Full text data of CSF1R
CSF1R
(FMS)
[Confidence: high (a blood group or CD marker)]
Macrophage colony-stimulating factor 1 receptor (CSF-1 receptor; CSF-1-R; CSF-1R; M-CSF-R; 2.7.10.1; Proto-oncogene c-Fms; CD115; Flags: Precursor)
Macrophage colony-stimulating factor 1 receptor (CSF-1 receptor; CSF-1-R; CSF-1R; M-CSF-R; 2.7.10.1; Proto-oncogene c-Fms; CD115; Flags: Precursor)
UniProt
P07333
ID CSF1R_HUMAN Reviewed; 972 AA.
AC P07333; B5A955; D3DQG2; Q6LDW5; Q6LDY4; Q86VW7;
DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-1994, sequence version 2.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Macrophage colony-stimulating factor 1 receptor;
DE AltName: Full=CSF-1 receptor;
DE Short=CSF-1-R;
DE Short=CSF-1R;
DE Short=M-CSF-R;
DE EC=2.7.10.1;
DE AltName: Full=Proto-oncogene c-Fms;
DE AltName: CD_antigen=CD115;
DE Flags: Precursor;
GN Name=CSF1R; Synonyms=FMS;
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 [GENOMIC DNA].
RX PubMed=2524025;
RA Hampe A., Shamoon B.M., Gobet M., Sherr C.J., Galibert F.;
RT "Nucleotide sequence and structural organization of the human FMS
RT proto-oncogene.";
RL Oncogene Res. 4:9-17(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2421165; DOI=10.1038/320277a0;
RA Coussens L., van Beveren C., Smith D., Chen E., Mitchell R.L.,
RA Isacke C.M., Verma I.M., Ullrich A.;
RT "Structural alteration of viral homologue of receptor proto-oncogene
RT fms at carboxyl terminus.";
RL Nature 320:277-280(1986).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Placenta;
RX PubMed=9027509; DOI=10.1006/geno.1996.4482;
RA Andre C., Hampe A., Lachaume P., Martin E., Wang X.P., Manus V.,
RA Hu W.X., Galibert F.;
RT "Sequence analysis of two genomic regions containing the KIT and the
RT FMS receptor tyrosine kinase genes.";
RL Genomics 39:216-226(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=18593464; DOI=10.1186/ar2447;
RA Jin P., Zhang J., Sumariwalla P.F., Ni I., Jorgensen B., Crawford D.,
RA Phillips S., Feldmann M., Shepard H.M., Paleolog E.M.;
RT "Novel splice variants derived from the receptor tyrosine kinase
RT superfamily are potential therapeutics for rheumatoid arthritis.";
RL Arthritis Res. Ther. 10:R73-R73(2008).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-16.
RX PubMed=2524648;
RA Visvader J., Verma I.M.;
RT "Differential transcription of exon 1 of the human c-fms gene in
RT placental trophoblasts and monocytes.";
RL Mol. Cell. Biol. 9:1336-1341(1989).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-16.
RX PubMed=3525854;
RA Wheeler E.F., Roussel M.F., Hampe A., Walker M.H., Fried V.A.,
RA Look A.T., Rettenmier C.W., Sherr C.J.;
RT "The amino-terminal domain of the v-fms oncogene product includes a
RT functional signal peptide that directs synthesis of a transforming
RT glycoprotein in the absence of feline leukemia virus gag sequences.";
RL J. Virol. 59:224-233(1986).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-16.
RC TISSUE=Placenta;
RA Flick M.B., Sapi E., Kacinski B.M.;
RT "Expression of a novel exon in the 5' UTR of human c-fms
RT transcripts.";
RL Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 244-295.
RX PubMed=4028159; DOI=10.1016/0092-8674(85)90099-6;
RA Nienhuis A.W., Bunn H.F., Turner P.H., Gopal T.V., Nash W.G.,
RA O'Brien S.J., Sherr C.J.;
RT "Expression of the human c-fms proto-oncogene in hematopoietic cells
RT and its deletion in the 5q- syndrome.";
RL Cell 42:421-428(1985).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 874-972 (ISOFORM 1).
RX PubMed=3532121; DOI=10.1073/pnas.83.20.7800;
RA Browning P.J., Bunn H.F., Cline A., Shuman M., Nienhuis A.W.;
RT "'Replacement' of COOH-terminal truncation of v-fms with c-fms
RT sequences markedly reduces transformation potential.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:7800-7804(1986).
RN [13]
RP FUNCTION IN CELL PROLIFERATION.
RX PubMed=7683918;
RA Bourette R.P., Mouchiroud G., Ouazana R., Morle F., Godet J.,
RA Blanchet J.P.;
RT "Expression of human colony-stimulating factor-1 (CSF-1) receptor in
RT murine pluripotent hematopoietic NFS-60 cells induces long-term
RT proliferation in response to CSF-1 without loss of erythroid
RT differentiation potential.";
RL Blood 81:2511-2520(1993).
RN [14]
RP INTERACTION WITH SRC; FYN AND YES1, AND MUTAGENESIS OF TYR-809.
RX PubMed=7681396;
RA Courtneidge S.A., Dhand R., Pilat D., Twamley G.M., Waterfield M.D.,
RA Roussel M.F.;
RT "Activation of Src family kinases by colony stimulating factor-1, and
RT their association with its receptor.";
RL EMBO J. 12:943-950(1993).
RN [15]
RP INDUCTION BY GLUCOCORTICOIDS.
RX PubMed=7845678;
RA Sapi E., Flick M.B., Gilmore-Hebert M., Rodov S., Kacinski B.M.;
RT "Transcriptional regulation of the c-fms (CSF-1R) proto-oncogene in
RT human breast carcinoma cells by glucocorticoids.";
RL Oncogene 10:529-542(1995).
RN [16]
RP MUTAGENESIS OF TYR-708 AND ASP-802.
RX PubMed=10340379; DOI=10.1038/sj.onc.1202646;
RA Morley G.M., Uden M., Gullick W.J., Dibb N.J.;
RT "Cell specific transformation by c-fms activating loop mutations is
RT attributable to constitutive receptor degradation.";
RL Oncogene 18:3076-3084(1999).
RN [17]
RP FUNCTION IN CELLULAR SIGNALING; PHOSPHORYLATION OF INPP5D AND
RP ACTIVATION OF AKT1.
RX PubMed=12882960; DOI=10.1074/jbc.M305021200;
RA Baran C.P., Tridandapani S., Helgason C.D., Humphries R.K.,
RA Krystal G., Marsh C.B.;
RT "The inositol 5'-phosphatase SHIP-1 and the Src kinase Lyn negatively
RT regulate macrophage colony-stimulating factor-induced Akt activity.";
RL J. Biol. Chem. 278:38628-38636(2003).
RN [18]
RP FUNCTION IN REGULATION OF CELL PROLIFERATION; CELL ADHESION; CELL
RP SHAPE AND INTEGRITY OF CELL JUNCTIONS, MUTAGENESIS OF LEU-301 AND
RP TYR-969, AND ROLE IN DISEASE.
RX PubMed=15117969; DOI=10.1083/jcb.200309102;
RA Wrobel C.N., Debnath J., Lin E., Beausoleil S., Roussel M.F.,
RA Brugge J.S.;
RT "Autocrine CSF-1R activation promotes Src-dependent disruption of
RT mammary epithelial architecture.";
RL J. Cell Biol. 165:263-273(2004).
RN [19]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-302 AND ASN-353, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [20]
RP FUNCTION AS CSF1 RECEPTOR, CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION,
RP ROLE IN DISEASE, AND ENZYME REGULATION.
RX PubMed=16648572; DOI=10.1158/1535-7163.MCT-05-0359;
RA Guo J., Marcotte P.A., McCall J.O., Dai Y., Pease L.J.,
RA Michaelides M.R., Davidsen S.K., Glaser K.B.;
RT "Inhibition of phosphorylation of the colony-stimulating factor-1
RT receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and
RT other tyrosine kinase inhibitors.";
RL Mol. Cancer Ther. 5:1007-1013(2006).
RN [21]
RP FUNCTION IN CELL PROLIFERATION, CATALYTIC ACTIVITY,
RP AUTOPHOSPHORYLATION, ROLE IN DISEASE, AND ENZYME REGULATION.
RX PubMed=17121910; DOI=10.1158/1535-7163.MCT-05-0313;
RA Ohno H., Kubo K., Murooka H., Kobayashi Y., Nishitoba T., Shibuya M.,
RA Yoneda T., Isoe T.;
RT "A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast
RT differentiation and osteolytic bone destruction in a bone metastasis
RT model.";
RL Mol. Cancer Ther. 5:2634-2643(2006).
RN [22]
RP FUNCTION IN REGULATION OF CELL PROLIFERATION AND CELL SHAPE, CATALYTIC
RP ACTIVITY, UBIQUITINATION, ENZYME REGULATION, AND MUTAGENESIS OF
RP ASP-802.
RX PubMed=16170366; DOI=10.1038/sj.onc.1209007;
RA Taylor J.R., Brownlow N., Domin J., Dibb N.J.;
RT "FMS receptor for M-CSF (CSF-1) is sensitive to the kinase inhibitor
RT imatinib and mutation of Asp-802 to Val confers resistance.";
RL Oncogene 25:147-151(2006).
RN [23]
RP FUNCTION AS IL34 RECEPTOR.
RX PubMed=18467591; DOI=10.1126/science.1154370;
RA Lin H., Lee E., Hestir K., Leo C., Huang M., Bosch E., Halenbeck R.,
RA Wu G., Zhou A., Behrens D., Hollenbaugh D., Linnemann T., Qin M.,
RA Wong J., Chu K., Doberstein S.K., Williams L.T.;
RT "Discovery of a cytokine and its receptor by functional screening of
RT the extracellular proteome.";
RL Science 320:807-811(2008).
RN [24]
RP ROLE IN DISEASE, AND ENZYME REGULATION.
RX PubMed=18814279; DOI=10.1002/ijc.23903;
RA Hiraga T., Nakamura H.;
RT "Imatinib mesylate suppresses bone metastases of breast cancer by
RT inhibiting osteoclasts through the blockade of c-Fms signals.";
RL Int. J. Cancer 124:215-222(2009).
RN [25]
RP ROLE IN DISEASE.
RX PubMed=19934330; DOI=10.1158/0008-5472.CAN-09-1868;
RA Patsialou A., Wyckoff J., Wang Y., Goswami S., Stanley E.R.,
RA Condeelis J.S.;
RT "Invasion of human breast cancer cells in vivo requires both paracrine
RT and autocrine loops involving the colony-stimulating factor-1
RT receptor.";
RL Cancer Res. 69:9498-9506(2009).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-699 AND SER-713, AND
RP MASS SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [27]
RP AUTOPHOSPHORYLATION, AND ENZYME REGULATION.
RX PubMed=20156689; DOI=10.1016/j.bmc.2010.01.056;
RA Mashkani B., Griffith R., Ashman L.K.;
RT "Colony stimulating factor-1 receptor as a target for small molecule
RT inhibitors.";
RL Bioorg. Med. Chem. 18:1789-1797(2010).
RN [28]
RP FUNCTION AS RECEPTOR FOR IL34 AND CSF1, PHOSPHORYLATION AT TYR-546;
RP TYR-699; TYR-708; TYR-723 AND TYR-809, AUTOPHOSPHORYLATION, ENZYME
RP REGULATION, AND INTERACTION WITH IL34 AND CSF1.
RX PubMed=20489731; DOI=10.1038/cdd.2010.60;
RA Chihara T., Suzu S., Hassan R., Chutiwitoonchai N., Hiyoshi M.,
RA Motoyoshi K., Kimura F., Okada S.;
RT "IL-34 and M-CSF share the receptor Fms but are not identical in
RT biological activity and signal activation.";
RL Cell Death Differ. 17:1917-1927(2010).
RN [29]
RP FUNCTION IN RELEASE OF PROINFLAMMATORY CHEMOKINES.
RX PubMed=20829061; DOI=10.1016/j.cyto.2010.08.005;
RA Eda H., Zhang J., Keith R.H., Michener M., Beidler D.R., Monahan J.B.;
RT "Macrophage-colony stimulating factor and interleukin-34 induce
RT chemokines in human whole blood.";
RL Cytokine 52:215-220(2010).
RN [30]
RP FUNCTION AS IL34 AND CSF1 RECEPTOR; ACTIVATION OF MAPK1/ERK2;
RP MAPK3/ERK1; PHOSPHORYLATION AT TYR-723, AND AUTOPHOSPHORYLATION.
RX PubMed=20504948; DOI=10.1189/jlb.1209822;
RA Wei S., Nandi S., Chitu V., Yeung Y.G., Yu W., Huang M.,
RA Williams L.T., Lin H., Stanley E.R.;
RT "Functional overlap but differential expression of CSF-1 and IL-34 in
RT their CSF-1 receptor-mediated regulation of myeloid cells.";
RL J. Leukoc. Biol. 88:495-505(2010).
RN [31]
RP REVIEW ON FUNCTION; SIGNALING PATHWAYS AND PHOSPHORYLATION.
RX PubMed=15519852; DOI=10.1016/j.tcb.2004.09.016;
RA Pixley F.J., Stanley E.R.;
RT "CSF-1 regulation of the wandering macrophage: complexity in action.";
RL Trends Cell Biol. 14:628-638(2004).
RN [32]
RP REVIEW ON FUNCTION IN IMMUNITY AND INFLAMMATION, AND ROLE IN DISEASE.
RX PubMed=16337366; DOI=10.1016/j.coi.2005.11.006;
RA Chitu V., Stanley E.R.;
RT "Colony-stimulating factor-1 in immunity and inflammation.";
RL Curr. Opin. Immunol. 18:39-48(2006).
RN [33]
RP REVIEW ON FUNCTION; SIGNALING PATHWAYS AND PHOSPHORYLATION.
RX PubMed=18687298; DOI=10.1016/j.intimp.2008.04.016;
RA Douglass T.G., Driggers L., Zhang J.G., Hoa N., Delgado C.,
RA Williams C.C., Dan Q., Sanchez R., Jeffes E.W., Wepsic H.T.,
RA Myers M.P., Koths K., Jadus M.R.;
RT "Macrophage colony stimulating factor: not just for macrophages
RT anymore! A gateway into complex biologies.";
RL Int. Immunopharmacol. 8:1354-1376(2008).
RN [34]
RP REVIEW.
RX PubMed=19132917; DOI=10.1146/annurev.immunol.021908.132557;
RA Auffray C., Sieweke M.H., Geissmann F.;
RT "Blood monocytes: development, heterogeneity, and relationship with
RT dendritic cells.";
RL Annu. Rev. Immunol. 27:669-692(2009).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 538-922 IN COMPLEXES WITH
RP ARYLAMIDE AND QUINOLONE INHIBITORS, AND DOMAIN.
RX PubMed=17132624; DOI=10.1074/jbc.M608183200;
RA Schubert C., Schalk-Hihi C., Struble G.T., Ma H.C., Petrounia I.P.,
RA Brandt B., Deckman I.C., Patch R.J., Player M.R., Spurlino J.C.,
RA Springer B.A.;
RT "Crystal structure of the tyrosine kinase domain of colony-stimulating
RT factor-1 receptor (cFMS) in complex with two inhibitors.";
RL J. Biol. Chem. 282:4094-4101(2007).
RN [36]
RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 543-918 IN AUTOINHIBITED
RP CONFORMATION, AND DOMAIN.
RX PubMed=17292918; DOI=10.1016/j.jmb.2007.01.036;
RA Walter M., Lucet I.S., Patel O., Broughton S.E., Bamert R.,
RA Williams N.K., Fantino E., Wilks A.F., Rossjohn J.;
RT "The 2.7 A crystal structure of the autoinhibited human c-Fms kinase
RT domain.";
RL J. Mol. Biol. 367:839-847(2007).
RN [37]
RP X-RAY CRYSTALLOGRAPHY (2.02 ANGSTROMS) OF 538-922 IN COMPLEX WITH
RP PYRIMIDINOPYRIDONE INHIBITOR, AND CATALYTIC ACTIVITY.
RX PubMed=18342505; DOI=10.1016/j.bmcl.2008.02.070;
RA Huang H., Hutta D.A., Hu H., DesJarlais R.L., Schubert C.,
RA Petrounia I.P., Chaikin M.A., Manthey C.L., Player M.R.;
RT "Design and synthesis of a pyrido[2,3-d]pyrimidin-5-one class of anti-
RT inflammatory FMS inhibitors.";
RL Bioorg. Med. Chem. Lett. 18:2355-2361(2008).
RN [38]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 538-922 IN COMPLEX WITH
RP INHIBITOR, CATALYTIC ACTIVITY, AND FUNCTION IN INFLAMMATION AND
RP DISEASE.
RX PubMed=19193011; DOI=10.1021/jm801406h;
RA Huang H., Hutta D.A., Rinker J.M., Hu H., Parsons W.H., Schubert C.,
RA DesJarlais R.L., Crysler C.S., Chaikin M.A., Donatelli R.R., Chen Y.,
RA Cheng D., Zhou Z., Yurkow E., Manthey C.L., Player M.R.;
RT "Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory
RT macrophage colony-stimulating factor-1 receptor inhibitors.";
RL J. Med. Chem. 52:1081-1099(2009).
RN [39]
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 538-922 IN COMPLEXES WITH
RP INHIBITORS, CATALYTIC ACTIVITY, AND ENZYME REGULATION.
RX PubMed=20137931; DOI=10.1016/j.bmcl.2010.01.078;
RA Meyers M.J., Pelc M., Kamtekar S., Day J., Poda G.I., Hall M.K.,
RA Michener M.L., Reitz B.A., Mathis K.J., Pierce B.S., Parikh M.D.,
RA Mischke D.A., Long S.A., Parlow J.J., Anderson D.R., Thorarensen A.;
RT "Structure-based drug design enables conversion of a DFG-in binding
RT CSF-1R kinase inhibitor to a DFG-out binding mode.";
RL Bioorg. Med. Chem. Lett. 20:1543-1547(2010).
RN [40]
RP VARIANTS [LARGE SCALE ANALYSIS] GLY-32; ARG-362; SER-413; VAL-536;
RP HIS-693; ASP-920 AND GLN-921.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [41]
RP VARIANTS HDLS 774-CYS--ASN-814 DEL; 585-GLY--LYS-619 DELINS ALA;
RP GLU-589; LYS-633; THR-766; PRO-770; ASN-775; THR-794; TYR-837;
RP SER-849; PHE-849 DEL; PRO-868; THR-875 AND THR-878, VARIANTS HIS-710;
RP ARG-747 AND ASP-920, AND CHARACTERIZATION OF VARIANTS HDLS LYS-633;
RP THR-766 AND THR-875.
RX PubMed=22197934; DOI=10.1038/ng.1027;
RA Rademakers R., Baker M., Nicholson A.M., Rutherford N.J., Finch N.,
RA Soto-Ortolaza A., Lash J., Wider C., Wojtas A., DeJesus-Hernandez M.,
RA Adamson J., Kouri N., Sundal C., Shuster E.A., Aasly J., MacKenzie J.,
RA Roeber S., Kretzschmar H.A., Boeve B.F., Knopman D.S., Petersen R.C.,
RA Cairns N.J., Ghetti B., Spina S., Garbern J., Tselis A.C., Uitti R.,
RA Das P., Van Gerpen J.A., Meschia J.F., Levy S., Broderick D.F.,
RA Graff-Radford N., Ross O.A., Miller B.B., Swerdlow R.H., Dickson D.W.,
RA Wszolek Z.K.;
RT "Mutations in the colony stimulating factor 1 receptor (CSF1R) gene
RT cause hereditary diffuse leukoencephalopathy with spheroids.";
RL Nat. Genet. 44:200-205(2012).
CC -!- FUNCTION: Tyrosine-protein kinase that acts as cell-surface
CC receptor for CSF1 and IL34 and plays an essential role in the
CC regulation of survival, proliferation and differentiation of
CC hematopoietic precursor cells, especially mononuclear phagocytes,
CC such as macrophages and monocytes. Promotes the release of
CC proinflammatory chemokines in response to IL34 and CSF1, and
CC thereby plays an important role in innate immunity and in
CC inflammatory processes. Plays an important role in the regulation
CC of osteoclast proliferation and differentiation, the regulation of
CC bone resorption, and is required for normal bone and tooth
CC development. Required for normal male and female fertility, and
CC for normal development of milk ducts and acinar structures in the
CC mammary gland during pregnancy. Promotes reorganization of the
CC actin cytoskeleton, regulates formation of membrane ruffles, cell
CC adhesion and cell migration, and promotes cancer cell invasion.
CC Activates several signaling pathways in response to ligand
CC binding. Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL.
CC Activation of PLCG2 leads to the production of the cellular
CC signaling molecules diacylglycerol and inositol 1,4,5-
CC trisphosphate, that then lead to the activation of protein kinase
CC C family members, especially PRKCD. Phosphorylation of PIK3R1, the
CC regulatory subunit of phosphatidylinositol 3-kinase, leads to
CC activation of the AKT1 signaling pathway. Activated CSF1R also
CC mediates activation of the MAP kinases MAPK1/ERK2 and/or
CC MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1.
CC Activated CSF1R transmits signals both via proteins that directly
CC interact with phosphorylated tyrosine residues in its
CC intracellular domain, or via adapter proteins, such as GRB2.
CC Promotes activation of STAT family members STAT3, STAT5A and/or
CC STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-
CC 1. Receptor signaling is down-regulated by protein phosphatases,
CC such as INPP5D/SHIP-1, that dephosphorylate the receptor and its
CC downstream effectors, and by rapid internalization of the
CC activated receptor.
CC -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a
CC [protein]-L-tyrosine phosphate.
CC -!- ENZYME REGULATION: Present in an inactive conformation in the
CC absence of bound ligand. CSF1 or IL34 binding leads to
CC dimerization and activation by autophosphorylation on tyrosine
CC residues. Inhibited by imatinib/STI-571 (Gleevec), dasatinib,
CC sunitinib/SU11248, lestaurtinib/CEP-701, midostaurin/PKC-412,
CC Ki20227, linifanib/ABT-869, Axitinib/AG013736, sorafenib/BAY 43-
CC 9006 and GW2580.
CC -!- SUBUNIT: Interacts with INPPL1/SHIP2 and THOC5 (By similarity).
CC Monomer. Homodimer. Interacts with CSF1 and IL34. Interaction with
CC dimeric CSF1 or IL34 leads to receptor homodimerization. Interacts
CC (tyrosine phosphorylated) with PLCG2 (via SH2 domain). Interacts
CC (tyrosine phosphorylated) with PIK3R1 (via SH2 domain). Interacts
CC (tyrosine phosphorylated) with FYN, YES1 and SRC (via SH2 domain).
CC Interacts (tyrosine phosphorylated) with CBL, GRB2 and SLA2.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P07333-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P07333-2; Sequence=VSP_047757, VSP_047758;
CC -!- TISSUE SPECIFICITY: Expressed in bone marrow and in differentiated
CC blood mononuclear cells.
CC -!- INDUCTION: Up-regulated by glucocorticoids.
CC -!- DOMAIN: The juxtamembrane domain functions as autoinhibitory
CC region. Phosphorylation of tyrosine residues in this region leads
CC to a conformation change and activation of the kinase.
CC -!- DOMAIN: The activation loop plays an important role in the
CC regulation of kinase activity. Phosphorylation of tyrosine
CC residues in this region leads to a conformation change and
CC activation of the kinase.
CC -!- PTM: Autophosphorylated in response to CSF1 or IL34 binding.
CC Phosphorylation at Tyr-561 is important for normal down-regulation
CC of signaling by ubiquitination, internalization and degradation.
CC Phosphorylation at Tyr-561 and Tyr-809 is important for
CC interaction with SRC family members, including FYN, YES1 and SRC,
CC and for subsequent activation of these protein kinases.
CC Phosphorylation at Tyr-699 and Tyr-923 is important for
CC interaction with GRB2. Phosphorylation at Tyr-723 is important for
CC interaction with PIK3R1. Phosphorylation at Tyr-708 is important
CC for normal receptor degradation. Phosphorylation at Tyr-723 and
CC Tyr-809 is important for interaction with PLCG2. Phosphorylation
CC at Tyr-969 is important for interaction with CBL.
CC Dephosphorylation by PTPN2 negatively regulates downstream
CC signaling and macrophage differentiation.
CC -!- PTM: Ubiquitinated. Becomes rapidly polyubiquitinated after
CC autophosphorylation, leading to its degradation.
CC -!- DISEASE: Note=Aberrant expression of CSF1 or CSF1R can promote
CC cancer cell proliferation, invasion and formation of metastases.
CC Overexpression of CSF1 or CSF1R is observed in a significant
CC percentage of breast, ovarian, prostate, and endometrial cancers.
CC -!- DISEASE: Note=Aberrant expression of CSF1 or CSF1R may play a role
CC in inflammatory diseases, such as rheumatoid arthritis,
CC glomerulonephritis, atherosclerosis, and allograft rejection.
CC -!- DISEASE: Leukoencephalopathy, diffuse hereditary, with spheroids
CC (HDLS) [MIM:221820]: An autosomal dominant adult-onset rapidly
CC progressive neurodegenerative disorder characterized by variable
CC behavioral, cognitive, and motor changes. Patients often die of
CC dementia within 6 years of onset. Brain imaging shows patchy
CC abnormalities in the cerebral white matter, predominantly
CC affecting the frontal and parietal lobes. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. CSF-1/PDGF receptor subfamily.
CC -!- SIMILARITY: Contains 5 Ig-like C2-type (immunoglobulin-like)
CC domains.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/CSF1RID40161ch5q32.html";
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DR EMBL; X03663; CAA27300.1; -; mRNA.
DR EMBL; U63963; AAB51696.1; -; Genomic_DNA.
DR EMBL; M25786; AAA58421.1; -; mRNA.
DR EMBL; EU826593; ACF47629.1; -; mRNA.
DR EMBL; AC011382; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471062; EAW61749.1; -; Genomic_DNA.
DR EMBL; CH471062; EAW61750.1; -; Genomic_DNA.
DR EMBL; BC047521; AAH47521.1; -; mRNA.
DR EMBL; M14002; AAA35849.1; -; Genomic_DNA.
DR EMBL; U78096; AAB51235.1; -; Genomic_DNA.
DR EMBL; M11067; AAA35848.1; -; Genomic_DNA.
DR EMBL; M14193; AAA35834.1; -; mRNA.
DR PIR; S08123; TVHUMD.
DR RefSeq; NP_005202.2; NM_005211.3.
DR UniGene; Hs.586219; -.
DR PDB; 2I0V; X-ray; 2.80 A; A=538-922.
DR PDB; 2I0Y; X-ray; 1.90 A; A=538-922.
DR PDB; 2I1M; X-ray; 1.80 A; A=538-922.
DR PDB; 2OGV; X-ray; 2.70 A; A=543-918.
DR PDB; 3BEA; X-ray; 2.02 A; A=538-922.
DR PDB; 3DPK; X-ray; 1.95 A; A=538-922.
DR PDB; 3KRJ; X-ray; 2.10 A; A=538-922.
DR PDB; 3KRL; X-ray; 2.40 A; A=538-922.
DR PDB; 3LCD; X-ray; 2.50 A; A=538-922.
DR PDB; 3LCO; X-ray; 3.40 A; A=550-919.
DR PDB; 4DKD; X-ray; 3.00 A; C=20-299.
DR PDB; 4HW7; X-ray; 2.90 A; A=542-919.
DR PDBsum; 2I0V; -.
DR PDBsum; 2I0Y; -.
DR PDBsum; 2I1M; -.
DR PDBsum; 2OGV; -.
DR PDBsum; 3BEA; -.
DR PDBsum; 3DPK; -.
DR PDBsum; 3KRJ; -.
DR PDBsum; 3KRL; -.
DR PDBsum; 3LCD; -.
DR PDBsum; 3LCO; -.
DR PDBsum; 4DKD; -.
DR PDBsum; 4HW7; -.
DR ProteinModelPortal; P07333; -.
DR SMR; P07333; 20-498, 544-945.
DR DIP; DIP-59421N; -.
DR IntAct; P07333; 9.
DR MINT; MINT-8019993; -.
DR STRING; 9606.ENSP00000286301; -.
DR BindingDB; P07333; -.
DR ChEMBL; CHEMBL1844; -.
DR DrugBank; DB00619; Imatinib.
DR DrugBank; DB01268; Sunitinib.
DR GuidetoPHARMACOLOGY; 1806; -.
DR PhosphoSite; P07333; -.
DR DMDM; 547770; -.
DR PaxDb; P07333; -.
DR PeptideAtlas; P07333; -.
DR PRIDE; P07333; -.
DR DNASU; 1436; -.
DR Ensembl; ENST00000286301; ENSP00000286301; ENSG00000182578.
DR Ensembl; ENST00000543093; ENSP00000445282; ENSG00000182578.
DR GeneID; 1436; -.
DR KEGG; hsa:1436; -.
DR UCSC; uc011dce.1; human.
DR CTD; 1436; -.
DR GeneCards; GC05M149413; -.
DR HGNC; HGNC:2433; CSF1R.
DR HPA; CAB008970; -.
DR HPA; HPA012323; -.
DR MIM; 164770; gene.
DR MIM; 221820; phenotype.
DR neXtProt; NX_P07333; -.
DR Orphanet; 313808; Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.
DR PharmGKB; PA26936; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000112008; -.
DR HOVERGEN; HBG004335; -.
DR InParanoid; P07333; -.
DR KO; K05090; -.
DR OMA; TVECVAF; -.
DR PhylomeDB; P07333; -.
DR BRENDA; 2.7.10.1; 2681.
DR SignaLink; P07333; -.
DR ChiTaRS; CSF1R; human.
DR EvolutionaryTrace; P07333; -.
DR GeneWiki; Colony_stimulating_factor_1_receptor; -.
DR GenomeRNAi; 1436; -.
DR NextBio; 35477774; -.
DR PRO; PR:P07333; -.
DR ArrayExpress; P07333; -.
DR Bgee; P07333; -.
DR CleanEx; HS_CSF1R; -.
DR Genevestigator; P07333; -.
DR GO; GO:0009986; C:cell surface; ISS:UniProtKB.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0043235; C:receptor complex; ISS:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0019955; F:cytokine binding; IDA:UniProtKB.
DR GO; GO:0005011; F:macrophage colony-stimulating factor receptor activity; IMP:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:BHF-UCL.
DR GO; GO:0008283; P:cell proliferation; IMP:UniProtKB.
DR GO; GO:0045217; P:cell-cell junction maintenance; IMP:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; TAS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0030225; P:macrophage differentiation; TAS:UniProtKB.
DR GO; GO:0060603; P:mammary gland duct morphogenesis; TAS:UniProtKB.
DR GO; GO:0030224; P:monocyte differentiation; TAS:UniProtKB.
DR GO; GO:0030316; P:osteoclast differentiation; ISS:UniProtKB.
DR GO; GO:0046488; P:phosphatidylinositol metabolic process; ISS:UniProtKB.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; ISS:UniProtKB.
DR GO; GO:0030335; P:positive regulation of cell migration; ISS:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IMP:UniProtKB.
DR GO; GO:0090197; P:positive regulation of chemokine secretion; IMP:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:0071902; P:positive regulation of protein serine/threonine kinase activity; ISS:UniProtKB.
DR GO; GO:0061098; P:positive regulation of protein tyrosine kinase activity; IMP:UniProtKB.
DR GO; GO:0042517; P:positive regulation of tyrosine phosphorylation of Stat3 protein; ISS:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:2000249; P:regulation of actin cytoskeleton reorganization; ISS:UniProtKB.
DR GO; GO:0045124; P:regulation of bone resorption; ISS:UniProtKB.
DR GO; GO:0008360; P:regulation of cell shape; IMP:UniProtKB.
DR GO; GO:0031529; P:ruffle organization; ISS:UniProtKB.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; ISS:UniProtKB.
DR Gene3D; 2.60.40.10; -; 5.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR003598; Ig_sub2.
DR InterPro; IPR013151; Immunoglobulin.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR016243; Tyr_kinase_CSF1/PDGF_rcpt.
DR InterPro; IPR001824; Tyr_kinase_rcpt_3_CS.
DR Pfam; PF00047; ig; 1.
DR Pfam; PF07714; Pkinase_Tyr; 1.
DR PIRSF; PIRSF500947; CSF-1_receptor; 1.
DR PIRSF; PIRSF000615; TyrPK_CSF1-R; 1.
DR SMART; SM00409; IG; 3.
DR SMART; SM00408; IGc2; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF56112; SSF56112; 2.
DR PROSITE; PS50835; IG_LIKE; 3.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS00240; RECEPTOR_TYR_KIN_III; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cell membrane;
KW Complete proteome; Disease mutation; Disulfide bond; Glycoprotein;
KW Immunity; Immunoglobulin domain; Inflammatory response;
KW Innate immunity; Kinase; Membrane; Nucleotide-binding; Phosphoprotein;
KW Polymorphism; Proto-oncogene; Receptor; Reference proteome; Repeat;
KW Signal; Transferase; Transmembrane; Transmembrane helix;
KW Tyrosine-protein kinase; Ubl conjugation.
FT SIGNAL 1 19 Potential.
FT CHAIN 20 972 Macrophage colony-stimulating factor 1
FT receptor.
FT /FTId=PRO_0000016765.
FT TOPO_DOM 20 517 Extracellular (Potential).
FT TRANSMEM 518 538 Helical; (Potential).
FT TOPO_DOM 539 972 Cytoplasmic (Potential).
FT DOMAIN 21 104 Ig-like C2-type 1.
FT DOMAIN 107 197 Ig-like C2-type 2.
FT DOMAIN 203 290 Ig-like C2-type 3.
FT DOMAIN 299 399 Ig-like C2-type 4.
FT DOMAIN 402 502 Ig-like C2-type 5.
FT DOMAIN 582 910 Protein kinase.
FT NP_BIND 588 596 ATP (By similarity).
FT REGION 542 574 Regulatory juxtamembrane domain.
FT REGION 796 818 Activation loop.
FT ACT_SITE 778 778 Proton acceptor (By similarity).
FT BINDING 616 616 ATP (Probable).
FT MOD_RES 546 546 Phosphotyrosine; by autocatalysis.
FT MOD_RES 561 561 Phosphotyrosine; by autocatalysis.
FT MOD_RES 699 699 Phosphotyrosine; by autocatalysis.
FT MOD_RES 708 708 Phosphotyrosine; by autocatalysis.
FT MOD_RES 713 713 Phosphoserine.
FT MOD_RES 723 723 Phosphotyrosine; by autocatalysis.
FT MOD_RES 809 809 Phosphotyrosine; by autocatalysis.
FT MOD_RES 923 923 Phosphotyrosine; by autocatalysis.
FT MOD_RES 969 969 Phosphotyrosine; by autocatalysis.
FT CARBOHYD 45 45 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 73 73 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 153 153 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 240 240 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 275 275 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 302 302 N-linked (GlcNAc...).
FT CARBOHYD 335 335 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 353 353 N-linked (GlcNAc...).
FT CARBOHYD 412 412 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 428 428 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 480 480 N-linked (GlcNAc...) (Potential).
FT DISULFID 42 84 By similarity.
FT DISULFID 127 177 By similarity.
FT DISULFID 224 278 By similarity.
FT DISULFID 419 485 By similarity.
FT VAR_SEQ 297 306 ESAYLNLSSE -> GTPSPSLCPA (in isoform 2).
FT /FTId=VSP_047757.
FT VAR_SEQ 307 972 Missing (in isoform 2).
FT /FTId=VSP_047758.
FT VARIANT 32 32 V -> G (in dbSNP:rs56048668).
FT /FTId=VAR_042038.
FT VARIANT 245 245 A -> S (in dbSNP:rs41338945).
FT /FTId=VAR_061290.
FT VARIANT 279 279 V -> M (in dbSNP:rs3829986).
FT /FTId=VAR_049718.
FT VARIANT 362 362 H -> R (in dbSNP:rs10079250).
FT /FTId=VAR_042039.
FT VARIANT 413 413 G -> S (in dbSNP:rs34951517).
FT /FTId=VAR_042040.
FT VARIANT 536 536 L -> V (in dbSNP:rs55942044).
FT /FTId=VAR_042041.
FT VARIANT 585 619 GKTLGAGAFGKVVEATAFGLGKEDAVLKVAVKMLK -> A
FT (in HDLS).
FT /FTId=VAR_067396.
FT VARIANT 589 589 G -> E (in HDLS).
FT /FTId=VAR_067397.
FT VARIANT 633 633 E -> K (in HDLS; impairs
FT autophosphorylation upon stimulation with
FT CSF1).
FT /FTId=VAR_067398.
FT VARIANT 693 693 P -> H (in a lung squamous cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_042042.
FT VARIANT 710 710 R -> H.
FT /FTId=VAR_067399.
FT VARIANT 747 747 G -> R (in dbSNP:rs41355444).
FT /FTId=VAR_067400.
FT VARIANT 766 766 M -> T (in HDLS; impairs
FT autophosphorylation upon stimulation with
FT CSF1).
FT /FTId=VAR_067401.
FT VARIANT 770 770 A -> P (in HDLS).
FT /FTId=VAR_067402.
FT VARIANT 774 814 Missing (in HDLS).
FT /FTId=VAR_067403.
FT VARIANT 775 775 I -> N (in HDLS; impairs
FT autophosphorylation upon stimulation with
FT CSF1).
FT /FTId=VAR_067404.
FT VARIANT 794 794 I -> T (in HDLS).
FT /FTId=VAR_067405.
FT VARIANT 837 837 D -> Y (in HDLS).
FT /FTId=VAR_067406.
FT VARIANT 849 849 F -> S (in HDLS).
FT /FTId=VAR_067407.
FT VARIANT 849 849 Missing (in HDLS).
FT /FTId=VAR_067408.
FT VARIANT 868 868 L -> P (in HDLS).
FT /FTId=VAR_067409.
FT VARIANT 875 875 M -> T (in HDLS).
FT /FTId=VAR_067410.
FT VARIANT 878 878 P -> T (in HDLS).
FT /FTId=VAR_067411.
FT VARIANT 920 920 E -> D (in dbSNP:rs34030164).
FT /FTId=VAR_042043.
FT VARIANT 921 921 R -> Q (in dbSNP:rs56059682).
FT /FTId=VAR_042044.
FT VARIANT 969 969 Y -> C (in dbSNP:rs1801271).
FT /FTId=VAR_011953.
FT MUTAGEN 301 301 L->S: Constitutive kinase activity.
FT MUTAGEN 708 708 Y->F: Impairs degradation of activated
FT CSF1R.
FT MUTAGEN 802 802 D->V: Constitutive kinase activity. Loss
FT of inhibition by imatinib.
FT MUTAGEN 809 809 Y->F: Reduced kinase activity. Reduced
FT interaction with SRC, FYN and YES1.
FT MUTAGEN 969 969 Y->F: Abolishes down-regulation of
FT activated CSF1R.
FT CONFLICT 54 54 P -> A (in Ref. 2; CAA27300).
FT CONFLICT 247 247 P -> H (in Ref. 7; AAH47521).
FT CONFLICT 354 354 A -> V (in Ref. 7; AAH47521).
FT CONFLICT 629 629 A -> S (in Ref. 7; AAH47521).
FT STRAND 22 25
FT STRAND 38 43
FT STRAND 66 73
FT HELIX 76 78
FT STRAND 82 84
FT STRAND 95 97
FT STRAND 108 111
FT STRAND 113 118
FT STRAND 127 131
FT HELIX 132 135
FT STRAND 136 142
FT HELIX 143 145
FT STRAND 158 160
FT STRAND 163 166
FT HELIX 169 171
FT STRAND 173 179
FT STRAND 191 196
FT STRAND 204 210
FT HELIX 215 217
FT HELIX 231 233
FT STRAND 234 236
FT STRAND 239 241
FT HELIX 246 261
FT HELIX 275 282
FT STRAND 286 293
FT HELIX 295 304
FT HELIX 309 311
FT HELIX 315 323
FT STRAND 556 560
FT HELIX 566 568
FT HELIX 573 575
FT STRAND 581 590
FT STRAND 592 601
FT STRAND 605 607
FT STRAND 612 618
FT HELIX 624 640
FT STRAND 649 653
FT STRAND 655 658
FT STRAND 660 664
FT HELIX 671 678
FT TURN 742 744
FT HELIX 753 771
FT HELIX 781 783
FT STRAND 785 787
FT HELIX 788 790
FT STRAND 791 794
FT HELIX 798 800
FT HELIX 803 805
FT TURN 806 808
FT STRAND 809 811
FT STRAND 815 817
FT HELIX 819 821
FT HELIX 824 829
FT HELIX 834 848
FT TURN 849 851
FT HELIX 863 871
FT HELIX 883 892
FT HELIX 897 899
FT HELIX 903 920
SQ SEQUENCE 972 AA; 107984 MW; A8D99BE237573FE8 CRC64;
MGPGVLLLLL VATAWHGQGI PVIEPSVPEL VVKPGATVTL RCVGNGSVEW DGPPSPHWTL
YSDGSSSILS TNNATFQNTG TYRCTEPGDP LGGSAAIHLY VKDPARPWNV LAQEVVVFED
QDALLPCLLT DPVLEAGVSL VRVRGRPLMR HTNYSFSPWH GFTIHRAKFI QSQDYQCSAL
MGGRKVMSIS IRLKVQKVIP GPPALTLVPA ELVRIRGEAA QIVCSASSVD VNFDVFLQHN
NTKLAIPQQS DFHNNRYQKV LTLNLDQVDF QHAGNYSCVA SNVQGKHSTS MFFRVVESAY
LNLSSEQNLI QEVTVGEGLN LKVMVEAYPG LQGFNWTYLG PFSDHQPEPK LANATTKDTY
RHTFTLSLPR LKPSEAGRYS FLARNPGGWR ALTFELTLRY PPEVSVIWTF INGSGTLLCA
ASGYPQPNVT WLQCSGHTDR CDEAQVLQVW DDPYPEVLSQ EPFHKVTVQS LLTVETLEHN
QTYECRAHNS VGSGSWAFIP ISAGAHTHPP DEFLFTPVVV ACMSIMALLL LLLLLLLYKY
KQKPKYQVRW KIIESYEGNS YTFIDPTQLP YNEKWEFPRN NLQFGKTLGA GAFGKVVEAT
AFGLGKEDAV LKVAVKMLKS TAHADEKEAL MSELKIMSHL GQHENIVNLL GACTHGGPVL
VITEYCCYGD LLNFLRRKAE AMLGPSLSPG QDPEGGVDYK NIHLEKKYVR RDSGFSSQGV
DTYVEMRPVS TSSNDSFSEQ DLDKEDGRPL ELRDLLHFSS QVAQGMAFLA SKNCIHRDVA
ARNVLLTNGH VAKIGDFGLA RDIMNDSNYI VKGNARLPVK WMAPESIFDC VYTVQSDVWS
YGILLWEIFS LGLNPYPGIL VNSKFYKLVK DGYQMAQPAF APKNIYSIMQ ACWALEPTHR
PTFQQICSFL QEQAQEDRRE RDYTNLPSSS RSGGSGSSSS ELEEESSSEH LTCCEQGDIA
QPLLQPNNYQ FC
//
ID CSF1R_HUMAN Reviewed; 972 AA.
AC P07333; B5A955; D3DQG2; Q6LDW5; Q6LDY4; Q86VW7;
DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-1994, sequence version 2.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Macrophage colony-stimulating factor 1 receptor;
DE AltName: Full=CSF-1 receptor;
DE Short=CSF-1-R;
DE Short=CSF-1R;
DE Short=M-CSF-R;
DE EC=2.7.10.1;
DE AltName: Full=Proto-oncogene c-Fms;
DE AltName: CD_antigen=CD115;
DE Flags: Precursor;
GN Name=CSF1R; Synonyms=FMS;
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 [GENOMIC DNA].
RX PubMed=2524025;
RA Hampe A., Shamoon B.M., Gobet M., Sherr C.J., Galibert F.;
RT "Nucleotide sequence and structural organization of the human FMS
RT proto-oncogene.";
RL Oncogene Res. 4:9-17(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2421165; DOI=10.1038/320277a0;
RA Coussens L., van Beveren C., Smith D., Chen E., Mitchell R.L.,
RA Isacke C.M., Verma I.M., Ullrich A.;
RT "Structural alteration of viral homologue of receptor proto-oncogene
RT fms at carboxyl terminus.";
RL Nature 320:277-280(1986).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Placenta;
RX PubMed=9027509; DOI=10.1006/geno.1996.4482;
RA Andre C., Hampe A., Lachaume P., Martin E., Wang X.P., Manus V.,
RA Hu W.X., Galibert F.;
RT "Sequence analysis of two genomic regions containing the KIT and the
RT FMS receptor tyrosine kinase genes.";
RL Genomics 39:216-226(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=18593464; DOI=10.1186/ar2447;
RA Jin P., Zhang J., Sumariwalla P.F., Ni I., Jorgensen B., Crawford D.,
RA Phillips S., Feldmann M., Shepard H.M., Paleolog E.M.;
RT "Novel splice variants derived from the receptor tyrosine kinase
RT superfamily are potential therapeutics for rheumatoid arthritis.";
RL Arthritis Res. Ther. 10:R73-R73(2008).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-16.
RX PubMed=2524648;
RA Visvader J., Verma I.M.;
RT "Differential transcription of exon 1 of the human c-fms gene in
RT placental trophoblasts and monocytes.";
RL Mol. Cell. Biol. 9:1336-1341(1989).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-16.
RX PubMed=3525854;
RA Wheeler E.F., Roussel M.F., Hampe A., Walker M.H., Fried V.A.,
RA Look A.T., Rettenmier C.W., Sherr C.J.;
RT "The amino-terminal domain of the v-fms oncogene product includes a
RT functional signal peptide that directs synthesis of a transforming
RT glycoprotein in the absence of feline leukemia virus gag sequences.";
RL J. Virol. 59:224-233(1986).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-16.
RC TISSUE=Placenta;
RA Flick M.B., Sapi E., Kacinski B.M.;
RT "Expression of a novel exon in the 5' UTR of human c-fms
RT transcripts.";
RL Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 244-295.
RX PubMed=4028159; DOI=10.1016/0092-8674(85)90099-6;
RA Nienhuis A.W., Bunn H.F., Turner P.H., Gopal T.V., Nash W.G.,
RA O'Brien S.J., Sherr C.J.;
RT "Expression of the human c-fms proto-oncogene in hematopoietic cells
RT and its deletion in the 5q- syndrome.";
RL Cell 42:421-428(1985).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 874-972 (ISOFORM 1).
RX PubMed=3532121; DOI=10.1073/pnas.83.20.7800;
RA Browning P.J., Bunn H.F., Cline A., Shuman M., Nienhuis A.W.;
RT "'Replacement' of COOH-terminal truncation of v-fms with c-fms
RT sequences markedly reduces transformation potential.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:7800-7804(1986).
RN [13]
RP FUNCTION IN CELL PROLIFERATION.
RX PubMed=7683918;
RA Bourette R.P., Mouchiroud G., Ouazana R., Morle F., Godet J.,
RA Blanchet J.P.;
RT "Expression of human colony-stimulating factor-1 (CSF-1) receptor in
RT murine pluripotent hematopoietic NFS-60 cells induces long-term
RT proliferation in response to CSF-1 without loss of erythroid
RT differentiation potential.";
RL Blood 81:2511-2520(1993).
RN [14]
RP INTERACTION WITH SRC; FYN AND YES1, AND MUTAGENESIS OF TYR-809.
RX PubMed=7681396;
RA Courtneidge S.A., Dhand R., Pilat D., Twamley G.M., Waterfield M.D.,
RA Roussel M.F.;
RT "Activation of Src family kinases by colony stimulating factor-1, and
RT their association with its receptor.";
RL EMBO J. 12:943-950(1993).
RN [15]
RP INDUCTION BY GLUCOCORTICOIDS.
RX PubMed=7845678;
RA Sapi E., Flick M.B., Gilmore-Hebert M., Rodov S., Kacinski B.M.;
RT "Transcriptional regulation of the c-fms (CSF-1R) proto-oncogene in
RT human breast carcinoma cells by glucocorticoids.";
RL Oncogene 10:529-542(1995).
RN [16]
RP MUTAGENESIS OF TYR-708 AND ASP-802.
RX PubMed=10340379; DOI=10.1038/sj.onc.1202646;
RA Morley G.M., Uden M., Gullick W.J., Dibb N.J.;
RT "Cell specific transformation by c-fms activating loop mutations is
RT attributable to constitutive receptor degradation.";
RL Oncogene 18:3076-3084(1999).
RN [17]
RP FUNCTION IN CELLULAR SIGNALING; PHOSPHORYLATION OF INPP5D AND
RP ACTIVATION OF AKT1.
RX PubMed=12882960; DOI=10.1074/jbc.M305021200;
RA Baran C.P., Tridandapani S., Helgason C.D., Humphries R.K.,
RA Krystal G., Marsh C.B.;
RT "The inositol 5'-phosphatase SHIP-1 and the Src kinase Lyn negatively
RT regulate macrophage colony-stimulating factor-induced Akt activity.";
RL J. Biol. Chem. 278:38628-38636(2003).
RN [18]
RP FUNCTION IN REGULATION OF CELL PROLIFERATION; CELL ADHESION; CELL
RP SHAPE AND INTEGRITY OF CELL JUNCTIONS, MUTAGENESIS OF LEU-301 AND
RP TYR-969, AND ROLE IN DISEASE.
RX PubMed=15117969; DOI=10.1083/jcb.200309102;
RA Wrobel C.N., Debnath J., Lin E., Beausoleil S., Roussel M.F.,
RA Brugge J.S.;
RT "Autocrine CSF-1R activation promotes Src-dependent disruption of
RT mammary epithelial architecture.";
RL J. Cell Biol. 165:263-273(2004).
RN [19]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-302 AND ASN-353, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [20]
RP FUNCTION AS CSF1 RECEPTOR, CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION,
RP ROLE IN DISEASE, AND ENZYME REGULATION.
RX PubMed=16648572; DOI=10.1158/1535-7163.MCT-05-0359;
RA Guo J., Marcotte P.A., McCall J.O., Dai Y., Pease L.J.,
RA Michaelides M.R., Davidsen S.K., Glaser K.B.;
RT "Inhibition of phosphorylation of the colony-stimulating factor-1
RT receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and
RT other tyrosine kinase inhibitors.";
RL Mol. Cancer Ther. 5:1007-1013(2006).
RN [21]
RP FUNCTION IN CELL PROLIFERATION, CATALYTIC ACTIVITY,
RP AUTOPHOSPHORYLATION, ROLE IN DISEASE, AND ENZYME REGULATION.
RX PubMed=17121910; DOI=10.1158/1535-7163.MCT-05-0313;
RA Ohno H., Kubo K., Murooka H., Kobayashi Y., Nishitoba T., Shibuya M.,
RA Yoneda T., Isoe T.;
RT "A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast
RT differentiation and osteolytic bone destruction in a bone metastasis
RT model.";
RL Mol. Cancer Ther. 5:2634-2643(2006).
RN [22]
RP FUNCTION IN REGULATION OF CELL PROLIFERATION AND CELL SHAPE, CATALYTIC
RP ACTIVITY, UBIQUITINATION, ENZYME REGULATION, AND MUTAGENESIS OF
RP ASP-802.
RX PubMed=16170366; DOI=10.1038/sj.onc.1209007;
RA Taylor J.R., Brownlow N., Domin J., Dibb N.J.;
RT "FMS receptor for M-CSF (CSF-1) is sensitive to the kinase inhibitor
RT imatinib and mutation of Asp-802 to Val confers resistance.";
RL Oncogene 25:147-151(2006).
RN [23]
RP FUNCTION AS IL34 RECEPTOR.
RX PubMed=18467591; DOI=10.1126/science.1154370;
RA Lin H., Lee E., Hestir K., Leo C., Huang M., Bosch E., Halenbeck R.,
RA Wu G., Zhou A., Behrens D., Hollenbaugh D., Linnemann T., Qin M.,
RA Wong J., Chu K., Doberstein S.K., Williams L.T.;
RT "Discovery of a cytokine and its receptor by functional screening of
RT the extracellular proteome.";
RL Science 320:807-811(2008).
RN [24]
RP ROLE IN DISEASE, AND ENZYME REGULATION.
RX PubMed=18814279; DOI=10.1002/ijc.23903;
RA Hiraga T., Nakamura H.;
RT "Imatinib mesylate suppresses bone metastases of breast cancer by
RT inhibiting osteoclasts through the blockade of c-Fms signals.";
RL Int. J. Cancer 124:215-222(2009).
RN [25]
RP ROLE IN DISEASE.
RX PubMed=19934330; DOI=10.1158/0008-5472.CAN-09-1868;
RA Patsialou A., Wyckoff J., Wang Y., Goswami S., Stanley E.R.,
RA Condeelis J.S.;
RT "Invasion of human breast cancer cells in vivo requires both paracrine
RT and autocrine loops involving the colony-stimulating factor-1
RT receptor.";
RL Cancer Res. 69:9498-9506(2009).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-699 AND SER-713, AND
RP MASS SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [27]
RP AUTOPHOSPHORYLATION, AND ENZYME REGULATION.
RX PubMed=20156689; DOI=10.1016/j.bmc.2010.01.056;
RA Mashkani B., Griffith R., Ashman L.K.;
RT "Colony stimulating factor-1 receptor as a target for small molecule
RT inhibitors.";
RL Bioorg. Med. Chem. 18:1789-1797(2010).
RN [28]
RP FUNCTION AS RECEPTOR FOR IL34 AND CSF1, PHOSPHORYLATION AT TYR-546;
RP TYR-699; TYR-708; TYR-723 AND TYR-809, AUTOPHOSPHORYLATION, ENZYME
RP REGULATION, AND INTERACTION WITH IL34 AND CSF1.
RX PubMed=20489731; DOI=10.1038/cdd.2010.60;
RA Chihara T., Suzu S., Hassan R., Chutiwitoonchai N., Hiyoshi M.,
RA Motoyoshi K., Kimura F., Okada S.;
RT "IL-34 and M-CSF share the receptor Fms but are not identical in
RT biological activity and signal activation.";
RL Cell Death Differ. 17:1917-1927(2010).
RN [29]
RP FUNCTION IN RELEASE OF PROINFLAMMATORY CHEMOKINES.
RX PubMed=20829061; DOI=10.1016/j.cyto.2010.08.005;
RA Eda H., Zhang J., Keith R.H., Michener M., Beidler D.R., Monahan J.B.;
RT "Macrophage-colony stimulating factor and interleukin-34 induce
RT chemokines in human whole blood.";
RL Cytokine 52:215-220(2010).
RN [30]
RP FUNCTION AS IL34 AND CSF1 RECEPTOR; ACTIVATION OF MAPK1/ERK2;
RP MAPK3/ERK1; PHOSPHORYLATION AT TYR-723, AND AUTOPHOSPHORYLATION.
RX PubMed=20504948; DOI=10.1189/jlb.1209822;
RA Wei S., Nandi S., Chitu V., Yeung Y.G., Yu W., Huang M.,
RA Williams L.T., Lin H., Stanley E.R.;
RT "Functional overlap but differential expression of CSF-1 and IL-34 in
RT their CSF-1 receptor-mediated regulation of myeloid cells.";
RL J. Leukoc. Biol. 88:495-505(2010).
RN [31]
RP REVIEW ON FUNCTION; SIGNALING PATHWAYS AND PHOSPHORYLATION.
RX PubMed=15519852; DOI=10.1016/j.tcb.2004.09.016;
RA Pixley F.J., Stanley E.R.;
RT "CSF-1 regulation of the wandering macrophage: complexity in action.";
RL Trends Cell Biol. 14:628-638(2004).
RN [32]
RP REVIEW ON FUNCTION IN IMMUNITY AND INFLAMMATION, AND ROLE IN DISEASE.
RX PubMed=16337366; DOI=10.1016/j.coi.2005.11.006;
RA Chitu V., Stanley E.R.;
RT "Colony-stimulating factor-1 in immunity and inflammation.";
RL Curr. Opin. Immunol. 18:39-48(2006).
RN [33]
RP REVIEW ON FUNCTION; SIGNALING PATHWAYS AND PHOSPHORYLATION.
RX PubMed=18687298; DOI=10.1016/j.intimp.2008.04.016;
RA Douglass T.G., Driggers L., Zhang J.G., Hoa N., Delgado C.,
RA Williams C.C., Dan Q., Sanchez R., Jeffes E.W., Wepsic H.T.,
RA Myers M.P., Koths K., Jadus M.R.;
RT "Macrophage colony stimulating factor: not just for macrophages
RT anymore! A gateway into complex biologies.";
RL Int. Immunopharmacol. 8:1354-1376(2008).
RN [34]
RP REVIEW.
RX PubMed=19132917; DOI=10.1146/annurev.immunol.021908.132557;
RA Auffray C., Sieweke M.H., Geissmann F.;
RT "Blood monocytes: development, heterogeneity, and relationship with
RT dendritic cells.";
RL Annu. Rev. Immunol. 27:669-692(2009).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 538-922 IN COMPLEXES WITH
RP ARYLAMIDE AND QUINOLONE INHIBITORS, AND DOMAIN.
RX PubMed=17132624; DOI=10.1074/jbc.M608183200;
RA Schubert C., Schalk-Hihi C., Struble G.T., Ma H.C., Petrounia I.P.,
RA Brandt B., Deckman I.C., Patch R.J., Player M.R., Spurlino J.C.,
RA Springer B.A.;
RT "Crystal structure of the tyrosine kinase domain of colony-stimulating
RT factor-1 receptor (cFMS) in complex with two inhibitors.";
RL J. Biol. Chem. 282:4094-4101(2007).
RN [36]
RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 543-918 IN AUTOINHIBITED
RP CONFORMATION, AND DOMAIN.
RX PubMed=17292918; DOI=10.1016/j.jmb.2007.01.036;
RA Walter M., Lucet I.S., Patel O., Broughton S.E., Bamert R.,
RA Williams N.K., Fantino E., Wilks A.F., Rossjohn J.;
RT "The 2.7 A crystal structure of the autoinhibited human c-Fms kinase
RT domain.";
RL J. Mol. Biol. 367:839-847(2007).
RN [37]
RP X-RAY CRYSTALLOGRAPHY (2.02 ANGSTROMS) OF 538-922 IN COMPLEX WITH
RP PYRIMIDINOPYRIDONE INHIBITOR, AND CATALYTIC ACTIVITY.
RX PubMed=18342505; DOI=10.1016/j.bmcl.2008.02.070;
RA Huang H., Hutta D.A., Hu H., DesJarlais R.L., Schubert C.,
RA Petrounia I.P., Chaikin M.A., Manthey C.L., Player M.R.;
RT "Design and synthesis of a pyrido[2,3-d]pyrimidin-5-one class of anti-
RT inflammatory FMS inhibitors.";
RL Bioorg. Med. Chem. Lett. 18:2355-2361(2008).
RN [38]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 538-922 IN COMPLEX WITH
RP INHIBITOR, CATALYTIC ACTIVITY, AND FUNCTION IN INFLAMMATION AND
RP DISEASE.
RX PubMed=19193011; DOI=10.1021/jm801406h;
RA Huang H., Hutta D.A., Rinker J.M., Hu H., Parsons W.H., Schubert C.,
RA DesJarlais R.L., Crysler C.S., Chaikin M.A., Donatelli R.R., Chen Y.,
RA Cheng D., Zhou Z., Yurkow E., Manthey C.L., Player M.R.;
RT "Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory
RT macrophage colony-stimulating factor-1 receptor inhibitors.";
RL J. Med. Chem. 52:1081-1099(2009).
RN [39]
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 538-922 IN COMPLEXES WITH
RP INHIBITORS, CATALYTIC ACTIVITY, AND ENZYME REGULATION.
RX PubMed=20137931; DOI=10.1016/j.bmcl.2010.01.078;
RA Meyers M.J., Pelc M., Kamtekar S., Day J., Poda G.I., Hall M.K.,
RA Michener M.L., Reitz B.A., Mathis K.J., Pierce B.S., Parikh M.D.,
RA Mischke D.A., Long S.A., Parlow J.J., Anderson D.R., Thorarensen A.;
RT "Structure-based drug design enables conversion of a DFG-in binding
RT CSF-1R kinase inhibitor to a DFG-out binding mode.";
RL Bioorg. Med. Chem. Lett. 20:1543-1547(2010).
RN [40]
RP VARIANTS [LARGE SCALE ANALYSIS] GLY-32; ARG-362; SER-413; VAL-536;
RP HIS-693; ASP-920 AND GLN-921.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [41]
RP VARIANTS HDLS 774-CYS--ASN-814 DEL; 585-GLY--LYS-619 DELINS ALA;
RP GLU-589; LYS-633; THR-766; PRO-770; ASN-775; THR-794; TYR-837;
RP SER-849; PHE-849 DEL; PRO-868; THR-875 AND THR-878, VARIANTS HIS-710;
RP ARG-747 AND ASP-920, AND CHARACTERIZATION OF VARIANTS HDLS LYS-633;
RP THR-766 AND THR-875.
RX PubMed=22197934; DOI=10.1038/ng.1027;
RA Rademakers R., Baker M., Nicholson A.M., Rutherford N.J., Finch N.,
RA Soto-Ortolaza A., Lash J., Wider C., Wojtas A., DeJesus-Hernandez M.,
RA Adamson J., Kouri N., Sundal C., Shuster E.A., Aasly J., MacKenzie J.,
RA Roeber S., Kretzschmar H.A., Boeve B.F., Knopman D.S., Petersen R.C.,
RA Cairns N.J., Ghetti B., Spina S., Garbern J., Tselis A.C., Uitti R.,
RA Das P., Van Gerpen J.A., Meschia J.F., Levy S., Broderick D.F.,
RA Graff-Radford N., Ross O.A., Miller B.B., Swerdlow R.H., Dickson D.W.,
RA Wszolek Z.K.;
RT "Mutations in the colony stimulating factor 1 receptor (CSF1R) gene
RT cause hereditary diffuse leukoencephalopathy with spheroids.";
RL Nat. Genet. 44:200-205(2012).
CC -!- FUNCTION: Tyrosine-protein kinase that acts as cell-surface
CC receptor for CSF1 and IL34 and plays an essential role in the
CC regulation of survival, proliferation and differentiation of
CC hematopoietic precursor cells, especially mononuclear phagocytes,
CC such as macrophages and monocytes. Promotes the release of
CC proinflammatory chemokines in response to IL34 and CSF1, and
CC thereby plays an important role in innate immunity and in
CC inflammatory processes. Plays an important role in the regulation
CC of osteoclast proliferation and differentiation, the regulation of
CC bone resorption, and is required for normal bone and tooth
CC development. Required for normal male and female fertility, and
CC for normal development of milk ducts and acinar structures in the
CC mammary gland during pregnancy. Promotes reorganization of the
CC actin cytoskeleton, regulates formation of membrane ruffles, cell
CC adhesion and cell migration, and promotes cancer cell invasion.
CC Activates several signaling pathways in response to ligand
CC binding. Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL.
CC Activation of PLCG2 leads to the production of the cellular
CC signaling molecules diacylglycerol and inositol 1,4,5-
CC trisphosphate, that then lead to the activation of protein kinase
CC C family members, especially PRKCD. Phosphorylation of PIK3R1, the
CC regulatory subunit of phosphatidylinositol 3-kinase, leads to
CC activation of the AKT1 signaling pathway. Activated CSF1R also
CC mediates activation of the MAP kinases MAPK1/ERK2 and/or
CC MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1.
CC Activated CSF1R transmits signals both via proteins that directly
CC interact with phosphorylated tyrosine residues in its
CC intracellular domain, or via adapter proteins, such as GRB2.
CC Promotes activation of STAT family members STAT3, STAT5A and/or
CC STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-
CC 1. Receptor signaling is down-regulated by protein phosphatases,
CC such as INPP5D/SHIP-1, that dephosphorylate the receptor and its
CC downstream effectors, and by rapid internalization of the
CC activated receptor.
CC -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a
CC [protein]-L-tyrosine phosphate.
CC -!- ENZYME REGULATION: Present in an inactive conformation in the
CC absence of bound ligand. CSF1 or IL34 binding leads to
CC dimerization and activation by autophosphorylation on tyrosine
CC residues. Inhibited by imatinib/STI-571 (Gleevec), dasatinib,
CC sunitinib/SU11248, lestaurtinib/CEP-701, midostaurin/PKC-412,
CC Ki20227, linifanib/ABT-869, Axitinib/AG013736, sorafenib/BAY 43-
CC 9006 and GW2580.
CC -!- SUBUNIT: Interacts with INPPL1/SHIP2 and THOC5 (By similarity).
CC Monomer. Homodimer. Interacts with CSF1 and IL34. Interaction with
CC dimeric CSF1 or IL34 leads to receptor homodimerization. Interacts
CC (tyrosine phosphorylated) with PLCG2 (via SH2 domain). Interacts
CC (tyrosine phosphorylated) with PIK3R1 (via SH2 domain). Interacts
CC (tyrosine phosphorylated) with FYN, YES1 and SRC (via SH2 domain).
CC Interacts (tyrosine phosphorylated) with CBL, GRB2 and SLA2.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P07333-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P07333-2; Sequence=VSP_047757, VSP_047758;
CC -!- TISSUE SPECIFICITY: Expressed in bone marrow and in differentiated
CC blood mononuclear cells.
CC -!- INDUCTION: Up-regulated by glucocorticoids.
CC -!- DOMAIN: The juxtamembrane domain functions as autoinhibitory
CC region. Phosphorylation of tyrosine residues in this region leads
CC to a conformation change and activation of the kinase.
CC -!- DOMAIN: The activation loop plays an important role in the
CC regulation of kinase activity. Phosphorylation of tyrosine
CC residues in this region leads to a conformation change and
CC activation of the kinase.
CC -!- PTM: Autophosphorylated in response to CSF1 or IL34 binding.
CC Phosphorylation at Tyr-561 is important for normal down-regulation
CC of signaling by ubiquitination, internalization and degradation.
CC Phosphorylation at Tyr-561 and Tyr-809 is important for
CC interaction with SRC family members, including FYN, YES1 and SRC,
CC and for subsequent activation of these protein kinases.
CC Phosphorylation at Tyr-699 and Tyr-923 is important for
CC interaction with GRB2. Phosphorylation at Tyr-723 is important for
CC interaction with PIK3R1. Phosphorylation at Tyr-708 is important
CC for normal receptor degradation. Phosphorylation at Tyr-723 and
CC Tyr-809 is important for interaction with PLCG2. Phosphorylation
CC at Tyr-969 is important for interaction with CBL.
CC Dephosphorylation by PTPN2 negatively regulates downstream
CC signaling and macrophage differentiation.
CC -!- PTM: Ubiquitinated. Becomes rapidly polyubiquitinated after
CC autophosphorylation, leading to its degradation.
CC -!- DISEASE: Note=Aberrant expression of CSF1 or CSF1R can promote
CC cancer cell proliferation, invasion and formation of metastases.
CC Overexpression of CSF1 or CSF1R is observed in a significant
CC percentage of breast, ovarian, prostate, and endometrial cancers.
CC -!- DISEASE: Note=Aberrant expression of CSF1 or CSF1R may play a role
CC in inflammatory diseases, such as rheumatoid arthritis,
CC glomerulonephritis, atherosclerosis, and allograft rejection.
CC -!- DISEASE: Leukoencephalopathy, diffuse hereditary, with spheroids
CC (HDLS) [MIM:221820]: An autosomal dominant adult-onset rapidly
CC progressive neurodegenerative disorder characterized by variable
CC behavioral, cognitive, and motor changes. Patients often die of
CC dementia within 6 years of onset. Brain imaging shows patchy
CC abnormalities in the cerebral white matter, predominantly
CC affecting the frontal and parietal lobes. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. CSF-1/PDGF receptor subfamily.
CC -!- SIMILARITY: Contains 5 Ig-like C2-type (immunoglobulin-like)
CC domains.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/CSF1RID40161ch5q32.html";
CC -----------------------------------------------------------------------
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DR EMBL; X03663; CAA27300.1; -; mRNA.
DR EMBL; U63963; AAB51696.1; -; Genomic_DNA.
DR EMBL; M25786; AAA58421.1; -; mRNA.
DR EMBL; EU826593; ACF47629.1; -; mRNA.
DR EMBL; AC011382; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471062; EAW61749.1; -; Genomic_DNA.
DR EMBL; CH471062; EAW61750.1; -; Genomic_DNA.
DR EMBL; BC047521; AAH47521.1; -; mRNA.
DR EMBL; M14002; AAA35849.1; -; Genomic_DNA.
DR EMBL; U78096; AAB51235.1; -; Genomic_DNA.
DR EMBL; M11067; AAA35848.1; -; Genomic_DNA.
DR EMBL; M14193; AAA35834.1; -; mRNA.
DR PIR; S08123; TVHUMD.
DR RefSeq; NP_005202.2; NM_005211.3.
DR UniGene; Hs.586219; -.
DR PDB; 2I0V; X-ray; 2.80 A; A=538-922.
DR PDB; 2I0Y; X-ray; 1.90 A; A=538-922.
DR PDB; 2I1M; X-ray; 1.80 A; A=538-922.
DR PDB; 2OGV; X-ray; 2.70 A; A=543-918.
DR PDB; 3BEA; X-ray; 2.02 A; A=538-922.
DR PDB; 3DPK; X-ray; 1.95 A; A=538-922.
DR PDB; 3KRJ; X-ray; 2.10 A; A=538-922.
DR PDB; 3KRL; X-ray; 2.40 A; A=538-922.
DR PDB; 3LCD; X-ray; 2.50 A; A=538-922.
DR PDB; 3LCO; X-ray; 3.40 A; A=550-919.
DR PDB; 4DKD; X-ray; 3.00 A; C=20-299.
DR PDB; 4HW7; X-ray; 2.90 A; A=542-919.
DR PDBsum; 2I0V; -.
DR PDBsum; 2I0Y; -.
DR PDBsum; 2I1M; -.
DR PDBsum; 2OGV; -.
DR PDBsum; 3BEA; -.
DR PDBsum; 3DPK; -.
DR PDBsum; 3KRJ; -.
DR PDBsum; 3KRL; -.
DR PDBsum; 3LCD; -.
DR PDBsum; 3LCO; -.
DR PDBsum; 4DKD; -.
DR PDBsum; 4HW7; -.
DR ProteinModelPortal; P07333; -.
DR SMR; P07333; 20-498, 544-945.
DR DIP; DIP-59421N; -.
DR IntAct; P07333; 9.
DR MINT; MINT-8019993; -.
DR STRING; 9606.ENSP00000286301; -.
DR BindingDB; P07333; -.
DR ChEMBL; CHEMBL1844; -.
DR DrugBank; DB00619; Imatinib.
DR DrugBank; DB01268; Sunitinib.
DR GuidetoPHARMACOLOGY; 1806; -.
DR PhosphoSite; P07333; -.
DR DMDM; 547770; -.
DR PaxDb; P07333; -.
DR PeptideAtlas; P07333; -.
DR PRIDE; P07333; -.
DR DNASU; 1436; -.
DR Ensembl; ENST00000286301; ENSP00000286301; ENSG00000182578.
DR Ensembl; ENST00000543093; ENSP00000445282; ENSG00000182578.
DR GeneID; 1436; -.
DR KEGG; hsa:1436; -.
DR UCSC; uc011dce.1; human.
DR CTD; 1436; -.
DR GeneCards; GC05M149413; -.
DR HGNC; HGNC:2433; CSF1R.
DR HPA; CAB008970; -.
DR HPA; HPA012323; -.
DR MIM; 164770; gene.
DR MIM; 221820; phenotype.
DR neXtProt; NX_P07333; -.
DR Orphanet; 313808; Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.
DR PharmGKB; PA26936; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000112008; -.
DR HOVERGEN; HBG004335; -.
DR InParanoid; P07333; -.
DR KO; K05090; -.
DR OMA; TVECVAF; -.
DR PhylomeDB; P07333; -.
DR BRENDA; 2.7.10.1; 2681.
DR SignaLink; P07333; -.
DR ChiTaRS; CSF1R; human.
DR EvolutionaryTrace; P07333; -.
DR GeneWiki; Colony_stimulating_factor_1_receptor; -.
DR GenomeRNAi; 1436; -.
DR NextBio; 35477774; -.
DR PRO; PR:P07333; -.
DR ArrayExpress; P07333; -.
DR Bgee; P07333; -.
DR CleanEx; HS_CSF1R; -.
DR Genevestigator; P07333; -.
DR GO; GO:0009986; C:cell surface; ISS:UniProtKB.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0043235; C:receptor complex; ISS:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0019955; F:cytokine binding; IDA:UniProtKB.
DR GO; GO:0005011; F:macrophage colony-stimulating factor receptor activity; IMP:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:BHF-UCL.
DR GO; GO:0008283; P:cell proliferation; IMP:UniProtKB.
DR GO; GO:0045217; P:cell-cell junction maintenance; IMP:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; TAS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0030225; P:macrophage differentiation; TAS:UniProtKB.
DR GO; GO:0060603; P:mammary gland duct morphogenesis; TAS:UniProtKB.
DR GO; GO:0030224; P:monocyte differentiation; TAS:UniProtKB.
DR GO; GO:0030316; P:osteoclast differentiation; ISS:UniProtKB.
DR GO; GO:0046488; P:phosphatidylinositol metabolic process; ISS:UniProtKB.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; ISS:UniProtKB.
DR GO; GO:0030335; P:positive regulation of cell migration; ISS:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IMP:UniProtKB.
DR GO; GO:0090197; P:positive regulation of chemokine secretion; IMP:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:0071902; P:positive regulation of protein serine/threonine kinase activity; ISS:UniProtKB.
DR GO; GO:0061098; P:positive regulation of protein tyrosine kinase activity; IMP:UniProtKB.
DR GO; GO:0042517; P:positive regulation of tyrosine phosphorylation of Stat3 protein; ISS:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:2000249; P:regulation of actin cytoskeleton reorganization; ISS:UniProtKB.
DR GO; GO:0045124; P:regulation of bone resorption; ISS:UniProtKB.
DR GO; GO:0008360; P:regulation of cell shape; IMP:UniProtKB.
DR GO; GO:0031529; P:ruffle organization; ISS:UniProtKB.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; ISS:UniProtKB.
DR Gene3D; 2.60.40.10; -; 5.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR003598; Ig_sub2.
DR InterPro; IPR013151; Immunoglobulin.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR016243; Tyr_kinase_CSF1/PDGF_rcpt.
DR InterPro; IPR001824; Tyr_kinase_rcpt_3_CS.
DR Pfam; PF00047; ig; 1.
DR Pfam; PF07714; Pkinase_Tyr; 1.
DR PIRSF; PIRSF500947; CSF-1_receptor; 1.
DR PIRSF; PIRSF000615; TyrPK_CSF1-R; 1.
DR SMART; SM00409; IG; 3.
DR SMART; SM00408; IGc2; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF56112; SSF56112; 2.
DR PROSITE; PS50835; IG_LIKE; 3.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS00240; RECEPTOR_TYR_KIN_III; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cell membrane;
KW Complete proteome; Disease mutation; Disulfide bond; Glycoprotein;
KW Immunity; Immunoglobulin domain; Inflammatory response;
KW Innate immunity; Kinase; Membrane; Nucleotide-binding; Phosphoprotein;
KW Polymorphism; Proto-oncogene; Receptor; Reference proteome; Repeat;
KW Signal; Transferase; Transmembrane; Transmembrane helix;
KW Tyrosine-protein kinase; Ubl conjugation.
FT SIGNAL 1 19 Potential.
FT CHAIN 20 972 Macrophage colony-stimulating factor 1
FT receptor.
FT /FTId=PRO_0000016765.
FT TOPO_DOM 20 517 Extracellular (Potential).
FT TRANSMEM 518 538 Helical; (Potential).
FT TOPO_DOM 539 972 Cytoplasmic (Potential).
FT DOMAIN 21 104 Ig-like C2-type 1.
FT DOMAIN 107 197 Ig-like C2-type 2.
FT DOMAIN 203 290 Ig-like C2-type 3.
FT DOMAIN 299 399 Ig-like C2-type 4.
FT DOMAIN 402 502 Ig-like C2-type 5.
FT DOMAIN 582 910 Protein kinase.
FT NP_BIND 588 596 ATP (By similarity).
FT REGION 542 574 Regulatory juxtamembrane domain.
FT REGION 796 818 Activation loop.
FT ACT_SITE 778 778 Proton acceptor (By similarity).
FT BINDING 616 616 ATP (Probable).
FT MOD_RES 546 546 Phosphotyrosine; by autocatalysis.
FT MOD_RES 561 561 Phosphotyrosine; by autocatalysis.
FT MOD_RES 699 699 Phosphotyrosine; by autocatalysis.
FT MOD_RES 708 708 Phosphotyrosine; by autocatalysis.
FT MOD_RES 713 713 Phosphoserine.
FT MOD_RES 723 723 Phosphotyrosine; by autocatalysis.
FT MOD_RES 809 809 Phosphotyrosine; by autocatalysis.
FT MOD_RES 923 923 Phosphotyrosine; by autocatalysis.
FT MOD_RES 969 969 Phosphotyrosine; by autocatalysis.
FT CARBOHYD 45 45 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 73 73 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 153 153 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 240 240 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 275 275 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 302 302 N-linked (GlcNAc...).
FT CARBOHYD 335 335 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 353 353 N-linked (GlcNAc...).
FT CARBOHYD 412 412 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 428 428 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 480 480 N-linked (GlcNAc...) (Potential).
FT DISULFID 42 84 By similarity.
FT DISULFID 127 177 By similarity.
FT DISULFID 224 278 By similarity.
FT DISULFID 419 485 By similarity.
FT VAR_SEQ 297 306 ESAYLNLSSE -> GTPSPSLCPA (in isoform 2).
FT /FTId=VSP_047757.
FT VAR_SEQ 307 972 Missing (in isoform 2).
FT /FTId=VSP_047758.
FT VARIANT 32 32 V -> G (in dbSNP:rs56048668).
FT /FTId=VAR_042038.
FT VARIANT 245 245 A -> S (in dbSNP:rs41338945).
FT /FTId=VAR_061290.
FT VARIANT 279 279 V -> M (in dbSNP:rs3829986).
FT /FTId=VAR_049718.
FT VARIANT 362 362 H -> R (in dbSNP:rs10079250).
FT /FTId=VAR_042039.
FT VARIANT 413 413 G -> S (in dbSNP:rs34951517).
FT /FTId=VAR_042040.
FT VARIANT 536 536 L -> V (in dbSNP:rs55942044).
FT /FTId=VAR_042041.
FT VARIANT 585 619 GKTLGAGAFGKVVEATAFGLGKEDAVLKVAVKMLK -> A
FT (in HDLS).
FT /FTId=VAR_067396.
FT VARIANT 589 589 G -> E (in HDLS).
FT /FTId=VAR_067397.
FT VARIANT 633 633 E -> K (in HDLS; impairs
FT autophosphorylation upon stimulation with
FT CSF1).
FT /FTId=VAR_067398.
FT VARIANT 693 693 P -> H (in a lung squamous cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_042042.
FT VARIANT 710 710 R -> H.
FT /FTId=VAR_067399.
FT VARIANT 747 747 G -> R (in dbSNP:rs41355444).
FT /FTId=VAR_067400.
FT VARIANT 766 766 M -> T (in HDLS; impairs
FT autophosphorylation upon stimulation with
FT CSF1).
FT /FTId=VAR_067401.
FT VARIANT 770 770 A -> P (in HDLS).
FT /FTId=VAR_067402.
FT VARIANT 774 814 Missing (in HDLS).
FT /FTId=VAR_067403.
FT VARIANT 775 775 I -> N (in HDLS; impairs
FT autophosphorylation upon stimulation with
FT CSF1).
FT /FTId=VAR_067404.
FT VARIANT 794 794 I -> T (in HDLS).
FT /FTId=VAR_067405.
FT VARIANT 837 837 D -> Y (in HDLS).
FT /FTId=VAR_067406.
FT VARIANT 849 849 F -> S (in HDLS).
FT /FTId=VAR_067407.
FT VARIANT 849 849 Missing (in HDLS).
FT /FTId=VAR_067408.
FT VARIANT 868 868 L -> P (in HDLS).
FT /FTId=VAR_067409.
FT VARIANT 875 875 M -> T (in HDLS).
FT /FTId=VAR_067410.
FT VARIANT 878 878 P -> T (in HDLS).
FT /FTId=VAR_067411.
FT VARIANT 920 920 E -> D (in dbSNP:rs34030164).
FT /FTId=VAR_042043.
FT VARIANT 921 921 R -> Q (in dbSNP:rs56059682).
FT /FTId=VAR_042044.
FT VARIANT 969 969 Y -> C (in dbSNP:rs1801271).
FT /FTId=VAR_011953.
FT MUTAGEN 301 301 L->S: Constitutive kinase activity.
FT MUTAGEN 708 708 Y->F: Impairs degradation of activated
FT CSF1R.
FT MUTAGEN 802 802 D->V: Constitutive kinase activity. Loss
FT of inhibition by imatinib.
FT MUTAGEN 809 809 Y->F: Reduced kinase activity. Reduced
FT interaction with SRC, FYN and YES1.
FT MUTAGEN 969 969 Y->F: Abolishes down-regulation of
FT activated CSF1R.
FT CONFLICT 54 54 P -> A (in Ref. 2; CAA27300).
FT CONFLICT 247 247 P -> H (in Ref. 7; AAH47521).
FT CONFLICT 354 354 A -> V (in Ref. 7; AAH47521).
FT CONFLICT 629 629 A -> S (in Ref. 7; AAH47521).
FT STRAND 22 25
FT STRAND 38 43
FT STRAND 66 73
FT HELIX 76 78
FT STRAND 82 84
FT STRAND 95 97
FT STRAND 108 111
FT STRAND 113 118
FT STRAND 127 131
FT HELIX 132 135
FT STRAND 136 142
FT HELIX 143 145
FT STRAND 158 160
FT STRAND 163 166
FT HELIX 169 171
FT STRAND 173 179
FT STRAND 191 196
FT STRAND 204 210
FT HELIX 215 217
FT HELIX 231 233
FT STRAND 234 236
FT STRAND 239 241
FT HELIX 246 261
FT HELIX 275 282
FT STRAND 286 293
FT HELIX 295 304
FT HELIX 309 311
FT HELIX 315 323
FT STRAND 556 560
FT HELIX 566 568
FT HELIX 573 575
FT STRAND 581 590
FT STRAND 592 601
FT STRAND 605 607
FT STRAND 612 618
FT HELIX 624 640
FT STRAND 649 653
FT STRAND 655 658
FT STRAND 660 664
FT HELIX 671 678
FT TURN 742 744
FT HELIX 753 771
FT HELIX 781 783
FT STRAND 785 787
FT HELIX 788 790
FT STRAND 791 794
FT HELIX 798 800
FT HELIX 803 805
FT TURN 806 808
FT STRAND 809 811
FT STRAND 815 817
FT HELIX 819 821
FT HELIX 824 829
FT HELIX 834 848
FT TURN 849 851
FT HELIX 863 871
FT HELIX 883 892
FT HELIX 897 899
FT HELIX 903 920
SQ SEQUENCE 972 AA; 107984 MW; A8D99BE237573FE8 CRC64;
MGPGVLLLLL VATAWHGQGI PVIEPSVPEL VVKPGATVTL RCVGNGSVEW DGPPSPHWTL
YSDGSSSILS TNNATFQNTG TYRCTEPGDP LGGSAAIHLY VKDPARPWNV LAQEVVVFED
QDALLPCLLT DPVLEAGVSL VRVRGRPLMR HTNYSFSPWH GFTIHRAKFI QSQDYQCSAL
MGGRKVMSIS IRLKVQKVIP GPPALTLVPA ELVRIRGEAA QIVCSASSVD VNFDVFLQHN
NTKLAIPQQS DFHNNRYQKV LTLNLDQVDF QHAGNYSCVA SNVQGKHSTS MFFRVVESAY
LNLSSEQNLI QEVTVGEGLN LKVMVEAYPG LQGFNWTYLG PFSDHQPEPK LANATTKDTY
RHTFTLSLPR LKPSEAGRYS FLARNPGGWR ALTFELTLRY PPEVSVIWTF INGSGTLLCA
ASGYPQPNVT WLQCSGHTDR CDEAQVLQVW DDPYPEVLSQ EPFHKVTVQS LLTVETLEHN
QTYECRAHNS VGSGSWAFIP ISAGAHTHPP DEFLFTPVVV ACMSIMALLL LLLLLLLYKY
KQKPKYQVRW KIIESYEGNS YTFIDPTQLP YNEKWEFPRN NLQFGKTLGA GAFGKVVEAT
AFGLGKEDAV LKVAVKMLKS TAHADEKEAL MSELKIMSHL GQHENIVNLL GACTHGGPVL
VITEYCCYGD LLNFLRRKAE AMLGPSLSPG QDPEGGVDYK NIHLEKKYVR RDSGFSSQGV
DTYVEMRPVS TSSNDSFSEQ DLDKEDGRPL ELRDLLHFSS QVAQGMAFLA SKNCIHRDVA
ARNVLLTNGH VAKIGDFGLA RDIMNDSNYI VKGNARLPVK WMAPESIFDC VYTVQSDVWS
YGILLWEIFS LGLNPYPGIL VNSKFYKLVK DGYQMAQPAF APKNIYSIMQ ACWALEPTHR
PTFQQICSFL QEQAQEDRRE RDYTNLPSSS RSGGSGSSSS ELEEESSSEH LTCCEQGDIA
QPLLQPNNYQ FC
//
MIM
164770
*RECORD*
*FIELD* NO
164770
*FIELD* TI
*164770 COLONY-STIMULATING FACTOR 1 RECEPTOR; CSF1R
;;MCSFR;;
ONCOGENE FMS; FMS;;
c-FMS;;
read moreCD115 ANTIGEN; CD115;;
V-FMS MCDONOUGH FELINE SARCOMA VIRAL ONCOGENE HOMOLOG, FORMERLY
*FIELD* TX
DESCRIPTION
The CSF1R gene, also known as c-FMS, encodes a tyrosine kinase growth
factor receptor for colony-stimulating factor-1 (CSF1; 120420), the
macrophage- and monocyte-specific growth factor (Ridge et al., 1990).
CLONING
How et al. (1996) determined the sequences of the homologs of the human
PDGFRB and CSF1R genes in the pufferfish (Fugu rubripes). Amino acid
sequences of the Fugu and human PGFRB and CSF1R genes showed an overall
homology of 45% and 39%, respectively.
GENE STRUCTURE
Hampe et al. (1989) demonstrated that the FMS gene consists of 21 small
exons interrupted by introns ranging in size from 6.3 kb to less than
0.1 kb.
Roberts et al. (1988) demonstrated that a 5-prime untranslated exon of
CSF1R is separated by a 26-kb intron from the 32-kb receptor coding
sequences. Furthermore, the 3-prime end of the PDGFRB gene is located
less than 0.5 kb upstream from this exon. The as-yet-unidentified CSF1R
promoter/enhancer sequences may be confined to the nucleotides
separating the 2 genes or could potentially lie within the PDGFR gene
itself. Similarities in chromosomal localization, organization, and
encoded amino acid sequences suggested that the CSF1R and PDGFR genes
arose through duplication. The human homolog of the murine Fim2 proviral
integration region corresponds to the 5-prime end of the FMS gene.
- Pseudogene
During sequence analysis of the first intron of the human FMS gene, Sapi
et al. (1994) identified an open reading frame encoding the ribosomal
protein L7 (RPL7; 604166). The sequence was identical to the full-length
RPL7 cDNA sequence but lacked any recognizable introns, had a 30-bp
poly(A) tail, and was bracketed by 2 perfect direct repeats of 14 bp.
Sapi et al. (1994) demonstrated that despite the fact that the 5-prime
flanking region of the RPL7 sequence contained a potential TATA box
upstream of an intact open reading frame, the pseudogene (RPL7P) was not
actively transcribed.
MAPPING
The FMS oncogene was assigned to chromosome 5 by study of mouse-man
somatic cell hybrids. The location was narrowed to 5q34 by the study of
hamster-human cell hybrids with well-defined deletions of 5q (Groffen et
al., 1984). The order on the long arm was found to be
centromere--leuS--HEXB--EMTB--FMS--CHR. By in situ hybridization, Le
Beau et al. (1986) assigned the FMS gene to chromosome 5q33.2 or 5q33.3
and the GMCSF (138960) gene to chromosome 5q23-q31.
Roberts et al. (1988) demonstrated that the CSF1R gene and the PDGFR1
(173410) gene are physically associated in a head-to-tail array, with
less than 500 bp between the polyadenylation signal of the PDGFRB gene
and the transcription start point of the CSF1R gene. By pulsed field gel
electrophoresis, Eccles (1991) demonstrated that the same is true in the
mouse where a 425-kb fragment hybridizes with the 3-prime end of PDGFR1
and the 5-prime end of CSF1R. In Fugu (pufferfish), How et al. (1996)
demonstrated that the 2 genes are closely linked in a head-to-tail array
with 2.2 kb of intergenic sequence.
Three mouse genomic domains, Fim1, Fim2, and Fim3, have been described
as proviral integration regions frequently involved in the early stages
of myeloblastic leukemogenesis induced in vivo or in vitro by the Friend
murine leukemia virus. Fim2 has been identified as the 5-prime end of
the Fms protooncogene. Van Cong et al. (1987, 1989) confirmed the
localization of human FIM2/FMS on chromosome 5q33. By Southern blot
analysis of DNA from human/rodent hybrids and by in situ hybridization,
they mapped FIM1 to human chromosome 6p23-p22.3 and FIM3 to human
chromosome 3q27.
Gross (2013) mapped the CSF1R gene to chromosome 5q32 based on an
alignment of the CSF1R sequence (GenBank GENBANK BC047521) with the
genomic sequence (GRCh37).
GENE FUNCTION
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 (138981, 306250). 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 GM-CSF and macrophage colony-stimulating factor
(CSF1R) 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.
Faccio et al. (2003) retrovirally transduced beta-3 integrin (ITGB3;
173470) -/- osteoclast precursors with chimeric CSF1R constructs
containing various cytoplasmic domain mutations and found that CSF1R
tyr697 was required for normalization of osteoclastogenesis and ERK
activation (see 176948). Overexpression of FOS (164810) normalized the
number of ITGB3 -/- osteoclasts in vitro but not their ability to resorb
dentin. Faccio et al. (2003) concluded that whereas CSF1R and
alpha-V-beta-3 integrin collaborate in the osteoclastogenic process
through shared activation of the ERK/FOS signaling pathway, the integrin
is essential for matrix degradation.
Using fate mapping analysis, Ginhoux et al. (2010) showed that adult
microglia derive from primitive macrophages. They showed that microglia
develop in mice that lack colony-stimulating factor-1 (CSF1; 120420) but
are absent in Csf1 receptor-deficient mice. In vivo lineage tracing
studies established that adult microglia derive from primitive myeloid
progenitors expressing Runx1 (151385) that arise before embryonic day 8.
Ginhoux et al. (2010) concluded that their results identified microglia
as an ontogenically distinct population in the mononuclear phagocyte
system and have implications for the use of embryonically derived
microglial progenitors for the treatment of various brain disorders.
CYTOGENETICS
Le Beau et al. (1986) found that the FMS and GM-CSF genes were both
deleted from chromosome 5q- in bone marrow cells of 2 patients with
refractory anemia and del(5)(q15-q33.3) (see chromosome 5q deletion
syndrome; 153550).
Morgan et al. (1986) pointed out that a break at 5q35 has been found in
several cases of malignant histiocytosis, a neoplastic process
characterized by fever, progressive wasting, lymphadenopathy,
hepatosplenomegaly, and the proliferation of atypical histiocytes at all
stages of maturation with frequent phagocytic activity. They suggested
that at the molecular level the change in band 5q35 may affect the FMS
oncogene responsible for the receptor for mononuclear-phagocyte growth
factor and thereby have a role in causing malignant histiocytosis.
Benz-Lemoine et al. (1988) also suggested that a breakpoint in 5q35 may
be critical to the development of malignant histiocytosis.
Boultwood et al. (1991) found loss of both CSF1R alleles in 10 patients
with myelodysplasia and a 5q deletion; 6 were hemizygous and 4 were
homozygous for CSF1R loss. Boultwood et al. (1991) suggested that loss
of this hemopoietic growth factor receptor gene may also be important in
the pathogenesis of myeloid leukemia.
MOLECULAR GENETICS
- Somatic Mutations
Among 110 patients with myelodysplastic and leukemic disorders, Ridge et
al. (1990) found somatic mutations in codon 969 of the CSF1R gene in 14
(12.7%) and in codon 301 in 2 (1.8%). The tyrosine residue at codon 969
was shown to be involved in a negative regulatory activity, which is
disrupted by amino acid substitutions. Mutations at codon 301 lead to
neoplastic transformation by ligand independence and constitutive
tyrosine kinase activity of the receptor. Somatic mutations were most
prevalent in chronic myelomonocytic leukemia (20%) and type M4 acute
myeloblastic leukemia (23%), both of which are characterized by
monocytic differentiation. One of 50 hematologically normal individuals
had a 969C-T transition as a constitutional change, which may represent
a predisposition to these particular malignancies.
Lamprecht et al. (2010) found that Reed-Sternberg cells in Hodgkin
lymphoma (236000) demonstrated upregulation of CSF1R and CSF1 mRNA and
constitutive activation of CSF1R, which correlated with increased
proliferation of the Reed-Sternberg cells. Non-Hodgkin cell lines did
not express either gene, suggesting that the expression in
Reed-Sternberg cells was aberrant. Analysis of CSF1R transcripts in
Reed-Sternberg cells showed use of an alternative transcription start
site located about 6.2-kb upstream of the normal myeloid transcription
start site: this sequence corresponded to a long terminal repeat (LTR)
of the mammalian apparent LTR retrotransposon (MALR) THE1B family. LTRs
derived from ancient retroviral infections have accumulated in the
mammalian genome, and mammalian organisms have devised a number of
surveillance mechanisms to silence these elements early in development,
usually by DNA methylation. The LTR region was found to contain a number
of putative binding sites for transcription factors (i.e., NFKB; 164011)
that were expressed in the Reed-Sternberg cells. Further studies
indicated that the LTR is normally repressed by epigenetic methylation,
and that Reed-Sternberg cells had lost this methylation. In addition,
nearly all Reed-Sternberg cells studied had lost expression of the
transcriptional repressor CBFA2T3 (603870). LTR-driven CSF1R transcripts
were also found in anaplastic large cell lymphoma. Lamprecht et al.
(2010) suggested that inhibition of CSF1R signaling may be of
therapeutic value in Hodgkin lymphoma.
- Hereditary Diffuse Leukoencephalopathy With Spheroids
By linkage analysis followed by whole-exome sequencing of the family
with hereditary diffuse leukoencephalopathy with spheroids (HDLS;
221820) reported by Swerdlow et al. (2009), Rademakers et al. (2012)
identified a heterozygous mutation in the CSF1R gene (164770.0001).
Sequencing of this gene in 13 additional probands with HDLS identified a
different heterozygous mutation in each (see, e.g.,
164770.0002-164770.0005). The mutations cosegregated with the disorder
in all families for which DNA from multiple affected individuals was
available, including the family reported by Baba et al. (2006). The
phenotype was characterized by adult-onset of a rapidly progressive
neurodegenerative disorder characterized by variable behavioral,
cognitive, and motor changes. Patients often died of dementia within 6
years of onset. Brain imaging showed patchy abnormalities in the
cerebral white matter, predominantly affecting the frontal and parietal
lobes. In vitro functional expression studies of some of the missense
mutations indicated that the mutant proteins did not show
autophosphorylation, suggesting a defect in kinase activity that likely
also affects downstream targets. The mutant proteins probably also act
in a dominant-negative manner, since CSF1R assembles into homodimers.
Overall, the findings indicated that a defect in microglial signaling
and function resulting from CSF1R mutations can cause central nervous
system degeneration.
ANIMAL MODEL
Aikawa et al. (2010) found that mouse MOZ/TIF2 (see 601408)-induced AML
stem cells with high expression of Csf1r had increased leukemia
initiating activity than AML stem cells with same amount of MOZ/TIF2
protein and low expression of Csf1r, when transplanted in irradiated
mice. The high Csf1r expressing cells had the phenotype of
granulocyte-macrophage progenitors and differentiated monocytes. In mice
with leukemia due to these cells, treatment with a drug-inducible
suicide gene targeting Csf1r-expressing cells resulted in curing of the
leukemia for up to 6 months compared to controls. Induction of AML was
suppressed in Csf1r-deficient mice, and Csf1r inhibitors slowed the
progression of MOZ/TIF2-induced AML. Increased Csf1r expression was due
mainly to the hematopoietic transcription factor PU.1 (165170), which
was required for the initiation and maintenance of MOZ/TIF2-induced AML
by increasing transcription of Csf1r. Aikawa et al. (2010) suggested
that CSF1R is crucial for leukemia induced by MOZ fusion and indicated
that targeting of PU.1 may be a therapeutic option.
*FIELD* AV
.0001
LEUKOENCEPHALOPATHY, DIFFUSE HEREDITARY, WITH SPHEROIDS
CSF1R, MET875THR
In affected members of a large family with hereditary diffuse
leukoencephalopathy with spheroids (HDLS; 221820) originally reported by
Swerdlow et al. (2009), Rademakers et al. (2012) identified a
heterozygous 2624T-C transition in exon 20 of the CSF1R gene, resulting
in a met875-to-thr (M875T) substitution in a highly conserved residue in
the intracellular tyrosine kinase domain. The mutation was not found in
1,436 controls. In vitro functional expression studies indicated that
the mutant protein did not show autophosphorylation, suggesting a defect
in kinase activity that likely also affects downstream targets. The
mutant protein probably also acts in a dominant-negative manner, since
CSF1R assembles into homodimers.
.0002
LEUKOENCEPHALOPATHY, DIFFUSE HEREDITARY, WITH SPHEROIDS
CSF1R, GLU633LYS
In affected members of a large family with HDLS (221820) originally
reported by Baba et al. (2006), Rademakers et al. (2012) identified a
heterozygous 1897G-A transition in exon 14 of the CSF1R gene, resulting
in a glu633-to-lys (E633K) substitution in a highly conserved residue in
the intracellular tyrosine kinase domain. The mutation was not found in
1,436 controls. In vitro functional expression studies indicated that
the mutant protein did not show autophosphorylation, suggesting a defect
in kinase activity that likely also affects downstream targets. The
mutant protein probably also acts in a dominant-negative manner, since
CSF1R assembles into homodimers.
.0003
LEUKOENCEPHALOPATHY, DIFFUSE HEREDITARY, WITH SPHEROIDS
CSF1R, IVS12AS, A-G, -2
In a pair of Norwegian monozygotic twins with HDLS (221820), Rademakers
et al. (2012) identified a heterozygous de novo A-to-G transition in
intron 12 of the CSF1R gene (1754-2A-G), resulting in the skipping of
exon 13, the in-frame loss of 34 consecutive amino acids, and the
insertion of an alanine residue. The mutation was predicted to result in
the loss of multiple amino acids in the intracellular tyrosine kinase
domain.
.0004
LEUKOENCEPHALOPATHY, DIFFUSE HEREDITARY, WITH SPHEROIDS
CSF1R, ILE794THR
In affected members of a family with HDLS (221820), Rademakers et al.
(2012) identified a heterozygous 2381T-C transition in exon 18 of the
CSF1R gene, resulting in an ile794-to-thr (I794T) substitution in a
highly conserved residue in the intracellular tyrosine kinase domain.
The mutation was not found in 1,436 controls.
.0005
LEUKOENCEPHALOPATHY, DIFFUSE HEREDITARY, WITH SPHEROIDS
CSF1R, ASP837TYR
In a woman with sporadic occurrence of HDLS (221820), Rademakers et al.
(2012) identified a heterozygous 2509G-T transversion in exon 19 of the
CSF1R gene, resulting in an asp837-to-tyr (D837Y) substitution in a
highly conserved residue in the intracellular tyrosine kinase domain.
The mutation was not found in 1,436 controls. The patient was diagnosed
clinically with a disorder resembling corticobasal syndrome, and was
identified from a cohort of 93 patients with various neurologic
symptoms. At age 43 years, she developed a gradual decline in expressing
herself, word-finding, and performing motor tasks with her right hand
and leg. About 2 years later, she had executive dysfunction,
bradykinesia, hyperreflexia, apraxia, rigidity in the upper limbs, and
spasticity in the lower limbs. There was rapid neurologic deterioration,
and she died at age 50. Brain MRI showed localized white matter
hyperintensities in the frontal and parietal white matter on T2-weighted
images.
*FIELD* SA
De Qi Xu et al. (1985); Gisselbrecht et al. (1987); Hampe et al. (1984);
Verbeek et al. (1985); Verbeek et al. (1985); Yarden and Ullrich (1988)
*FIELD* RF
1. Aikawa, Y.; Katsumoto, T.; Zhang, P.; Shima, H.; Shino, M.; Terui,
K.; Ito, E.; Ohno, H.; Stanley, E. R.; Singh, H.; Tenen, D. G.; Kitabayashi,
I.: PU.1-mediated upregulation of CSF1R is crucial for leukemia stem
cell potential induced by MOZ-TIF2. (Letter) Nature Med. 16: 580-585,
2010.
2. Baba, Y.; Ghetti, B.; Baker, M. C.; Uitti, R. J.; Hutton, M. L.;
Yamaguchi, K.; Bird, T.; Lin, W.; DeLucia, M. W.; Dickson, D. W.;
Wszolek, Z. K.: Hereditary diffuse leukoencephalopathy with spheroids:
clinical, pathologic and genetic studies of a new kindred. Acta Neuropath. 111:
300-311, 2006.
3. Benz-Lemoine, E.; Brizard, A.; Huret, J.-L.; Babin, P.; Guilhot,
F.; Couet, D.; Tanzer, J.: Malignant histiocytosis: a specific t(2;5)(p23;q35)
translocation? Review of the literature. Blood 72: 1045-1047, 1988.
4. Boultwood, J.; Rack, K.; Kelly, S.; Madden, J.; Sakaguchi, A. Y.;
Wang, L.-M.; Oscier, D. G.; Buckle, V. J.; Wainscoat, J. S.: Loss
of both CSF1R (FMS) alleles in patients with myelodysplasia and a
chromosome 5 deletion. Proc. Nat. Acad. Sci. 88: 6176-6180, 1991.
5. De Qi Xu; Guilhot, S.; Galibert, F.: Restriction fragment length
polymorphism of the human c-fms gene. Proc. Nat. Acad. Sci. 82:
2862-2865, 1985.
6. Eccles, M. R.: Genes encoding the platelet-derived growth factor
(PDGF) receptor and colony-stimulating factor 1 (CSF-1) receptor are
physically associated in mice as in humans. Gene 108: 285-288, 1991.
7. Faccio, R.; Takeshita, S.; Zallone, A.; Ross, F. P.; Teitelbaum,
S. L.: c-Fms and the alpha-V-beta-3 integrin collaborate during osteoclast
differentiation. J. Clin. Invest. 111: 749-758, 2003.
8. Ginhoux, F.; Greter, M.; Leboeuf, M.; Nandi, S.; See, P.; Gokhan,
S.; Mehler, M. F.; Conway, S. J.; Ng, L. G.; Stanley, E. R.; Samokhvalov,
I. M.; Merad, M.: Fate mapping analysis reveals that adult microglia
derive from primitive macrophages. Science 330: 841-845, 2010.
9. Gisselbrecht, S.; Fichelson, S.; Sola, B.; Bordereaux, D.; Hampe,
A.; Andre, C.; Galibert, F.; Tambourin, P. E.: Frequent c-fms activation
by proviral insertion in mouse myeloblastic leukaemias. Nature 329:
259-261, 1987.
10. Groffen, J.; Heisterkamp, N.; Spurr, N. K.; Dana, S. L.; Wasmuth,
J. J.; Stephenson, J. R.: Regional assignment of the human c-fms
oncogene to band q34 of chromosome 5. (Abstract) Cytogenet. Cell
Genet. 37: 484 only, 1984.
11. Gross, M. B.: Personal Communication. Baltimore, Md. 1/8/2013.
12. Hampe, A.; Gobet, M.; Sherr, C. J.; Galibert, F.: Nucleotide
sequence of the feline retroviral oncogene v-fms shows unexpected
homology with oncogenes encoding tyrosine-specific protein kinases. Proc.
Nat. Acad. Sci. 81: 85-89, 1984.
13. Hampe, A.; Shamoon, B.-M.; Gobet, M.; Sherr, C. J.; Galibert,
F.: Nucleotide sequence and structural organization of the human
FMS proto-oncogene. Oncogene Res. 4: 9-17, 1989.
14. How, G.-F.; Venkatesh, B.; Brenner, S.: Conserved linkage between
the puffer fish (Fugu rubripes) and human genes for platelet-derived
growth factor receptor and macrophage colony-stimulating factor receptor. Genome
Res. 6: 1185-1191, 1996.
15. 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.
16. Lamprecht, B.; Walter, K.; Kreher, S.; Kumar, R.; Hummel, M.;
Lenze, D.; Kochert, K.; Bouhlel, M. A.; Richter, J.; Soler, E.; Stadhouders,
R.; Johrens, K.; and 13 others: Derepression of an endogenous long
terminal repeat activates the CSF1R proto-oncogene in human lymphoma. Nature
Med. 16: 571-579, 2010.
17. Le Beau, M. M.; Westbrook, C. A.; Diaz, M. O.; Larson, R. A.;
Rowley, J. D.; Gasson, J. C.; Golde, D. W.; Sherr, C. J.: Evidence
for the involvement of GM-CSF and FMS in the deletion (5q) in myeloid
disorders. Science 231: 984-987, 1986.
18. Morgan, R.; Hecht, B. K.; Sandberg, A. A.; Hecht, F.; Smith, S.
D.: Chromosome 5q35 breakpoint in malignant histiocytosis. (Letter) New
Eng. J. Med. 314: 1322 only, 1986.
19. Rademakers, R.; Baker, M.; Nicholson, A. M.; Rutherford, N. J.;
Finch, N.; Soto-Ortolaza, A.; Lash, J.; Wider, C.; Wojtas, A.; DeJesus-Hernandez,
M.; Adamson, J.; Kouri, N.; and 26 others: Mutations in the colony
stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse
leukoencephalopathy with spheroids. Nature Genet. 44: 200-205, 2012.
20. Ridge, S. A.; Worwood, M.; Oscier, D.; Jacobs, A.; Padua, R. A.
: FMS mutations in myelodysplastic, leukemic, and normal subjects. Proc.
Nat. Acad. Sci. 87: 1377-1380, 1990.
21. Roberts, W. M.; Look, A. T.; Roussel, M. F.; Sherr, C. J.: Tandem
linkage of human CSF-1 receptor (c-fms) and PDGF receptor genes. Cell 55:
655-661, 1988.
22. Sapi, E.; Flick, M. B.; Kacinski, B. M.: The first intron of
human c-fms proto-oncogene contains a processed pseudogene (RPL7P)
for ribosomal protein L7. Genomics 22: 641-645, 1994.
23. Swerdlow, R. H.; Miller, B. B.; Lopes, M. B. S.; Mandell, J. W.;
Wooten, G. F.; Damgaard, P.; Manning, C.; Fowler, M.; Brashear, H.
R.: Autosomal dominant subcortical gliosis presenting as frontotemporal
dementia. Neurology 72: 260-267, 2009.
24. Van Cong, N.; Fichelson, S.; Gross, M. S.; Sola, B.; Bordereaux,
D.; de Tand, M. F.; Guilhot, S.; Gisselbrecht, S.; Frezal, J.; Tambourin,
P.: The human homologues of Fim1, Fim2/c-Fms, and Fim3, three retroviral
integration regions involved in mouse myeloblastic leukemias, are
respectively located on chromosomes 6p23, 5q33, and 3q27. Hum. Genet. 81:
257-263, 1989.
25. Van Cong, N.; Fichelson, S.; Sola, B.; Gross, M. S.; Jegou-Foubert,
C.; Bordereaux, D.; Gisselbrecht, S.; Tambourin, P. E.; Frezal, J.
: Assignment of Fim-2 (CSF1R) to chromosome 5q33 (in situ hybridization)
and Fim-3 to chromosome 3 (somatic cell analysis) region 3q27 (in
situ hybridization). (Abstract) Cytogenet. Cell Genet. 46: 670 only,
1987.
26. Verbeek, J. S.; Roebroek, A. J. M.; van den Ouweland, A. M. W.;
Bloemers, H. P. J.; Van de Ven, W. J. M.: Human c-fms proto-oncogene:
comparative analysis with an abnormal allele. Molec. Cell. Biol. 5:
422-426, 1985.
27. Verbeek, J. S.; van Heerikhuizen, H.; de Pauw, B. E.; Haanen,
C.; Bloemers, H. P. J.; Van de Ven, W. J. M.: A hereditary abnormal
c-fms proto-oncogene in a patient with acute lymphocytic leukaemia
and congenital hypothyroidism. Brit. J. Haemat. 61: 135-138, 1985.
28. Yarden, Y.; Ullrich, A.: Growth factor receptor tyrosine kinases. Ann.
Rev. Biochem. 57: 443-478, 1988.
*FIELD* CN
Matthew B. Gross - updated: 1/8/2013
Matthew B. Gross - updated: 3/14/2012
Cassandra L. Kniffin - updated: 2/6/2012
Ada Hamosh - updated: 12/28/2010
Cassandra L. Kniffin - updated: 5/27/2010
Marla J. F. O'Neill - updated: 2/17/2005
Ada Hamosh - updated: 9/20/2000
Victor A. McKusick - updated: 3/4/1997
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 01/08/2013
mgross: 1/8/2013
carol: 11/6/2012
mgross: 3/14/2012
carol: 2/7/2012
ckniffin: 2/6/2012
alopez: 1/3/2011
terry: 12/28/2010
wwang: 6/15/2010
ckniffin: 5/27/2010
wwang: 3/7/2005
terry: 2/17/2005
alopez: 9/20/2000
psherman: 9/10/1999
psherman: 11/23/1998
psherman: 11/21/1998
carol: 7/8/1998
dkim: 6/30/1998
jamie: 3/4/1997
jenny: 3/4/1997
terry: 2/24/1997
carol: 9/13/1994
carol: 1/8/1993
carol: 1/6/1993
supermim: 3/16/1992
carol: 2/16/1992
carol: 12/4/1991
*RECORD*
*FIELD* NO
164770
*FIELD* TI
*164770 COLONY-STIMULATING FACTOR 1 RECEPTOR; CSF1R
;;MCSFR;;
ONCOGENE FMS; FMS;;
c-FMS;;
read moreCD115 ANTIGEN; CD115;;
V-FMS MCDONOUGH FELINE SARCOMA VIRAL ONCOGENE HOMOLOG, FORMERLY
*FIELD* TX
DESCRIPTION
The CSF1R gene, also known as c-FMS, encodes a tyrosine kinase growth
factor receptor for colony-stimulating factor-1 (CSF1; 120420), the
macrophage- and monocyte-specific growth factor (Ridge et al., 1990).
CLONING
How et al. (1996) determined the sequences of the homologs of the human
PDGFRB and CSF1R genes in the pufferfish (Fugu rubripes). Amino acid
sequences of the Fugu and human PGFRB and CSF1R genes showed an overall
homology of 45% and 39%, respectively.
GENE STRUCTURE
Hampe et al. (1989) demonstrated that the FMS gene consists of 21 small
exons interrupted by introns ranging in size from 6.3 kb to less than
0.1 kb.
Roberts et al. (1988) demonstrated that a 5-prime untranslated exon of
CSF1R is separated by a 26-kb intron from the 32-kb receptor coding
sequences. Furthermore, the 3-prime end of the PDGFRB gene is located
less than 0.5 kb upstream from this exon. The as-yet-unidentified CSF1R
promoter/enhancer sequences may be confined to the nucleotides
separating the 2 genes or could potentially lie within the PDGFR gene
itself. Similarities in chromosomal localization, organization, and
encoded amino acid sequences suggested that the CSF1R and PDGFR genes
arose through duplication. The human homolog of the murine Fim2 proviral
integration region corresponds to the 5-prime end of the FMS gene.
- Pseudogene
During sequence analysis of the first intron of the human FMS gene, Sapi
et al. (1994) identified an open reading frame encoding the ribosomal
protein L7 (RPL7; 604166). The sequence was identical to the full-length
RPL7 cDNA sequence but lacked any recognizable introns, had a 30-bp
poly(A) tail, and was bracketed by 2 perfect direct repeats of 14 bp.
Sapi et al. (1994) demonstrated that despite the fact that the 5-prime
flanking region of the RPL7 sequence contained a potential TATA box
upstream of an intact open reading frame, the pseudogene (RPL7P) was not
actively transcribed.
MAPPING
The FMS oncogene was assigned to chromosome 5 by study of mouse-man
somatic cell hybrids. The location was narrowed to 5q34 by the study of
hamster-human cell hybrids with well-defined deletions of 5q (Groffen et
al., 1984). The order on the long arm was found to be
centromere--leuS--HEXB--EMTB--FMS--CHR. By in situ hybridization, Le
Beau et al. (1986) assigned the FMS gene to chromosome 5q33.2 or 5q33.3
and the GMCSF (138960) gene to chromosome 5q23-q31.
Roberts et al. (1988) demonstrated that the CSF1R gene and the PDGFR1
(173410) gene are physically associated in a head-to-tail array, with
less than 500 bp between the polyadenylation signal of the PDGFRB gene
and the transcription start point of the CSF1R gene. By pulsed field gel
electrophoresis, Eccles (1991) demonstrated that the same is true in the
mouse where a 425-kb fragment hybridizes with the 3-prime end of PDGFR1
and the 5-prime end of CSF1R. In Fugu (pufferfish), How et al. (1996)
demonstrated that the 2 genes are closely linked in a head-to-tail array
with 2.2 kb of intergenic sequence.
Three mouse genomic domains, Fim1, Fim2, and Fim3, have been described
as proviral integration regions frequently involved in the early stages
of myeloblastic leukemogenesis induced in vivo or in vitro by the Friend
murine leukemia virus. Fim2 has been identified as the 5-prime end of
the Fms protooncogene. Van Cong et al. (1987, 1989) confirmed the
localization of human FIM2/FMS on chromosome 5q33. By Southern blot
analysis of DNA from human/rodent hybrids and by in situ hybridization,
they mapped FIM1 to human chromosome 6p23-p22.3 and FIM3 to human
chromosome 3q27.
Gross (2013) mapped the CSF1R gene to chromosome 5q32 based on an
alignment of the CSF1R sequence (GenBank GENBANK BC047521) with the
genomic sequence (GRCh37).
GENE FUNCTION
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 (138981, 306250). 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 GM-CSF and macrophage colony-stimulating factor
(CSF1R) 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.
Faccio et al. (2003) retrovirally transduced beta-3 integrin (ITGB3;
173470) -/- osteoclast precursors with chimeric CSF1R constructs
containing various cytoplasmic domain mutations and found that CSF1R
tyr697 was required for normalization of osteoclastogenesis and ERK
activation (see 176948). Overexpression of FOS (164810) normalized the
number of ITGB3 -/- osteoclasts in vitro but not their ability to resorb
dentin. Faccio et al. (2003) concluded that whereas CSF1R and
alpha-V-beta-3 integrin collaborate in the osteoclastogenic process
through shared activation of the ERK/FOS signaling pathway, the integrin
is essential for matrix degradation.
Using fate mapping analysis, Ginhoux et al. (2010) showed that adult
microglia derive from primitive macrophages. They showed that microglia
develop in mice that lack colony-stimulating factor-1 (CSF1; 120420) but
are absent in Csf1 receptor-deficient mice. In vivo lineage tracing
studies established that adult microglia derive from primitive myeloid
progenitors expressing Runx1 (151385) that arise before embryonic day 8.
Ginhoux et al. (2010) concluded that their results identified microglia
as an ontogenically distinct population in the mononuclear phagocyte
system and have implications for the use of embryonically derived
microglial progenitors for the treatment of various brain disorders.
CYTOGENETICS
Le Beau et al. (1986) found that the FMS and GM-CSF genes were both
deleted from chromosome 5q- in bone marrow cells of 2 patients with
refractory anemia and del(5)(q15-q33.3) (see chromosome 5q deletion
syndrome; 153550).
Morgan et al. (1986) pointed out that a break at 5q35 has been found in
several cases of malignant histiocytosis, a neoplastic process
characterized by fever, progressive wasting, lymphadenopathy,
hepatosplenomegaly, and the proliferation of atypical histiocytes at all
stages of maturation with frequent phagocytic activity. They suggested
that at the molecular level the change in band 5q35 may affect the FMS
oncogene responsible for the receptor for mononuclear-phagocyte growth
factor and thereby have a role in causing malignant histiocytosis.
Benz-Lemoine et al. (1988) also suggested that a breakpoint in 5q35 may
be critical to the development of malignant histiocytosis.
Boultwood et al. (1991) found loss of both CSF1R alleles in 10 patients
with myelodysplasia and a 5q deletion; 6 were hemizygous and 4 were
homozygous for CSF1R loss. Boultwood et al. (1991) suggested that loss
of this hemopoietic growth factor receptor gene may also be important in
the pathogenesis of myeloid leukemia.
MOLECULAR GENETICS
- Somatic Mutations
Among 110 patients with myelodysplastic and leukemic disorders, Ridge et
al. (1990) found somatic mutations in codon 969 of the CSF1R gene in 14
(12.7%) and in codon 301 in 2 (1.8%). The tyrosine residue at codon 969
was shown to be involved in a negative regulatory activity, which is
disrupted by amino acid substitutions. Mutations at codon 301 lead to
neoplastic transformation by ligand independence and constitutive
tyrosine kinase activity of the receptor. Somatic mutations were most
prevalent in chronic myelomonocytic leukemia (20%) and type M4 acute
myeloblastic leukemia (23%), both of which are characterized by
monocytic differentiation. One of 50 hematologically normal individuals
had a 969C-T transition as a constitutional change, which may represent
a predisposition to these particular malignancies.
Lamprecht et al. (2010) found that Reed-Sternberg cells in Hodgkin
lymphoma (236000) demonstrated upregulation of CSF1R and CSF1 mRNA and
constitutive activation of CSF1R, which correlated with increased
proliferation of the Reed-Sternberg cells. Non-Hodgkin cell lines did
not express either gene, suggesting that the expression in
Reed-Sternberg cells was aberrant. Analysis of CSF1R transcripts in
Reed-Sternberg cells showed use of an alternative transcription start
site located about 6.2-kb upstream of the normal myeloid transcription
start site: this sequence corresponded to a long terminal repeat (LTR)
of the mammalian apparent LTR retrotransposon (MALR) THE1B family. LTRs
derived from ancient retroviral infections have accumulated in the
mammalian genome, and mammalian organisms have devised a number of
surveillance mechanisms to silence these elements early in development,
usually by DNA methylation. The LTR region was found to contain a number
of putative binding sites for transcription factors (i.e., NFKB; 164011)
that were expressed in the Reed-Sternberg cells. Further studies
indicated that the LTR is normally repressed by epigenetic methylation,
and that Reed-Sternberg cells had lost this methylation. In addition,
nearly all Reed-Sternberg cells studied had lost expression of the
transcriptional repressor CBFA2T3 (603870). LTR-driven CSF1R transcripts
were also found in anaplastic large cell lymphoma. Lamprecht et al.
(2010) suggested that inhibition of CSF1R signaling may be of
therapeutic value in Hodgkin lymphoma.
- Hereditary Diffuse Leukoencephalopathy With Spheroids
By linkage analysis followed by whole-exome sequencing of the family
with hereditary diffuse leukoencephalopathy with spheroids (HDLS;
221820) reported by Swerdlow et al. (2009), Rademakers et al. (2012)
identified a heterozygous mutation in the CSF1R gene (164770.0001).
Sequencing of this gene in 13 additional probands with HDLS identified a
different heterozygous mutation in each (see, e.g.,
164770.0002-164770.0005). The mutations cosegregated with the disorder
in all families for which DNA from multiple affected individuals was
available, including the family reported by Baba et al. (2006). The
phenotype was characterized by adult-onset of a rapidly progressive
neurodegenerative disorder characterized by variable behavioral,
cognitive, and motor changes. Patients often died of dementia within 6
years of onset. Brain imaging showed patchy abnormalities in the
cerebral white matter, predominantly affecting the frontal and parietal
lobes. In vitro functional expression studies of some of the missense
mutations indicated that the mutant proteins did not show
autophosphorylation, suggesting a defect in kinase activity that likely
also affects downstream targets. The mutant proteins probably also act
in a dominant-negative manner, since CSF1R assembles into homodimers.
Overall, the findings indicated that a defect in microglial signaling
and function resulting from CSF1R mutations can cause central nervous
system degeneration.
ANIMAL MODEL
Aikawa et al. (2010) found that mouse MOZ/TIF2 (see 601408)-induced AML
stem cells with high expression of Csf1r had increased leukemia
initiating activity than AML stem cells with same amount of MOZ/TIF2
protein and low expression of Csf1r, when transplanted in irradiated
mice. The high Csf1r expressing cells had the phenotype of
granulocyte-macrophage progenitors and differentiated monocytes. In mice
with leukemia due to these cells, treatment with a drug-inducible
suicide gene targeting Csf1r-expressing cells resulted in curing of the
leukemia for up to 6 months compared to controls. Induction of AML was
suppressed in Csf1r-deficient mice, and Csf1r inhibitors slowed the
progression of MOZ/TIF2-induced AML. Increased Csf1r expression was due
mainly to the hematopoietic transcription factor PU.1 (165170), which
was required for the initiation and maintenance of MOZ/TIF2-induced AML
by increasing transcription of Csf1r. Aikawa et al. (2010) suggested
that CSF1R is crucial for leukemia induced by MOZ fusion and indicated
that targeting of PU.1 may be a therapeutic option.
*FIELD* AV
.0001
LEUKOENCEPHALOPATHY, DIFFUSE HEREDITARY, WITH SPHEROIDS
CSF1R, MET875THR
In affected members of a large family with hereditary diffuse
leukoencephalopathy with spheroids (HDLS; 221820) originally reported by
Swerdlow et al. (2009), Rademakers et al. (2012) identified a
heterozygous 2624T-C transition in exon 20 of the CSF1R gene, resulting
in a met875-to-thr (M875T) substitution in a highly conserved residue in
the intracellular tyrosine kinase domain. The mutation was not found in
1,436 controls. In vitro functional expression studies indicated that
the mutant protein did not show autophosphorylation, suggesting a defect
in kinase activity that likely also affects downstream targets. The
mutant protein probably also acts in a dominant-negative manner, since
CSF1R assembles into homodimers.
.0002
LEUKOENCEPHALOPATHY, DIFFUSE HEREDITARY, WITH SPHEROIDS
CSF1R, GLU633LYS
In affected members of a large family with HDLS (221820) originally
reported by Baba et al. (2006), Rademakers et al. (2012) identified a
heterozygous 1897G-A transition in exon 14 of the CSF1R gene, resulting
in a glu633-to-lys (E633K) substitution in a highly conserved residue in
the intracellular tyrosine kinase domain. The mutation was not found in
1,436 controls. In vitro functional expression studies indicated that
the mutant protein did not show autophosphorylation, suggesting a defect
in kinase activity that likely also affects downstream targets. The
mutant protein probably also acts in a dominant-negative manner, since
CSF1R assembles into homodimers.
.0003
LEUKOENCEPHALOPATHY, DIFFUSE HEREDITARY, WITH SPHEROIDS
CSF1R, IVS12AS, A-G, -2
In a pair of Norwegian monozygotic twins with HDLS (221820), Rademakers
et al. (2012) identified a heterozygous de novo A-to-G transition in
intron 12 of the CSF1R gene (1754-2A-G), resulting in the skipping of
exon 13, the in-frame loss of 34 consecutive amino acids, and the
insertion of an alanine residue. The mutation was predicted to result in
the loss of multiple amino acids in the intracellular tyrosine kinase
domain.
.0004
LEUKOENCEPHALOPATHY, DIFFUSE HEREDITARY, WITH SPHEROIDS
CSF1R, ILE794THR
In affected members of a family with HDLS (221820), Rademakers et al.
(2012) identified a heterozygous 2381T-C transition in exon 18 of the
CSF1R gene, resulting in an ile794-to-thr (I794T) substitution in a
highly conserved residue in the intracellular tyrosine kinase domain.
The mutation was not found in 1,436 controls.
.0005
LEUKOENCEPHALOPATHY, DIFFUSE HEREDITARY, WITH SPHEROIDS
CSF1R, ASP837TYR
In a woman with sporadic occurrence of HDLS (221820), Rademakers et al.
(2012) identified a heterozygous 2509G-T transversion in exon 19 of the
CSF1R gene, resulting in an asp837-to-tyr (D837Y) substitution in a
highly conserved residue in the intracellular tyrosine kinase domain.
The mutation was not found in 1,436 controls. The patient was diagnosed
clinically with a disorder resembling corticobasal syndrome, and was
identified from a cohort of 93 patients with various neurologic
symptoms. At age 43 years, she developed a gradual decline in expressing
herself, word-finding, and performing motor tasks with her right hand
and leg. About 2 years later, she had executive dysfunction,
bradykinesia, hyperreflexia, apraxia, rigidity in the upper limbs, and
spasticity in the lower limbs. There was rapid neurologic deterioration,
and she died at age 50. Brain MRI showed localized white matter
hyperintensities in the frontal and parietal white matter on T2-weighted
images.
*FIELD* SA
De Qi Xu et al. (1985); Gisselbrecht et al. (1987); Hampe et al. (1984);
Verbeek et al. (1985); Verbeek et al. (1985); Yarden and Ullrich (1988)
*FIELD* RF
1. Aikawa, Y.; Katsumoto, T.; Zhang, P.; Shima, H.; Shino, M.; Terui,
K.; Ito, E.; Ohno, H.; Stanley, E. R.; Singh, H.; Tenen, D. G.; Kitabayashi,
I.: PU.1-mediated upregulation of CSF1R is crucial for leukemia stem
cell potential induced by MOZ-TIF2. (Letter) Nature Med. 16: 580-585,
2010.
2. Baba, Y.; Ghetti, B.; Baker, M. C.; Uitti, R. J.; Hutton, M. L.;
Yamaguchi, K.; Bird, T.; Lin, W.; DeLucia, M. W.; Dickson, D. W.;
Wszolek, Z. K.: Hereditary diffuse leukoencephalopathy with spheroids:
clinical, pathologic and genetic studies of a new kindred. Acta Neuropath. 111:
300-311, 2006.
3. Benz-Lemoine, E.; Brizard, A.; Huret, J.-L.; Babin, P.; Guilhot,
F.; Couet, D.; Tanzer, J.: Malignant histiocytosis: a specific t(2;5)(p23;q35)
translocation? Review of the literature. Blood 72: 1045-1047, 1988.
4. Boultwood, J.; Rack, K.; Kelly, S.; Madden, J.; Sakaguchi, A. Y.;
Wang, L.-M.; Oscier, D. G.; Buckle, V. J.; Wainscoat, J. S.: Loss
of both CSF1R (FMS) alleles in patients with myelodysplasia and a
chromosome 5 deletion. Proc. Nat. Acad. Sci. 88: 6176-6180, 1991.
5. De Qi Xu; Guilhot, S.; Galibert, F.: Restriction fragment length
polymorphism of the human c-fms gene. Proc. Nat. Acad. Sci. 82:
2862-2865, 1985.
6. Eccles, M. R.: Genes encoding the platelet-derived growth factor
(PDGF) receptor and colony-stimulating factor 1 (CSF-1) receptor are
physically associated in mice as in humans. Gene 108: 285-288, 1991.
7. Faccio, R.; Takeshita, S.; Zallone, A.; Ross, F. P.; Teitelbaum,
S. L.: c-Fms and the alpha-V-beta-3 integrin collaborate during osteoclast
differentiation. J. Clin. Invest. 111: 749-758, 2003.
8. Ginhoux, F.; Greter, M.; Leboeuf, M.; Nandi, S.; See, P.; Gokhan,
S.; Mehler, M. F.; Conway, S. J.; Ng, L. G.; Stanley, E. R.; Samokhvalov,
I. M.; Merad, M.: Fate mapping analysis reveals that adult microglia
derive from primitive macrophages. Science 330: 841-845, 2010.
9. Gisselbrecht, S.; Fichelson, S.; Sola, B.; Bordereaux, D.; Hampe,
A.; Andre, C.; Galibert, F.; Tambourin, P. E.: Frequent c-fms activation
by proviral insertion in mouse myeloblastic leukaemias. Nature 329:
259-261, 1987.
10. Groffen, J.; Heisterkamp, N.; Spurr, N. K.; Dana, S. L.; Wasmuth,
J. J.; Stephenson, J. R.: Regional assignment of the human c-fms
oncogene to band q34 of chromosome 5. (Abstract) Cytogenet. Cell
Genet. 37: 484 only, 1984.
11. Gross, M. B.: Personal Communication. Baltimore, Md. 1/8/2013.
12. Hampe, A.; Gobet, M.; Sherr, C. J.; Galibert, F.: Nucleotide
sequence of the feline retroviral oncogene v-fms shows unexpected
homology with oncogenes encoding tyrosine-specific protein kinases. Proc.
Nat. Acad. Sci. 81: 85-89, 1984.
13. Hampe, A.; Shamoon, B.-M.; Gobet, M.; Sherr, C. J.; Galibert,
F.: Nucleotide sequence and structural organization of the human
FMS proto-oncogene. Oncogene Res. 4: 9-17, 1989.
14. How, G.-F.; Venkatesh, B.; Brenner, S.: Conserved linkage between
the puffer fish (Fugu rubripes) and human genes for platelet-derived
growth factor receptor and macrophage colony-stimulating factor receptor. Genome
Res. 6: 1185-1191, 1996.
15. 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.
16. Lamprecht, B.; Walter, K.; Kreher, S.; Kumar, R.; Hummel, M.;
Lenze, D.; Kochert, K.; Bouhlel, M. A.; Richter, J.; Soler, E.; Stadhouders,
R.; Johrens, K.; and 13 others: Derepression of an endogenous long
terminal repeat activates the CSF1R proto-oncogene in human lymphoma. Nature
Med. 16: 571-579, 2010.
17. Le Beau, M. M.; Westbrook, C. A.; Diaz, M. O.; Larson, R. A.;
Rowley, J. D.; Gasson, J. C.; Golde, D. W.; Sherr, C. J.: Evidence
for the involvement of GM-CSF and FMS in the deletion (5q) in myeloid
disorders. Science 231: 984-987, 1986.
18. Morgan, R.; Hecht, B. K.; Sandberg, A. A.; Hecht, F.; Smith, S.
D.: Chromosome 5q35 breakpoint in malignant histiocytosis. (Letter) New
Eng. J. Med. 314: 1322 only, 1986.
19. Rademakers, R.; Baker, M.; Nicholson, A. M.; Rutherford, N. J.;
Finch, N.; Soto-Ortolaza, A.; Lash, J.; Wider, C.; Wojtas, A.; DeJesus-Hernandez,
M.; Adamson, J.; Kouri, N.; and 26 others: Mutations in the colony
stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse
leukoencephalopathy with spheroids. Nature Genet. 44: 200-205, 2012.
20. Ridge, S. A.; Worwood, M.; Oscier, D.; Jacobs, A.; Padua, R. A.
: FMS mutations in myelodysplastic, leukemic, and normal subjects. Proc.
Nat. Acad. Sci. 87: 1377-1380, 1990.
21. Roberts, W. M.; Look, A. T.; Roussel, M. F.; Sherr, C. J.: Tandem
linkage of human CSF-1 receptor (c-fms) and PDGF receptor genes. Cell 55:
655-661, 1988.
22. Sapi, E.; Flick, M. B.; Kacinski, B. M.: The first intron of
human c-fms proto-oncogene contains a processed pseudogene (RPL7P)
for ribosomal protein L7. Genomics 22: 641-645, 1994.
23. Swerdlow, R. H.; Miller, B. B.; Lopes, M. B. S.; Mandell, J. W.;
Wooten, G. F.; Damgaard, P.; Manning, C.; Fowler, M.; Brashear, H.
R.: Autosomal dominant subcortical gliosis presenting as frontotemporal
dementia. Neurology 72: 260-267, 2009.
24. Van Cong, N.; Fichelson, S.; Gross, M. S.; Sola, B.; Bordereaux,
D.; de Tand, M. F.; Guilhot, S.; Gisselbrecht, S.; Frezal, J.; Tambourin,
P.: The human homologues of Fim1, Fim2/c-Fms, and Fim3, three retroviral
integration regions involved in mouse myeloblastic leukemias, are
respectively located on chromosomes 6p23, 5q33, and 3q27. Hum. Genet. 81:
257-263, 1989.
25. Van Cong, N.; Fichelson, S.; Sola, B.; Gross, M. S.; Jegou-Foubert,
C.; Bordereaux, D.; Gisselbrecht, S.; Tambourin, P. E.; Frezal, J.
: Assignment of Fim-2 (CSF1R) to chromosome 5q33 (in situ hybridization)
and Fim-3 to chromosome 3 (somatic cell analysis) region 3q27 (in
situ hybridization). (Abstract) Cytogenet. Cell Genet. 46: 670 only,
1987.
26. Verbeek, J. S.; Roebroek, A. J. M.; van den Ouweland, A. M. W.;
Bloemers, H. P. J.; Van de Ven, W. J. M.: Human c-fms proto-oncogene:
comparative analysis with an abnormal allele. Molec. Cell. Biol. 5:
422-426, 1985.
27. Verbeek, J. S.; van Heerikhuizen, H.; de Pauw, B. E.; Haanen,
C.; Bloemers, H. P. J.; Van de Ven, W. J. M.: A hereditary abnormal
c-fms proto-oncogene in a patient with acute lymphocytic leukaemia
and congenital hypothyroidism. Brit. J. Haemat. 61: 135-138, 1985.
28. Yarden, Y.; Ullrich, A.: Growth factor receptor tyrosine kinases. Ann.
Rev. Biochem. 57: 443-478, 1988.
*FIELD* CN
Matthew B. Gross - updated: 1/8/2013
Matthew B. Gross - updated: 3/14/2012
Cassandra L. Kniffin - updated: 2/6/2012
Ada Hamosh - updated: 12/28/2010
Cassandra L. Kniffin - updated: 5/27/2010
Marla J. F. O'Neill - updated: 2/17/2005
Ada Hamosh - updated: 9/20/2000
Victor A. McKusick - updated: 3/4/1997
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 01/08/2013
mgross: 1/8/2013
carol: 11/6/2012
mgross: 3/14/2012
carol: 2/7/2012
ckniffin: 2/6/2012
alopez: 1/3/2011
terry: 12/28/2010
wwang: 6/15/2010
ckniffin: 5/27/2010
wwang: 3/7/2005
terry: 2/17/2005
alopez: 9/20/2000
psherman: 9/10/1999
psherman: 11/23/1998
psherman: 11/21/1998
carol: 7/8/1998
dkim: 6/30/1998
jamie: 3/4/1997
jenny: 3/4/1997
terry: 2/24/1997
carol: 9/13/1994
carol: 1/8/1993
carol: 1/6/1993
supermim: 3/16/1992
carol: 2/16/1992
carol: 12/4/1991
MIM
221820
*RECORD*
*FIELD* NO
221820
*FIELD* TI
#221820 LEUKOENCEPHALOPATHY, DIFFUSE HEREDITARY, WITH SPHEROIDS; HDLS
;;LEUKOENCEPHALOPATHY WITH NEUROAXONAL SPHEROIDS, AUTOSOMAL DOMINANT;;
read moreGLIOSIS, FAMILIAL PROGRESSIVE SUBCORTICAL; GPSC;;
DEMENTIA, FAMILIAL, NEUMANN TYPE;;
SUBCORTICAL GLIOSIS OF NEUMANN
*FIELD* TX
A number sign (#) is used with this entry because hereditary diffuse
leukoencephalopathy with spheroids (HDLS) is caused by heterozygous
mutation in the CSF1R gene (164770) on chromosome 5q.
DESCRIPTION
Hereditary diffuse leukoencephalopathy with spheroids is an autosomal
dominant adult-onset rapidly progressive neurodegenerative disorder
characterized by variable behavioral, cognitive, and motor changes.
Patients often die of dementia within 6 years of onset. Brain imaging
shows patchy abnormalities in the cerebral white matter, predominantly
affecting the frontal and parietal lobes (summary by Rademakers et al.,
2012).
CLINICAL FEATURES
Lanska et al. (1994) presented clinical and pathologic information on 2
large multigenerational families with a form of autosomal dominant
adult-onset dementia termed progressive subcortical gliosis. Affected
individuals presented in the fifth or sixth decade of life with
personality change and degeneration of social ability which later
developed into a profound dementia with mutism, dysphagia, and
extrapyramidal signs. The presentation was similar to that of Pick
disease. Autopsies were done on 7 affected individuals. These showed
moderately severe atrophy with preferential involvement of the frontal
and temporal lobes but without the knife edge pattern characteristic of
Pick disease. The most striking microscopic finding was a marked
fibrillary astrocytosis, particularly in the area of the short cortical
association tracts (U fibers) at the junction of cortical lamina VI and
the subcortical white matter, and in the subpial cerebral cortex (lamina
I). There was also laminar spongiosis, particularly in laminae II and
III similar to that observed in Pick disease and Alzheimer disease, but
different from the pancortical spongiform change in Creutzfeldt-Jakob
disease which is usually most prominent in deeper layers. Neuronal
inclusions and amyloid deposits, which are pathologic hallmarks of
Alzheimer disease and Pick disease, were uniformly absent. One of the
families reported by Lanska et al. (1994) was found by Goedert et al.
(1999) to have a mutation in the MAPT gene (157140.0006), thus
confirming a diagnosis of MAPT-related frontotemporal dementia (FTD;
600274).
Van der Knaap et al. (2000) reported a father and daughter with
adult-onset deterioration of frontal lobe function, spasticity, ataxia,
and mild extrapyramidal signs. MRI showed cerebral atrophy and patchy
white matter changes. Postmortem examination showed leukoencephalopathy
with numerous neuroaxonal spheroids. The frontal and frontoparietal
lobes were most affected.
Baba et al. (2006) reported a kindred in which 6 individuals had
dementia, depression, and frontal lobe signs variably associated with
parkinsonism, apraxia, and seizures. The mean age at onset was 54 years.
Postmortem examination of the brains showed loss of myelinated fibers,
bizarre astrocytosis, white matter gliosis, and axonal spheroids.
Inheritance was autosomal dominant. Molecular analysis excluded
mutations in the MAPT gene and in several genes involved in
leukoencephalopathy with white matter disease (603896).
Swerdlow et al. (2009) reported a multigenerational family with
frontotemporal dementia associated with subcortical gliosis inherited in
an autosomal dominant pattern. Age at onset ranged from the forties to
sixties in affected individuals. The phenotype was characterized mainly
by progressive behavioral changes, disorientation, frontal release
signs, and memory loss. Later symptoms and signs included dementia,
mutism, and incontinence. Some individuals developed parkinsonism.
Neuropathologic studies showed frontotemporal cortical atrophy,
ventriculomegaly, neuronal loss, hypertrophic astrogliosis in the
superficial and deep white matter, loss of axons, dystrophic axons, and
axonal spheroids containing neurofilaments. Immunohistochemical studies
did not identify tau, ubiquitin, or prion (PRNP; 176640) inclusions.
Swerdlow et al. (2009) noted that the disorder shared some
characteristics with leukoencephalopathy with neuroaxonal spheroids, as
described by van der Knaap et al. (2000) and Baba et al. (2006).
Rademakers et al. (2012) reported 14 families with HDLS, including those
reported previously by Swerdlow et al. (2009) and Baba et al. (2006).
Clinical features of 24 affected individuals showed that the mean age at
onset was 47.2 years (range, 18-78 years), with a mean age of death at
57.2 years (range, 40-84 years). One patient was described in detail. He
developed mild depression and forgetfulness at age 50 years. Two years
later, he had a flat affect, inappropriate behavior, poor concentration,
executive dysfunction, restless legs syndrome, and insomnia. There was
psychomotor slowing, and ideomotor and constructional apraxia. He had a
slow, shuffling gait, postural instability, rigidity, and bradykinesia.
Brain imaging showed hyperintense foci in both the frontal and parietal
lobes, involving the periventricular, deep and subcortical white matter,
but sparing the subcortical U fibers. At the end of his illness, he was
mute and in a vegetative state; death occurred at age 55 years.
Neuropathologic examination showed myelin loss, axonal spheroids
containing neurofilaments, astrocytes, gliosis, and ballooned neurons.
There was inter- and intrafamilial variability, with different ages at
onset and death, as well as variable clinical features. Antemortem
clinical diagnoses in mutation carriers included frontotemporal dementia
(FTD; 600275), corticobasal syndrome, Alzheimer disease (AD; 104300),
multiple sclerosis (MS; 126200), atypical cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL;
125310), and Parkinson disease (PD; 168600).
- Neuroradiologic Findings
Sundal et al. (2012) reviewed 20 brain MRI scans of 15 patients from 9
HDLS families, all of Caucasian descent with genetically confirmed
disease, and assigned a severity score based on the lesion load. The
mean age at onset was 44.3 years and the mean age at death was 53.2
years. All patients had a progressive clinical course, except 1, who had
mild disease burden on initial MRI. At onset, 14 of 15 patients had
localized white matter lesions (WML) with deep, subcortical, and
periventricular involvement, whereas 1 more severely affected patient
had generalized WML. All lesions were bilateral, but asymmetric, and
predominantly in the frontal/parietal regions. There was cortical
atrophy and involvement of the corpus callosum, but gray matter
pathology and brainstem atrophy were absent; corticospinal tracts were
involved late in the disease course. There was no enhancement, and there
was minimal cerebellar pathology. Indicators of rapid disease
progression included onset before age 45 years, female sex, WML
extending beyond the frontal regions, an MRI severity score greater than
15 points, and deletion mutations. Sundal et al. (2012) concluded that
recognition of the typical MRI patterns of HDLS and the use of an MRI
severity score might help during the diagnostic evaluation to
characterize the natural history and to monitor potential future
treatments.
INHERITANCE
The transmission pattern in the families with HDLS reported by
Rademakers et al. (2012) was consistent with autosomal dominant
inheritance.
MOLECULAR GENETICS
By linkage analysis followed by whole-exome sequencing of the family
with HDLS reported by Swerdlow et al. (2009), Rademakers et al. (2012)
identified a heterozygous mutation in the CSF1R gene (164770.0001).
Sequencing of this gene in 13 additional probands with HDLS identified a
different heterozygous mutation in each (see, e.g.,
164770.0002-164770.0005). The mutations cosegregated with the disorder
in all families for which DNA from multiple affected individuals was
available, including the family reported by Baba et al. (2006). In vitro
functional expression studies of some of the missense mutations
indicated that the mutant proteins did not show autophosphorylation,
suggesting a defect in kinase activity that likely also affects
downstream targets. The mutant proteins probably also act in a
dominant-negative manner, since CSF1R assembles into homodimers.
Overall, the findings indicated that a defect in microglial signaling
and function resulting from CSF1R mutations can cause central nervous
system degeneration.
HISTORY
Khoubesserian et al. (1985) reported a 70-year-old man with dementia who
had 2 brothers who died at age 59 with dementia. Pick disease (172700)
and Alzheimer disease (AD; 104300) were ruled out by cerebral biopsy and
normal levels of neurotransmitters in the biopsy tissue and CSF. These
and histologic changes suggested that this may be the disorder reported
by Neumann (1949) and designated 'subcortical gliosis' (Neumann and
Cohn, 1967). This was the first familial observation.
*FIELD* RF
1. Baba, Y.; Ghetti, B.; Baker, M. C.; Uitti, R. J.; Hutton, M. L.;
Yamaguchi, K.; Bird, T.; Lin, W.; DeLucia, M. W.; Dickson, D. W.;
Wszolek, Z. K.: Hereditary diffuse leukoencephalopathy with spheroids:
clinical, pathologic and genetic studies of a new kindred. Acta Neuropath. 111:
300-311, 2006.
2. Goedert, M.; Spillantini, M. G.; Crowther, R. A.; Chen, S. G.;
Parchi, P.; Tabaton, M.; Lanska, D. J.; Markesbery, W. R.; Wilhelmsen,
K. C.; Dickson, D. W.; Petersen, R. B.; Gambetti, P.: Tau gene mutation
in familial progressive subcortical gliosis. Nature Med. 5: 454-457,
1999.
3. Khoubesserian, P.; Davous, P.; Bianco, C.; Puymirat, J.; Fontaine,
C.; de Recondo, J.; Rondot, P.: Demence familiale de type Neumann
(gliose sous corticale). Rev. Neurol. 141: 706-712, 1985.
4. Lanska, D. J.; Currier, R. D.; Cohen, M.; Gambetti, P.; Smith,
E. E.; Bebin, J.; Jackson, J. F.; Whitehouse, P. J.; Markesbery, W.
R.: Familial progressive subcortical gliosis. Neurology 44: 1633-1643,
1994.
5. Neumann, M. A.: Pick's disease. J. Neuropath. Exp. Neurol. 8:
255-282, 1949.
6. Neumann, M. A.; Cohn, R.: Progressive subcortical gliosis: a rare
form of presenile dementia. Brain 90: 405-418, 1967.
7. Rademakers, R.; Baker, M.; Nicholson, A. M.; Rutherford, N. J.;
Finch, N.; Soto-Ortolaza, A.; Lash, J.; Wider, C.; Wojtas, A.; DeJesus-Hernandez,
M.; Adamson, J.; Kouri, N.; and 26 others: Mutations in the colony
stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse
leukoencephalopathy with spheroids. Nature Genet. 44: 200-205, 2012.
8. Sundal, C.; Van Gerpen, J. A.; Nicholson, A. M.; Wider, C.; Shuster,
E. A.; Aasly, J.; Spina, S.; Ghetti, B.; Roeber, S.; Garbern, J.;
Borjesson-Hanson, A.; Tselis, A.; and 12 others: MRI characteristics
and scoring in HDLS due to CSF1R gene mutations. Neurology 79: 566-574,
2012.
9. Swerdlow, R. H.; Miller, B. B.; Lopes, M. B. S.; Mandell, J. W.;
Wooten, G. F.; Damgaard, P.; Manning, C.; Fowler, M.; Brashear, H.
R.: Autosomal dominant subcortical gliosis presenting as frontotemporal
dementia. Neurology 72: 260-267, 2009.
10. van der Knaap, M. S.; Naidu, S.; Kleinschmidt-DeMasters, B. K.;
Kamphorst, W.; Weinstein, H. C.: Autosomal dominant diffuse leukoencephalopathy
with neuroaxonal spheroids. Neurology 54: 463-468, 2000.
*FIELD* CS
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Cognitive decline;
Memory loss;
Dementia;
Frontal lobe dementia;
Apraxia;
Rigidity;
Bradykinesia;
Postural instability;
Shuffling gait;
Mutism;
Spasticity;
Hyperreflexia;
Brain imaging shows deep white matter lesions, particularly affecting
the frontal and parietal lobes;
Brain tissue shows myelin loss;
Neuronal loss;
Axonal spheroids;
Spheroids contain neurofilaments;
Astrocytes;
Gliosis;
Ballooned neurons;
[Behavioral/psychiatric manifestations];
Depression;
Flat affect;
Executive dysfunction;
Behavioral changes
MISCELLANEOUS:
Adult onset;
Variable presentation and evolution of symptoms;
Rapidly progressive;
Death within 6 years after onset
MOLECULAR BASIS:
Caused by mutation in the colony-stimulating factor 1 receptor gene
(CSF1R, 164770.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 2/8/2012
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 03/12/2012
ckniffin: 2/8/2012
*FIELD* CN
Cassandra L. Kniffin - updated: 10/31/2012
Cassandra L. Kniffin - updated: 2/6/2012
Cassandra L. Kniffin - updated: 3/16/2009
Victor A. McKusick - updated: 12/10/1997
Victor A. McKusick - updated: 11/26/1997
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 11/06/2012
carol: 11/6/2012
ckniffin: 10/31/2012
carol: 2/7/2012
ckniffin: 2/6/2012
terry: 9/9/2010
wwang: 3/27/2009
ckniffin: 3/16/2009
alopez: 1/8/2001
dholmes: 12/31/1997
mark: 12/17/1997
terry: 12/12/1997
terry: 12/10/1997
terry: 12/3/1997
terry: 11/26/1997
mark: 9/22/1995
carol: 12/14/1994
mimadm: 4/14/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
*RECORD*
*FIELD* NO
221820
*FIELD* TI
#221820 LEUKOENCEPHALOPATHY, DIFFUSE HEREDITARY, WITH SPHEROIDS; HDLS
;;LEUKOENCEPHALOPATHY WITH NEUROAXONAL SPHEROIDS, AUTOSOMAL DOMINANT;;
read moreGLIOSIS, FAMILIAL PROGRESSIVE SUBCORTICAL; GPSC;;
DEMENTIA, FAMILIAL, NEUMANN TYPE;;
SUBCORTICAL GLIOSIS OF NEUMANN
*FIELD* TX
A number sign (#) is used with this entry because hereditary diffuse
leukoencephalopathy with spheroids (HDLS) is caused by heterozygous
mutation in the CSF1R gene (164770) on chromosome 5q.
DESCRIPTION
Hereditary diffuse leukoencephalopathy with spheroids is an autosomal
dominant adult-onset rapidly progressive neurodegenerative disorder
characterized by variable behavioral, cognitive, and motor changes.
Patients often die of dementia within 6 years of onset. Brain imaging
shows patchy abnormalities in the cerebral white matter, predominantly
affecting the frontal and parietal lobes (summary by Rademakers et al.,
2012).
CLINICAL FEATURES
Lanska et al. (1994) presented clinical and pathologic information on 2
large multigenerational families with a form of autosomal dominant
adult-onset dementia termed progressive subcortical gliosis. Affected
individuals presented in the fifth or sixth decade of life with
personality change and degeneration of social ability which later
developed into a profound dementia with mutism, dysphagia, and
extrapyramidal signs. The presentation was similar to that of Pick
disease. Autopsies were done on 7 affected individuals. These showed
moderately severe atrophy with preferential involvement of the frontal
and temporal lobes but without the knife edge pattern characteristic of
Pick disease. The most striking microscopic finding was a marked
fibrillary astrocytosis, particularly in the area of the short cortical
association tracts (U fibers) at the junction of cortical lamina VI and
the subcortical white matter, and in the subpial cerebral cortex (lamina
I). There was also laminar spongiosis, particularly in laminae II and
III similar to that observed in Pick disease and Alzheimer disease, but
different from the pancortical spongiform change in Creutzfeldt-Jakob
disease which is usually most prominent in deeper layers. Neuronal
inclusions and amyloid deposits, which are pathologic hallmarks of
Alzheimer disease and Pick disease, were uniformly absent. One of the
families reported by Lanska et al. (1994) was found by Goedert et al.
(1999) to have a mutation in the MAPT gene (157140.0006), thus
confirming a diagnosis of MAPT-related frontotemporal dementia (FTD;
600274).
Van der Knaap et al. (2000) reported a father and daughter with
adult-onset deterioration of frontal lobe function, spasticity, ataxia,
and mild extrapyramidal signs. MRI showed cerebral atrophy and patchy
white matter changes. Postmortem examination showed leukoencephalopathy
with numerous neuroaxonal spheroids. The frontal and frontoparietal
lobes were most affected.
Baba et al. (2006) reported a kindred in which 6 individuals had
dementia, depression, and frontal lobe signs variably associated with
parkinsonism, apraxia, and seizures. The mean age at onset was 54 years.
Postmortem examination of the brains showed loss of myelinated fibers,
bizarre astrocytosis, white matter gliosis, and axonal spheroids.
Inheritance was autosomal dominant. Molecular analysis excluded
mutations in the MAPT gene and in several genes involved in
leukoencephalopathy with white matter disease (603896).
Swerdlow et al. (2009) reported a multigenerational family with
frontotemporal dementia associated with subcortical gliosis inherited in
an autosomal dominant pattern. Age at onset ranged from the forties to
sixties in affected individuals. The phenotype was characterized mainly
by progressive behavioral changes, disorientation, frontal release
signs, and memory loss. Later symptoms and signs included dementia,
mutism, and incontinence. Some individuals developed parkinsonism.
Neuropathologic studies showed frontotemporal cortical atrophy,
ventriculomegaly, neuronal loss, hypertrophic astrogliosis in the
superficial and deep white matter, loss of axons, dystrophic axons, and
axonal spheroids containing neurofilaments. Immunohistochemical studies
did not identify tau, ubiquitin, or prion (PRNP; 176640) inclusions.
Swerdlow et al. (2009) noted that the disorder shared some
characteristics with leukoencephalopathy with neuroaxonal spheroids, as
described by van der Knaap et al. (2000) and Baba et al. (2006).
Rademakers et al. (2012) reported 14 families with HDLS, including those
reported previously by Swerdlow et al. (2009) and Baba et al. (2006).
Clinical features of 24 affected individuals showed that the mean age at
onset was 47.2 years (range, 18-78 years), with a mean age of death at
57.2 years (range, 40-84 years). One patient was described in detail. He
developed mild depression and forgetfulness at age 50 years. Two years
later, he had a flat affect, inappropriate behavior, poor concentration,
executive dysfunction, restless legs syndrome, and insomnia. There was
psychomotor slowing, and ideomotor and constructional apraxia. He had a
slow, shuffling gait, postural instability, rigidity, and bradykinesia.
Brain imaging showed hyperintense foci in both the frontal and parietal
lobes, involving the periventricular, deep and subcortical white matter,
but sparing the subcortical U fibers. At the end of his illness, he was
mute and in a vegetative state; death occurred at age 55 years.
Neuropathologic examination showed myelin loss, axonal spheroids
containing neurofilaments, astrocytes, gliosis, and ballooned neurons.
There was inter- and intrafamilial variability, with different ages at
onset and death, as well as variable clinical features. Antemortem
clinical diagnoses in mutation carriers included frontotemporal dementia
(FTD; 600275), corticobasal syndrome, Alzheimer disease (AD; 104300),
multiple sclerosis (MS; 126200), atypical cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL;
125310), and Parkinson disease (PD; 168600).
- Neuroradiologic Findings
Sundal et al. (2012) reviewed 20 brain MRI scans of 15 patients from 9
HDLS families, all of Caucasian descent with genetically confirmed
disease, and assigned a severity score based on the lesion load. The
mean age at onset was 44.3 years and the mean age at death was 53.2
years. All patients had a progressive clinical course, except 1, who had
mild disease burden on initial MRI. At onset, 14 of 15 patients had
localized white matter lesions (WML) with deep, subcortical, and
periventricular involvement, whereas 1 more severely affected patient
had generalized WML. All lesions were bilateral, but asymmetric, and
predominantly in the frontal/parietal regions. There was cortical
atrophy and involvement of the corpus callosum, but gray matter
pathology and brainstem atrophy were absent; corticospinal tracts were
involved late in the disease course. There was no enhancement, and there
was minimal cerebellar pathology. Indicators of rapid disease
progression included onset before age 45 years, female sex, WML
extending beyond the frontal regions, an MRI severity score greater than
15 points, and deletion mutations. Sundal et al. (2012) concluded that
recognition of the typical MRI patterns of HDLS and the use of an MRI
severity score might help during the diagnostic evaluation to
characterize the natural history and to monitor potential future
treatments.
INHERITANCE
The transmission pattern in the families with HDLS reported by
Rademakers et al. (2012) was consistent with autosomal dominant
inheritance.
MOLECULAR GENETICS
By linkage analysis followed by whole-exome sequencing of the family
with HDLS reported by Swerdlow et al. (2009), Rademakers et al. (2012)
identified a heterozygous mutation in the CSF1R gene (164770.0001).
Sequencing of this gene in 13 additional probands with HDLS identified a
different heterozygous mutation in each (see, e.g.,
164770.0002-164770.0005). The mutations cosegregated with the disorder
in all families for which DNA from multiple affected individuals was
available, including the family reported by Baba et al. (2006). In vitro
functional expression studies of some of the missense mutations
indicated that the mutant proteins did not show autophosphorylation,
suggesting a defect in kinase activity that likely also affects
downstream targets. The mutant proteins probably also act in a
dominant-negative manner, since CSF1R assembles into homodimers.
Overall, the findings indicated that a defect in microglial signaling
and function resulting from CSF1R mutations can cause central nervous
system degeneration.
HISTORY
Khoubesserian et al. (1985) reported a 70-year-old man with dementia who
had 2 brothers who died at age 59 with dementia. Pick disease (172700)
and Alzheimer disease (AD; 104300) were ruled out by cerebral biopsy and
normal levels of neurotransmitters in the biopsy tissue and CSF. These
and histologic changes suggested that this may be the disorder reported
by Neumann (1949) and designated 'subcortical gliosis' (Neumann and
Cohn, 1967). This was the first familial observation.
*FIELD* RF
1. Baba, Y.; Ghetti, B.; Baker, M. C.; Uitti, R. J.; Hutton, M. L.;
Yamaguchi, K.; Bird, T.; Lin, W.; DeLucia, M. W.; Dickson, D. W.;
Wszolek, Z. K.: Hereditary diffuse leukoencephalopathy with spheroids:
clinical, pathologic and genetic studies of a new kindred. Acta Neuropath. 111:
300-311, 2006.
2. Goedert, M.; Spillantini, M. G.; Crowther, R. A.; Chen, S. G.;
Parchi, P.; Tabaton, M.; Lanska, D. J.; Markesbery, W. R.; Wilhelmsen,
K. C.; Dickson, D. W.; Petersen, R. B.; Gambetti, P.: Tau gene mutation
in familial progressive subcortical gliosis. Nature Med. 5: 454-457,
1999.
3. Khoubesserian, P.; Davous, P.; Bianco, C.; Puymirat, J.; Fontaine,
C.; de Recondo, J.; Rondot, P.: Demence familiale de type Neumann
(gliose sous corticale). Rev. Neurol. 141: 706-712, 1985.
4. Lanska, D. J.; Currier, R. D.; Cohen, M.; Gambetti, P.; Smith,
E. E.; Bebin, J.; Jackson, J. F.; Whitehouse, P. J.; Markesbery, W.
R.: Familial progressive subcortical gliosis. Neurology 44: 1633-1643,
1994.
5. Neumann, M. A.: Pick's disease. J. Neuropath. Exp. Neurol. 8:
255-282, 1949.
6. Neumann, M. A.; Cohn, R.: Progressive subcortical gliosis: a rare
form of presenile dementia. Brain 90: 405-418, 1967.
7. Rademakers, R.; Baker, M.; Nicholson, A. M.; Rutherford, N. J.;
Finch, N.; Soto-Ortolaza, A.; Lash, J.; Wider, C.; Wojtas, A.; DeJesus-Hernandez,
M.; Adamson, J.; Kouri, N.; and 26 others: Mutations in the colony
stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse
leukoencephalopathy with spheroids. Nature Genet. 44: 200-205, 2012.
8. Sundal, C.; Van Gerpen, J. A.; Nicholson, A. M.; Wider, C.; Shuster,
E. A.; Aasly, J.; Spina, S.; Ghetti, B.; Roeber, S.; Garbern, J.;
Borjesson-Hanson, A.; Tselis, A.; and 12 others: MRI characteristics
and scoring in HDLS due to CSF1R gene mutations. Neurology 79: 566-574,
2012.
9. Swerdlow, R. H.; Miller, B. B.; Lopes, M. B. S.; Mandell, J. W.;
Wooten, G. F.; Damgaard, P.; Manning, C.; Fowler, M.; Brashear, H.
R.: Autosomal dominant subcortical gliosis presenting as frontotemporal
dementia. Neurology 72: 260-267, 2009.
10. van der Knaap, M. S.; Naidu, S.; Kleinschmidt-DeMasters, B. K.;
Kamphorst, W.; Weinstein, H. C.: Autosomal dominant diffuse leukoencephalopathy
with neuroaxonal spheroids. Neurology 54: 463-468, 2000.
*FIELD* CS
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Cognitive decline;
Memory loss;
Dementia;
Frontal lobe dementia;
Apraxia;
Rigidity;
Bradykinesia;
Postural instability;
Shuffling gait;
Mutism;
Spasticity;
Hyperreflexia;
Brain imaging shows deep white matter lesions, particularly affecting
the frontal and parietal lobes;
Brain tissue shows myelin loss;
Neuronal loss;
Axonal spheroids;
Spheroids contain neurofilaments;
Astrocytes;
Gliosis;
Ballooned neurons;
[Behavioral/psychiatric manifestations];
Depression;
Flat affect;
Executive dysfunction;
Behavioral changes
MISCELLANEOUS:
Adult onset;
Variable presentation and evolution of symptoms;
Rapidly progressive;
Death within 6 years after onset
MOLECULAR BASIS:
Caused by mutation in the colony-stimulating factor 1 receptor gene
(CSF1R, 164770.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 2/8/2012
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 03/12/2012
ckniffin: 2/8/2012
*FIELD* CN
Cassandra L. Kniffin - updated: 10/31/2012
Cassandra L. Kniffin - updated: 2/6/2012
Cassandra L. Kniffin - updated: 3/16/2009
Victor A. McKusick - updated: 12/10/1997
Victor A. McKusick - updated: 11/26/1997
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 11/06/2012
carol: 11/6/2012
ckniffin: 10/31/2012
carol: 2/7/2012
ckniffin: 2/6/2012
terry: 9/9/2010
wwang: 3/27/2009
ckniffin: 3/16/2009
alopez: 1/8/2001
dholmes: 12/31/1997
mark: 12/17/1997
terry: 12/12/1997
terry: 12/10/1997
terry: 12/3/1997
terry: 11/26/1997
mark: 9/22/1995
carol: 12/14/1994
mimadm: 4/14/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989