin. It plays an important role in granulopoiesis
during the inflammatory process. CSF3 exerts its biologic effects
through interaction with specific cell-surface receptors. Binding
studies with radiolabeled CSF3 indicated that CSF3 receptor is expressed
not only by progenitor and mature neutrophilic granulocytes, but also by
nonhematopoietic cells such as placental cells, endothelial cells, and
various carcinoma cell lines. Fukunaga et al. (1990) cloned and
characterized cDNAs for human CSF3 receptor. They found that it is
abundantly expressed in the human placenta. The receptor contains 813
amino acids and shows marked homology (62.5%) with its murine
counterpart. It was found to consist of extracellular, transmembrane,
and cytoplasmic domains. Two other classes of the human CSF3 receptor
were identified, one of which had a deletion of the transmembrane domain
and seemed to represent a secreted, soluble receptor. The third class
contained a 27-amino acid insertion in the cytoplasmic domain and was
highly expressed in the placenta.

Seto et al. (1992) found that CSF3R is subdivided into several regions:
an Ig-like domain, a cytokine receptor homologous domain, 3 fibronectin
type III domains, a transmembrane domain, and a cytoplasmic region. No
canonical 'TATA' box was found upstream of the cap site. About 110 bp
upstream of the transcription initiation site, an 18-bp element was
found that is homologous to sequences found in the promoter of human
myeloperoxidase (606989) and neutrophil elastase (130120) genes.

GENE FUNCTION

Dong et al. (2001) reported that the C terminus of CSF3R is required for
SHP1 (176883) downregulation of CSF3-induced STAT activation. The
authors proposed that this mechanism inhibits cell proliferation and
survival in response to CSF3.

GENE STRUCTURE

Seto et al. (1992) found that the CSF3R gene consists of 17 exons.

MAPPING

By in situ hybridization using human CSF3R cDNA as a probe, Inazawa et
al. (1991) localized the gene to 1p35-p34.3. The localization on
chromosome 1 was confirmed by 2 further methods: the use of
oligonucleotides specific for human CSF3R for PCR amplification of DNA
from mouse A9 cells that contained chromosome 1 as the only human
chromosome; and spot-blot hybridization of sorted human chromosomes.
Tweardy et al. (1992) assigned the gene to the distal short arm of human
chromosome 1 by Southern blot analysis of its segregation pattern in a
panel of rodent-human hybrid DNAs. By chromosomal in situ hybridization,
they refined the localization to 1p34-p32 and concluded that the gene is
located telomeric to the CSF1 (120420), JUN (165160), and TCL5 (187040)
genes.

MOLECULAR GENETICS

Dong et al. (1994) identified a somatic point mutation in the GCSFR gene
as the cause of acute myeloid leukemia (AML) in a patient with severe
congenital neutropenia (202700). Dong et al. (1995) described somatic
mutations in the GCSFR gene in 2 males with acute myeloid leukemia
preceded by severe congenital neutropenia. In 1 patient, the mutation
was also found in the neutropenic stage, before the progression to acute
myeloid leukemia. Transfection of the cDNA encoding the mutant GCSF
receptor into mouse cells resulted in abnormally high proliferative
responses but failure to mature when cultured in GCSF. The mutant
receptors also interfered with terminal maturation mediated by the
wildtype GCSF receptor and the murine cells that coexpressed the
wildtype and mutant receptors, an apparent dominant-negative effect.

Tidow et al. (1997) investigated the frequency of these specific
mutations in patients with congenital neutropenia undergoing treatment
with recombinant human granulocyte colony-stimulating factor
(Filgrastim). The critical region (nucleotides 2384-2429) from the
intracellular domain of the GCSFR gene was studied in both genomic DNA
and cDNA from neutrophils and mononuclear cells from 28 patients with
severe congenital neutropenia. In 4 of the patients, a point mutation in
the tested cytoplasmic region of the GCSFR gene was found. The point
mutations replaced a glutamine codon by a stop codon. Among these 4
congenital neutropenia patients with a mutated GCSFR gene, 2 developed
AML. All 4 patients were investigated regularly and no correlation
between occurrence of GCSFR mutation and time or dose of Filgrastim was
found. No point mutations in the GCSFR critical domain could be detected
in cells from the other 24 congenital neutropenia patients. Furthermore,
Tidow et al. (1997) tested 6 family members of the 2 patients with AML,
including mothers and fathers, 1 sister, and 1 brother who also suffered
from congenital neutropenia. All family members had a normal GCSFR gene.
After the acquisition of the GCSFR mutations, the congenital neutropenia
patients continued to respond to G-CSFR therapy with an increase in
absolute neutrophils in the peripheral blood. Tidow et al. (1997)
concluded that the point mutations in the critical region of the
intracellular part of the G-CSF receptor occur spontaneously and are not
inherited. They suggested, furthermore, that the described point
mutations do not alter the response to treatment and are not the cause
of severe congenital neutropenia.

Dale et al. (2000) quoted prevalence data suggesting that a minority of
patients with congenital neutropenia show mutations in GCSFR. On the
other hand, mutations in the neutrophil elastase gene (ELA2; 130130)
have been identified in a majority of these patients. Dale et al. (2000)
suggested that it is much more likely that mutations in the ELA2 gene
compromise myeloid differentiation and create a risk for development of
acute myeloid leukemia.

In a 3-generation family segregating autosomal dominant neutrophilia
(162830), Plo et al. (2009) sequenced the CSF3R gene and identified a
heterozygous mutation (T617N; 138971.0001) in all 12 affected
individuals that was not found in the 4 unaffected family members. The
mutation disappeared after remission and was not detected at relapse,
indicating that the T617N mutation was a secondary event in the leukemic
process. The T617N mutation had previously been reported as an acquired
activating mutation in 2 of 555 patients with acute myeloid leukemia by
Forbes et al. (2002).

Maxson et al. (2013) identified activating mutations in the CSF3R gene
in 16 of 27 patients (59%) with chronic neutrophilic leukemia (CNL) or
atypical (BCR-ABL1-negative; see 608232) chronic myeloid leukemia (CML).
These mutations segregated within 2 distinct regions of CSF3R and led to
preferential downstream kinase signaling through SRC family (see
190090)-TNK2 (606994) or JAK kinases and differential sensitivity to
kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R
mutation had marked clinical improvement after the administration of the
JAK1/2 (see 147795) inhibitor ruxolitinib.

ANIMAL MODEL

Despite the demonstration of mutations in CSF3R, their role in the
pathogenesis of SCN and the subsequent development of acute myeloid
leukemia remained controversial. McLemore et al. (1998) generated mice
carrying a targeted mutation in their Csf3r gene that reproduced a
mutation found in a patient with SCN and AML reported by Dong et al.
(1995). They found that the mutant Csf3r allele was expressed in a
myeloid-specific fashion at levels comparable to the wildtype allele.
Mice heterozygous or homozygous for this mutation had normal levels of
circulating neutrophils and no evidence for a block in myeloid
maturation, indicating that resting granulopoiesis was normal. However,
in response to GCSF treatment, these mice demonstrated a significantly
greater increase in the level of circulating neutrophils. This effect
appeared to be due to increased neutrophil production. Furthermore, the
in vitro survival and GCSF-dependent suppression of apoptosis of mutant
neutrophils were normal. Despite this evidence for a hyperproliferative
response to GCSF, no cases of AML were detected. McLemore et al. (1998)
interpreted the results as providing strong evidence that mutations in
the CSF3R gene are not responsible for the impaired granulopoiesis
present in patients with SCN.

Schweizerhof et al. (2009) presented evidence that GCSF and GMCSF (CSF2;
138960) 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
and GMCSFR (CSF2RA; 306250) 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 mouse sarcoma model led to
reduced tumor growth and nerve remodeling, and abrogated bone cancer
pain.

*FIELD* AV
.0001
NEUTROPHILIA, HEREDITARY
CSF3R, THR617ASN

In 12 affected members of a 3-generation family segregating autosomal
dominant hereditary neutrophilia (162830), Plo et al. (2009) identified
heterozygosity for a 2088C-A transversion in the CSF3R gene, resulting
in a thr617-to-asn (T617N) substitution located in the transmembrane
domain of the receptor. The mutation disappeared after remission and was
not detected at relapse, indicating that the T617N mutation was a
secondary event in the leukemic process. Computational analysis by Plo
et al. (2009) indicated that T617N strongly favors dimerization of the
receptor transmembrane domain, and studies in CD34+ cells from patients
and controls demonstrated constitutive activation of the mutant receptor
with hypersensitivity to GCSF. Mutant hematopoietic stem cells yielded a
myeloproliferative-like disorder in xenotransplantation and syngenic
mouse bone marrow engraftment assays. The T617N mutation had previously
been reported as an acquired activating mutation in 2 of 555 patients
with acute myeloid leukemia by Forbes et al. (2002).

*FIELD* SA
Wong et al. (1993)
*FIELD* RF
1. Dale, D. C.; Person, R. E.; Bolyard, A. A.; Aprikyan, A. G.; Bos,
C.; Bonilla, M. A.; Boxer, L. A.; Kannourakis, G.; Zeidler, C.; Welte,
K.; Benson, K. F.; Horwitz, M.: Mutations in the gene encoding neutrophil
elastase in congenital and cyclic neutropenia. Blood 96: 2317-2322,
2000.

2. Dong, F.; Brynes, R. K.; Tidow, N.; Welte, K.; Lowenberg, B.; Touw,
I. P.: Mutations in the gene for the granulocyte colony-stimulating-factor
receptor in patients with acute myeloid leukemia preceded by severe
congenital neutropenia. New Eng. J. Med. 333: 487-493, 1995.

3. Dong, F.; Hoefsloot, L. H.; Schelen, A. M.; Broeders, L. C. A.
M.; Meijer, Y.; Veerman, A. J. P.; Touw, I. P.; Lowenberg, B.: Identification
of a nonsense mutation in the granulocyte-colony-stimulating factor
receptor in severe congenital neutropenia. Proc. Nat. Acad. Sci. 91:
4480-4484, 1994.

4. Dong, F.; Qiu, Y.; Yi, T.; Touw, I. P.; Larner, A. C.: The carboxyl
terminus of the granulocyte colony-stimulating factor receptor, truncated
in patients with severe congenital neutropenia/acute myeloid leukemia,
is required for SH2-containing phosphatase-1 suppression of Stat activation. J.
Immun. 167: 6447-6452, 2001.

5. Forbes, L. V.; Gale, R. E.; Pizzey, A.; Pouwels, K.; Nathwani,
A.; Linch, D. C.: An activating mutation in the transmembrane domain
of the granulocyte colony-stimulating factor receptor in patients
with acute myeloid leukemia. Oncogene 21: 5981-5989, 2002.

6. Fukunaga, R.; Seto, Y.; Mizushima, S.; Nagata, S.: Three different
mRNAs encoding human granulocyte colony-stimulating factor receptor. Proc.
Nat. Acad. Sci. 87: 8702-8706, 1990.

7. Inazawa, J.; Fukunaga, R.; Seto, Y.; Nakagawa, H.; Misawa, S.;
Abe, T.; Nagata, S.: Assignment of the human granulocyte colony-stimulating
factor receptor gene (CSF3R) to chromosome 1 at region p35-p34.3. Genomics 10:
1075-1078, 1991.

8. Maxson, J. E.; Gotlib, J.; Pollyea, D. A.; Fleischman, A. G.; Agarwal,
A.; Eide, C. A.; Bottomly, D.; Wilmot, B.; McWeeney, S. K.; Tognon,
C. E.; Pond, J. B.; Collins, R. H.; Goueli, B.; Oh. S. T.; Deininger,
M. W.; Chang, B. H.; Loriaux, M. M.; Druker, B. J.; Tyner, J. W.:
Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical
CML. New Eng. J. Med. 368: 1781-1790, 2013.

9. McLemore, M. L.; Poursine-Laurent, J.; Link, D. C.: Increased
granulocyte colony-stimulating factor responsiveness but normal resting
granulopoiesis in mice carrying a targeted granulocyte colony-stimulating
factor receptor mutation derived from a patient with severe congenital
neutropenia. J. Clin. Invest. 102: 483-492, 1998.

10. Plo, I.; Zhang, Y.; Le Couedic, J.-P.; Nakatake, M.; Boulet, J.-M.;
Itaya, M.; Smith, S. O.; Debili, N.; Constantinescu, S. N.; Vainchenker,
W.; Louache, F.; de Botton, S.: An activating mutation in the CSF3R
gene induces a hereditary chronic neutrophilia. J. Exp. Med. 206:
1701-1707, 2009.

11. 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.

12. Seto, Y.; Fukunaga, R.; Nagata, S.: Chromosomal gene organization
of the human granulocyte colony-stimulating factor receptor. J. Immun. 148:
259-266, 1992.

13. Tidow, N.; Pilz, C.; Teichmann, B.; Muller-Brechlin, A.; Germeshausen,
M.; Kasper, B.; Rauprich, P.; Sykora, K.-W.; Welte, K.: Clinical
relevance of point mutations in the cytoplasmic domain of the granulocyte
colony-stimulating factor receptor gene in patients with severe congenital
neutropenia. Blood 89: 2369-2375, 1997.

14. Tweardy, D. J.; Anderson, K.; Cannizzaro, L. A.; Steinman, R.
A.; Croce, C. M.; Huebner, K.: Molecular cloning of cDNAs for the
human granulocyte colony-stimulating factor receptor from HL-60 and
mapping of the gene to chromosome region 1p32-34. Blood 79: 1148-1154,
1992.

15. Wong, W.-Y.; Williams, D.; Slovak, M. L.; Charak, B.; Mazumder,
A.; Snyder, D.; Powars, D. R.; Byrnes, R. K.: Terminal acute myelogenous
leukemia in a patient with congenital agranulocytosis. Am. J. Hemat. 43:
133-138, 1993.

*FIELD* CN
Ada Hamosh - updated: 07/08/2013
Marla J. F. O'Neill - updated: 9/28/2009
Cassandra L. Kniffin - updated: 8/18/2009
Paul J. Converse - updated: 1/16/2002
Victor A. McKusick - updated: 1/9/2001
Ada Hamosh - updated: 11/6/2000
Victor A. McKusick - updated: 10/1/1998
Victor A. McKusick - updated: 5/28/1997

*FIELD* CD
Victor A. McKusick: 12/21/1990

*FIELD* ED
alopez: 07/08/2013
wwang: 9/28/2009
wwang: 9/8/2009
ckniffin: 8/18/2009
alopez: 2/1/2007
ckniffin: 5/29/2002
mgross: 1/16/2002
mcapotos: 1/12/2001
terry: 1/9/2001
carol: 11/6/2000
carol: 10/6/1998
terry: 10/1/1998
dkim: 9/11/1998
jenny: 6/3/1997
terry: 5/28/1997
mark: 10/18/1995
jason: 6/13/1994
carol: 10/26/1993
carol: 5/5/1992
supermim: 3/16/1992
carol: 2/16/1992

MIM 162830
*RECORD*
*FIELD* NO
162830
*FIELD* TI
#162830 NEUTROPHILIA, HEREDITARY
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read morehereditary neutrophilia is caused by heterozygous mutation in the CSF3R
gene (138971) on chromosome 1p34.

CLINICAL FEATURES

Herring et al. (1974) described an apparently autosomal dominant form of
lifelong, persistent neutrophilia in a mother and 3 of her 4 children.
The neutrophils were morphologically and functionally normal. Associated
findings were hepatosplenomegaly, histiocytes of Gaucher type, and
thickened calvaria due to widened diploe. Leukocyte alkaline
phosphatase, serum vitamin B12 levels and heat-labile serum alkaline
phosphatase were elevated. The course was benign. No previous report was
found. This disorder differs from the familial myeloproliferative
syndrome (254700) by the mode of inheritance and benign course. It is
also distinct from hereditary eosinophilia (131400).

Plo et al. (2009) described a 3-generation family in which 12 of 16
members had chronic neutrophilia, with median white blood cell (WBC)
counts of 21,350 cells per cubic millimeter involving greater than 70%
segmented neutrophils or band cells and less than 10% immature
granulocytes; median neutrophil counts were 16,900 cells per cubic
millimeter. All affected individuals were clinically asymptomatic except
the proband, who presented with a unique episode of systemic
inflammatory response syndrome that combined fever, tachycardia,
dyspnea, pleural and pericardial effusion, hepatosplenomegaly, and
weight loss. He had a WBC of 102,000 cells per cubic millimeter, with
75% segmented neutrophils and 20% immature granulocytes; bone marrow
analysis showed an increase in granulocyte precursors without an excess
of blasts. After this episode, the patient returned to chronic
neutrophilia, but 18 months later he developed a myelodysplastic
syndrome involving refractory anemia with an excess of blasts (RAEB);
bone marrow aspirate showed marked dysgranulopoiesis but no
dyserythropoiesis or dysmegakaryopoiesis, and cytogenetic analysis
revealed a clonal abnormality (chromosome 3q26 deletion) in 70% of
metaphases.

INHERITANCE

The families with neutrophilia reported by Herring et al. (1974) and Plo
et al. (2009) indicated autosomal dominant inheritance.

MOLECULAR GENETICS

In a 3-generation family segregating autosomal dominant neutrophilia,
Plo et al. (2009) sequenced the CSF3R gene and identified a heterozygous
activating mutation (T617N; 138971.0001) in all 12 affected individuals
that was not found in the 4 unaffected family members.

*FIELD* RF
1. Herring, W. B.; Smith, L. G.; Walker, R. I.; Herion, J. C.: Hereditary
neutrophilia. Am. J. Med. 56: 729-734, 1974.

2. Plo, I.; Zhang, Y.; Le Couedic, J.-P.; Nakatake, M.; Boulet, J.-M.;
Itaya, M.; Smith, S. O.; Debili, N.; Constantinescu, S. N.; Vainchenker,
W.; Louache, F.; de Botton, S.: An activating mutation in the CSF3R
gene induces a hereditary chronic neutrophilia. J. Exp. Med. 206:
1701-1707, 2009.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEMATOLOGY:
Neutrophilia;
Segmented neutrophils or band cells greater than 70%

MISCELLANEOUS:
Most patients clinically asymptomatic;
Myelodysplastic syndrome developed in 1 of 12 mutation-positive patients

MOLECULAR BASIS:
Caused by mutation in the granulocyte colony-stimulating factor-3
receptor gene (CSF3R, 138971.0001)

*FIELD* CN
Marla J. F. O'Neill - revised: 10/02/2009

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 10/02/2009

*FIELD* CN
Marla J. F. O'Neill - updated: 9/28/2009

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 03/15/2012
wwang: 9/28/2009
carol: 6/20/1997
mimadm: 12/2/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
reenie: 10/18/1986

RBCC Red Blood Cell Collection

Full text data of CSF3R