RBCC Red Blood Cell Collection

IL4R (IL4RA) [Confidence: high (a blood group or CD marker)]
Interleukin-4 receptor subunit alpha; IL-4 receptor subunit alpha; IL-4R subunit alpha; IL-4R-alpha; IL-4RA (CD124; Soluble interleukin-4 receptor subunit alpha; Soluble IL-4 receptor subunit alpha; Soluble IL-4R-alpha; sIL4Ralpha/prot; IL-4-binding protein; IL4-BP; Flags: Precursor)

UniProt P24394
ID IL4RA_HUMAN Reviewed; 825 AA.
AC P24394; B9EKU8; H3BSY5; Q96P01; Q9H181; Q9H182; Q9H183; Q9H184;
read moreAC Q9H185; Q9H186; Q9H187; Q9H188;
DT 01-MAR-1992, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-1992, sequence version 1.
DT 22-JAN-2014, entry version 166.
DE RecName: Full=Interleukin-4 receptor subunit alpha;
DE Short=IL-4 receptor subunit alpha;
DE Short=IL-4R subunit alpha;
DE Short=IL-4R-alpha;
DE Short=IL-4RA;
DE AltName: CD_antigen=CD124;
DE Contains:
DE RecName: Full=Soluble interleukin-4 receptor subunit alpha;
DE Short=Soluble IL-4 receptor subunit alpha;
DE Short=Soluble IL-4R-alpha;
DE Short=sIL4Ralpha/prot;
DE AltName: Full=IL-4-binding protein;
DE Short=IL4-BP;
DE Flags: Precursor;
GN Name=IL4R; Synonyms=IL4RA; ORFNames=582J2.1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Peripheral blood;
RX PubMed=2307934; DOI=10.1084/jem.171.3.861;
RA Idzerda R.L., March C.J., Mosley B., Lyman S.D., Bos T.V.,
RA Gimpel S.D., Din W.S., Grabstein K.H., Widmer M.B., Park L.S.,
RA Cosman D., Beckmann M.P.;
RT "Human interleukin 4 receptor confers biological responsiveness and
RT defines a novel receptor superfamily.";
RL J. Exp. Med. 171:861-873(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Myeloid leukemia cell;
RX PubMed=2278997; DOI=10.1093/intimm/2.7.669;
RA Galizzi J.-P., Zuber C.E., Harada N., Gorman D.M., Djossou O.,
RA Kastelein R., Banchereau J., Howard M., Miyajima A.;
RT "Molecular cloning of a cDNA encoding the human interleukin 4
RT receptor.";
RL Int. Immunol. 2:669-675(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING.
RC TISSUE=Blood;
RX PubMed=10590262; DOI=10.1093/intimm/11.12.1965;
RA Kruse S., Forster J., Kuehr J., Deichmann K.A.;
RT "Characterization of the membrane-bound and a soluble form of human
RT IL-4 receptor alpha produced by alternative splicing.";
RL Int. Immunol. 11:1965-1970(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] (ISOFORM 1).
RX PubMed=10493829; DOI=10.1006/geno.1999.5927;
RA Loftus B.J., Kim U.-J., Sneddon V.P., Kalush F., Brandon R.,
RA Fuhrmann J., Mason T., Crosby M.L., Barnstead M., Cronin L.,
RA Mays A.D., Cao Y., Xu R.X., Kang H.-L., Mitchell S., Eichler E.E.,
RA Harris P.C., Venter J.C., Adams M.D.;
RT "Genome duplications and other features in 12 Mb of DNA sequence from
RT human chromosome 16p and 16q.";
RL Genomics 60:295-308(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS VAL-75; ALA-400;
RP ARG-431; LEU-436; PRO-503; ARG-576; ILE-579; SER-675 AND ALA-752.
RG SeattleSNPs variation discovery resource;
RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Testis;
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 301-825 (ISOFORM 1), AND VARIANTS
RP ALA-400; ARG-431; LEU-436; PRO-503; ARG-576 AND ILE-579.
RX PubMed=11285129; DOI=10.1034/j.1399-0039.2001.057003216.x;
RA Lozano F., Places L., Vila J.-M., Padilla O., Arman M., Gimferrer I.,
RA Suarez B., Lopez de la Iglesia A., Miserachs N., Vives J.;
RT "Identification of a novel single-nucleotide polymorphism (Val554Ile)
RT and definition of eight common alleles for human IL4RA exon 11.";
RL Tissue Antigens 57:216-220(2001).
RN [9]
RP FUNCTION IN IRS1 ACTIVATION, AND MUTAGENESIS OF TYR-497.
RX PubMed=8124718; DOI=10.1016/0092-8674(94)90356-5;
RA Keegan A.D., Nelms K., White M., Wang L.-M., Pierce J.H., Paul W.E.;
RT "An IL-4 receptor region containing an insulin receptor motif is
RT important for IL-4-mediated IRS-1 phosphorylation and cell growth.";
RL Cell 76:811-820(1994).
RN [10]
RP DOMAIN JAK3 ACTIVATION.
RX PubMed=7721895; DOI=10.1074/jbc.270.16.9630;
RA Malabarba M.G., Kirken R.A., Rui H., Koettnitz K., Kawamura M.,
RA O'Shea J.J., Kalthoff F.S., Farrar W.L.;
RT "Activation of JAK3, but not JAK1, is critical to interleukin-4 (IL4)
RT stimulated proliferation and requires a membrane-proximal region of
RT IL4 receptor alpha.";
RL J. Biol. Chem. 270:9630-9637(1995).
RN [11]
RP INTERACTION WITH IL13RA1.
RX PubMed=7775445; DOI=10.1074/jbc.270.23.13869;
RA Zurawski S.M., Chomarat P., Djossou O., Bidaud C., McKenzie A.N.,
RA Miossec P., Banchereau J., Zurawski G.;
RT "The primary binding subunit of the human interleukin-4 receptor is
RT also a component of the interleukin-13 receptor.";
RL J. Biol. Chem. 270:13869-13878(1995).
RN [12]
RP INTERACTION WITH JAK3.
RX PubMed=7538655;
RA Rolling C., Treton D., Beckmann P., Galanaud P., Richard Y.;
RT "JAK3 associates with the human interleukin 4 receptor and is tyrosine
RT phosphorylated following receptor triggering.";
RL Oncogene 10:1757-1761(1995).
RN [13]
RP INTERACTION WITH IL13RA1, AND PHOSPHORYLATION.
RX PubMed=8804422; DOI=10.1016/0014-5793(96)00835-6;
RA Rolling C., Treton D., Pellegrini S., Galanaud P., Richard Y.;
RT "IL4 and IL13 receptors share the gamma c chain and activate STAT6,
RT STAT3 and STAT5 proteins in normal human B cells.";
RL FEBS Lett. 393:53-56(1996).
RN [14]
RP DOMAIN STAT6 ACTIVATION, AND MUTAGENESIS OF TYR-575; TYR-603 AND
RP TYR-631.
RX PubMed=8624803; DOI=10.1016/S1074-7613(00)80677-9;
RA Ryan J.J., McReynolds L.J., Keegan A., Wang L.-H., Garfein E.,
RA Rothman P., Nelms K., Paul W.E.;
RT "Growth and gene expression are predominantly controlled by distinct
RT regions of the human IL-4 receptor.";
RL Immunity 4:123-132(1996).
RN [15]
RP PROTEOLYTIC PROCESSING.
RX PubMed=10341317; DOI=10.1159/000024171;
RA Jung T., Schrader N., Hellwig M., Enssle K.H., Neumann C.;
RT "Soluble human interleukin-4 receptor is produced by activated T cells
RT under the control of metalloproteinases.";
RL Int. Arch. Allergy Immunol. 119:23-30(1999).
RN [16]
RP INTERACTION WITH PTPN6; PTPN11 AND INPP5D, STAT6 ACTIVATION, AND
RP MUTAGENESIS OF TYR-713.
RX PubMed=11714803;
RA Kashiwada M., Giallourakis C.C., Pan P.-Y., Rothman P.B.;
RT "Immunoreceptor tyrosine-based inhibitory motif of the IL-4 receptor
RT associates with SH2-containing phosphatases and regulates IL-4-induced
RT proliferation.";
RL J. Immunol. 167:6382-6387(2001).
RN [17]
RP LIGAND-BINDING SITES, AND MUTAGENESIS OF TYR-38; MET-39; SER-40;
RP LEU-64; PHE-66; LEU-67; LEU-68; ASP-91; ASP-92; VAL-93; VAL-94;
RP SER-95; ASP-97; ASN-98; TYR-99; LYS-116; PRO-117; SER-118; GLU-119;
RP ASP-150; ASN-151; TYR-152; LEU-153; TYR-154 AND TYR-208.
RX PubMed=11786020; DOI=10.1006/jmbi.2001.5243;
RA Zhang J.-L., Simeonowa I., Wang Y., Sebald W.;
RT "The high-affinity interaction of human IL-4 and the receptor alpha
RT chain is constituted by two independent binding clusters.";
RL J. Mol. Biol. 315:399-407(2002).
RN [18]
RP STAT6 ACTIVATION, AND INHIBITION BY TYROSINE PHOSPHATASE SHP1.
RX PubMed=12459556; DOI=10.1074/jbc.M211747200;
RA Hanson E.M., Dickensheets H., Qu C.K., Donnelly R.P., Keegan A.D.;
RT "Regulation of the dephosphorylation of Stat6. Participation of Tyr-
RT 713 in the interleukin-4 receptor alpha, the tyrosine phosphatase SHP-
RT 1, and the proteasome.";
RL J. Biol. Chem. 278:3903-3911(2003).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 26-232 IN COMPLEX WITH IL4.
RX PubMed=10219247; DOI=10.1016/S0092-8674(00)80736-9;
RA Hage T., Sebald W., Reinemer P.;
RT "Crystal structure of the interleukin-4/receptor alpha chain complex
RT reveals a mosaic binding interface.";
RL Cell 97:271-281(1999).
RN [20]
RP VARIANTS VAL-75; ALA-400; ARG-431; LEU-436 AND PRO-786.
RX PubMed=9070874; DOI=10.1006/bbrc.1997.6115;
RA Deichmann K., Bardutzky J., Forster J., Heinzmann A., Kuehr J.;
RT "Common polymorphisms in the coding part of the IL4-receptor gene.";
RL Biochem. Biophys. Res. Commun. 231:696-697(1997).
RN [21]
RP VARIANT ARG-576.
RX PubMed=9392697; DOI=10.1056/NEJM199712113372403;
RA Hershey G.K.K., Friedrich M.F., Esswein L.A., Thomas M.L.,
RA Chatila T.A.;
RT "The association of atopy with a gain-of-function mutation in the
RT alpha subunit of the interleukin-4 receptor.";
RL N. Engl. J. Med. 337:1720-1725(1997).
RN [22]
RP VARIANT VAL-75.
RX PubMed=9620765; DOI=10.1038/472;
RA Mitsuyasu H., Izuhara K., Mao X.-Q., Gao P.S., Arinobu Y., Enomoto T.,
RA Kawai M., Sasaki S., Dake Y., Hamasaki N., Shirakawa T., Hopkin J.M.;
RT "Ile50Val variant of IL4R alpha upregulates IgE synthesis and
RT associates with atopic asthma.";
RL Nat. Genet. 19:119-120(1998).
RN [23]
RP VARIANT VAL-75.
RX PubMed=10390422; DOI=10.1164/ajrccm.160.1.9807130;
RA Noguchi E., Shibasaki M., Arinami T., Takeda K., Yokouchi Y.,
RA Kobayashi K., Imoto N., Nakahara S., Matsui A., Hamaguchi H.;
RT "No association between atopy/asthma and the Ile50Val polymorphism of
RT IL-4 receptor.";
RL Am. J. Respir. Crit. Care Med. 160:342-345(1999).
RN [24]
RP VARIANTS PRO-503 AND ARG-576.
RX PubMed=10233717; DOI=10.1046/j.1365-2567.1999.00705.x;
RA Kruse S., Japha T., Tedner M., Sparholt S.H., Forster J., Kuehr J.,
RA Deichmann K.A.;
RT "The polymorphisms S503P and Q576R in the interleukin-4 receptor alpha
RT gene are associated with atopy and influence the signal
RT transduction.";
RL Immunology 96:365-371(1999).
RN [25]
RP CHARACTERIZATION OF VARIANT ARG-576, AND MUTAGENESIS OF TYR-575.
RX PubMed=10201973;
RA Wang H.Y., Shelburne C.P., Zamorano J., Kelly A.E., Ryan J.J.,
RA Keegan A.D.;
RT "Effects of an allergy-associated mutation in the human IL-4R alpha
RT (Q576R) on human IL-4-induced signal transduction.";
RL J. Immunol. 162:4385-4389(1999).
RN [26]
RP VARIANT ALA-752.
RX PubMed=10677312; DOI=10.1086/302781;
RA Ober C., Leavitt S.A., Tsalenko A., Howard T.D., Hoki D.M., Daniel R.,
RA Newman D.L., Wu X., Parry R., Lester L.A., Solway J., Blumenthal M.,
RA King R.A., Xu J., Meyers D.A., Bleecker E.R., Cox N.J.;
RT "Variation in the interleukin 4-receptor alpha gene confers
RT susceptibility to asthma and atopy in ethnically diverse
RT populations.";
RL Am. J. Hum. Genet. 66:517-526(2000).
RN [27]
RP VARIANT ARG-576.
RX PubMed=10809862; DOI=10.1046/j.1365-2133.2000.03485.x;
RA Oiso N., Fukai K., Ishii M.;
RT "Interleukin 4 receptor alpha chain polymorphism Gln551Arg is
RT associated with adult atopic dermatitis in Japan.";
RL Br. J. Dermatol. 142:1003-1006(2000).
RN [28]
RP VARIANT PRO-786.
RX PubMed=11513543; DOI=10.1006/clim.2001.5082;
RA Andrews R.P., Burrell L., Rosa-Rosa L., Cunningham C.M.,
RA Brzezinski J.L., Bernstein J.A., Khurana Hershey G.K.;
RT "Analysis of the Ser786Pro interleukin-4 receptor alpha allelic
RT variant in allergic and nonallergic asthma and its functional
RT consequences.";
RL Clin. Immunol. 100:298-304(2001).
RN [29]
RP VARIANTS VAL-75 AND ALA-400, AND POLYMORPHISM.
RX PubMed=14657871; DOI=10.1016/j.jaci.2003.08.051;
RA Nakamura H., Miyagawa K., Ogino K., Endo T., Imai T., Ozasa K.,
RA Motohashi Y., Matsuzaki I., Sasahara S., Hatta K., Eboshida A.;
RT "High contribution contrast between the genes of eosinophil peroxidase
RT and IL-4 receptor alpha-chain in Japanese cedar pollinosis.";
RL J. Allergy Clin. Immunol. 112:1127-1131(2003).
CC -!- FUNCTION: Receptor for both interleukin 4 and interleukin 13.
CC Couples to the JAK1/2/3-STAT6 pathway. The IL4 response is
CC involved in promoting Th2 differentiation. The IL4/IL13 responses
CC are involved in regulating IgE production and, chemokine and mucus
CC production at sites of allergic inflammation. In certain cell
CC types, can signal through activation of insulin receptor
CC substrates, IRS1/IRS2.
CC -!- FUNCTION: Soluble IL4R (sIL4R) inhibits IL4-mediated cell
CC proliferation and IL5 up-regulation by T-cells.
CC -!- SUBUNIT: The functional IL4 receptor is formed by initial binding
CC of IL4 to IL4R. Subsequent recruitment to the complex of the
CC common gamma chain, in immune cells, creates a type I receptor
CC and, in non-immune cells, of IL13RA1 forms a type II receptor.
CC IL4R can also interact with the IL13/IL13RA1 complex to form a
CC similar type II receptor. Interacts with PIK3C3 (By similarity).
CC Interacts with the SH2-containing phosphatases, PTPN6/SHIP1,
CC PTPN11/SHIP2 and INPP5D/SHIP (By similarity). Interacts with JAK1
CC through a Box 1-containing region; inhibited by SOCS5. Interacts
CC with SOCS5; inhibits IL4 signaling (By similarity).
CC -!- INTERACTION:
CC P05112:IL4; NbExp=7; IntAct=EBI-367009, EBI-367025;
CC P42226:STAT6; NbExp=4; IntAct=EBI-367009, EBI-1186478;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=Membrane-bound form;
CC IsoId=P24394-1; Sequence=Displayed;
CC Name=2; Synonyms=Soluble form, sIL4Ralpha/splice;
CC IsoId=P24394-2; Sequence=VSP_011116, VSP_011117;
CC -!- TISSUE SPECIFICITY: Isoform 1 and isoform 2 are highly expressed
CC in activated T-cells.
CC -!- DOMAIN: The extracellular domain represents the IL4 binding
CC protein (IL4BP).
CC -!- DOMAIN: The WSXWS motif appears to be necessary for proper protein
CC folding and thereby efficient intracellular transport and cell-
CC surface receptor binding.
CC -!- DOMAIN: The box 1 motif is required for JAK interaction and/or
CC activation.
CC -!- DOMAIN: Contains 1 copy of a cytoplasmic motif that is referred to
CC as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This
CC motif is involved in modulation of cellular responses. The
CC phosphorylated ITIM motif can bind the SH2 domain of several SH2-
CC containing phosphatases.
CC -!- PTM: On IL4 binding, phosphorylated on C-terminal tyrosine
CC residues. Phosphorylation on any one of tyrosine residues, Tyr-
CC 575, Tyr-603 or Tyr-631, is required for STAT6-induced gene
CC induction.
CC -!- PTM: The soluble form (sIL4R/IL4BP) can also be produced by
CC proteolytic cleavage at the cell surface (shedding) by a
CC metalloproteinase.
CC -!- POLYMORPHISM: Allelic variants in IL4RA are associated with a
CC susceptibility to atopy, an immunological condition that can lead
CC to clinical symptoms such as allergic rhinitis, sinusitis, asthma
CC and eczema.
CC -!- POLYMORPHISM: Allelic variants in IL4RA are associated with cedar
CC pollen sensitization. Individuals develop Japanese cedar
CC pollinosis with increased exposure to cedar pollen. Japanese cedar
CC pollinosis is a type I allergic disease with ocular and nasal
CC symptoms that develop paroxysmally on contact with Japanese cedar
CC pollen. These symptoms, which occur seasonally each year, are
CC typical features of allergic rhinitis, such as sneezing, excessive
CC nasal secretion, nasal congestion, and conjunctival itching.
CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 4
CC subfamily.
CC -!- SIMILARITY: Contains 1 fibronectin type-III domain.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/il4r/";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename;=IL4R";
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DR EMBL; X52425; CAA36672.1; -; mRNA.
DR EMBL; AC004525; AAC23495.1; -; Genomic_DNA.
DR EMBL; AF421855; AAL12163.1; -; Genomic_DNA.
DR EMBL; AJ293647; CAC20445.1; -; Genomic_DNA.
DR EMBL; AJ293648; CAC20446.1; -; Genomic_DNA.
DR EMBL; AJ293649; CAC20447.1; -; Genomic_DNA.
DR EMBL; AJ293650; CAC20448.1; -; Genomic_DNA.
DR EMBL; AJ293651; CAC20449.1; -; Genomic_DNA.
DR EMBL; AJ293652; CAC20450.1; -; Genomic_DNA.
DR EMBL; AJ293653; CAC20451.1; -; Genomic_DNA.
DR EMBL; AC106739; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC151131; AAI51132.1; -; mRNA.
DR EMBL; AJ293654; CAC20452.1; -; Genomic_DNA.
DR PIR; A60386; A60386.
DR RefSeq; NP_000409.1; NM_000418.3.
DR RefSeq; NP_001244335.1; NM_001257406.1.
DR RefSeq; NP_001244336.1; NM_001257407.1.
DR UniGene; Hs.513457; -.
DR UniGene; Hs.742121; -.
DR PDB; 1IAR; X-ray; 2.30 A; B=27-232.
DR PDB; 1IRS; NMR; -; B=489-499.
DR PDB; 1ITE; Model; -; C=26-232.
DR PDB; 3BPL; X-ray; 2.93 A; B=27-227.
DR PDB; 3BPN; X-ray; 3.02 A; B=27-227.
DR PDB; 3BPO; X-ray; 3.00 A; B=27-227.
DR PDBsum; 1IAR; -.
DR PDBsum; 1IRS; -.
DR PDBsum; 1ITE; -.
DR PDBsum; 3BPL; -.
DR PDBsum; 3BPN; -.
DR PDBsum; 3BPO; -.
DR ProteinModelPortal; P24394; -.
DR SMR; P24394; 27-224.
DR DIP; DIP-3223N; -.
DR IntAct; P24394; 10.
DR MINT; MINT-90363; -.
DR PhosphoSite; P24394; -.
DR DMDM; 124335; -.
DR PaxDb; P24394; -.
DR PRIDE; P24394; -.
DR Ensembl; ENST00000170630; ENSP00000170630; ENSG00000077238.
DR Ensembl; ENST00000395762; ENSP00000379111; ENSG00000077238.
DR Ensembl; ENST00000449195; ENSP00000410322; ENSG00000077238.
DR Ensembl; ENST00000543915; ENSP00000441667; ENSG00000077238.
DR GeneID; 3566; -.
DR KEGG; hsa:3566; -.
DR UCSC; uc002don.4; human.
DR CTD; 3566; -.
DR GeneCards; GC16P027325; -.
DR HGNC; HGNC:6015; IL4R.
DR HPA; CAB004451; -.
DR MIM; 147781; gene.
DR neXtProt; NX_P24394; -.
DR PharmGKB; PA29832; -.
DR eggNOG; NOG46569; -.
DR HOVERGEN; HBG052116; -.
DR InParanoid; P24394; -.
DR KO; K05071; -.
DR OMA; SPCCGCC; -.
DR OrthoDB; EOG73RBCJ; -.
DR PhylomeDB; P24394; -.
DR SignaLink; P24394; -.
DR ChiTaRS; IL4R; human.
DR EvolutionaryTrace; P24394; -.
DR GeneWiki; Interleukin-4_receptor; -.
DR GenomeRNAi; 3566; -.
DR NextBio; 13926; -.
DR PRO; PR:P24394; -.
DR ArrayExpress; P24394; -.
DR Bgee; P24394; -.
DR Genevestigator; P24394; -.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0004913; F:interleukin-4 receptor activity; TAS:ProtInc.
DR GO; GO:0005057; F:receptor signaling protein activity; TAS:ProtInc.
DR GO; GO:0042832; P:defense response to protozoan; IEA:Ensembl.
DR GO; GO:0006955; P:immune response; TAS:ProtInc.
DR GO; GO:0045626; P:negative regulation of T-helper 1 cell differentiation; IEA:Ensembl.
DR GO; GO:0030728; P:ovulation; IEA:Ensembl.
DR GO; GO:0090197; P:positive regulation of chemokine secretion; IEA:Ensembl.
DR GO; GO:0043032; P:positive regulation of macrophage activation; IEA:Ensembl.
DR GO; GO:0045630; P:positive regulation of T-helper 2 cell differentiation; IEA:Ensembl.
DR GO; GO:0002532; P:production of molecular mediator involved in inflammatory response; IEA:InterPro.
DR GO; GO:0042127; P:regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0043627; P:response to estrogen stimulus; IEA:Ensembl.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR003531; Hempt_rcpt_S_F1_CS.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR015319; IL-4_rcpt-alpha_N.
DR Pfam; PF09238; IL4Ra_N; 1.
DR SMART; SM00060; FN3; 1.
DR SUPFAM; SSF49265; SSF49265; 2.
DR PROSITE; PS50853; FN3; 1.
DR PROSITE; PS01355; HEMATOPO_REC_S_F1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Complete proteome;
KW Disulfide bond; Glycoprotein; Immunity; Membrane; Phosphoprotein;
KW Polymorphism; Receptor; Reference proteome; Secreted; Signal;
KW Transmembrane; Transmembrane helix.
FT SIGNAL 1 25 By similarity.
FT CHAIN 26 825 Interleukin-4 receptor subunit alpha.
FT /FTId=PRO_0000010887.
FT CHAIN 26 ? Soluble interleukin-4 receptor subunit
FT alpha.
FT /FTId=PRO_0000010888.
FT TOPO_DOM 26 232 Extracellular (Potential).
FT TRANSMEM 233 256 Helical; (Potential).
FT TOPO_DOM 257 825 Cytoplasmic (Potential).
FT DOMAIN 125 224 Fibronectin type-III.
FT REGION 437 557 Required for IRS1 activation and IL4-
FT induced cell growth.
FT REGION 558 657 Required for IL4-induced gene expression.
FT MOTIF 212 216 WSXWS motif.
FT MOTIF 262 270 Box 1 motif.
FT MOTIF 711 716 ITIM motif.
FT COMPBIAS 370 380 Poly-Glu.
FT COMPBIAS 563 566 Poly-Ala.
FT COMPBIAS 789 794 Poly-Ser.
FT SITE 38 38 Major IL4 binding determinant.
FT SITE 64 64 Minor IL4 binding determinant.
FT SITE 66 66 Minor IL4 binding determinant.
FT SITE 92 92 Minor IL4 binding determinant.
FT SITE 94 94 Minor IL4 binding determinant.
FT SITE 97 97 Major IL4 binding determinant.
FT SITE 152 152 Minor IL4 binding determinant.
FT SITE 208 208 Major IL4 binding determinant.
FT MOD_RES 497 497 Phosphotyrosine.
FT MOD_RES 575 575 Phosphotyrosine (Probable).
FT MOD_RES 603 603 Phosphotyrosine (Probable).
FT MOD_RES 631 631 Phosphotyrosine (Probable).
FT CARBOHYD 53 53 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 98 98 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 128 128 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 134 134 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 176 176 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 209 209 N-linked (GlcNAc...) (Potential).
FT DISULFID 34 44 By similarity.
FT DISULFID 74 86 By similarity.
FT VAR_SEQ 225 227 YRE -> NIC (in isoform 2).
FT /FTId=VSP_011116.
FT VAR_SEQ 228 825 Missing (in isoform 2).
FT /FTId=VSP_011117.
FT VARIANT 75 75 I -> F (in dbSNP:rs1805010).
FT /FTId=VAR_059302.
FT VARIANT 75 75 I -> L (in dbSNP:rs1805010).
FT /FTId=VAR_059303.
FT VARIANT 75 75 I -> V (associated with atopic asthma and
FT cedar pollen sensitization;
FT dbSNP:rs1805010).
FT /FTId=VAR_008034.
FT VARIANT 387 387 S -> L (in dbSNP:rs6413500).
FT /FTId=VAR_019999.
FT VARIANT 400 400 E -> A (associated with cedar pollen
FT sensitization; dbSNP:rs1805011).
FT /FTId=VAR_011657.
FT VARIANT 431 431 C -> R (in dbSNP:rs1805012).
FT /FTId=VAR_011658.
FT VARIANT 436 436 S -> L (in dbSNP:rs1805013).
FT /FTId=VAR_011659.
FT VARIANT 492 492 A -> T (in dbSNP:rs35606110).
FT /FTId=VAR_049164.
FT VARIANT 492 492 A -> V (in dbSNP:rs34727572).
FT /FTId=VAR_049165.
FT VARIANT 503 503 S -> P (lowered total IgE concentration;
FT dbSNP:rs1805015).
FT /FTId=VAR_011660.
FT VARIANT 576 576 Q -> R (associated with atopic
FT dermatitis; lowered total IgE
FT concentration; no effect on IL4-induced
FT signal transduction; dbSNP:rs1801275).
FT /FTId=VAR_008035.
FT VARIANT 579 579 V -> I (in dbSNP:rs3024677).
FT /FTId=VAR_011661.
FT VARIANT 675 675 P -> S (in dbSNP:rs3024678).
FT /FTId=VAR_020000.
FT VARIANT 752 752 S -> A (in dbSNP:rs1805016).
FT /FTId=VAR_011662.
FT VARIANT 786 786 S -> P (in 1.8% of the population;
FT dbSNP:rs1805014).
FT /FTId=VAR_011663.
FT MUTAGEN 38 38 Y->A: 700-fold reduction in IL4 binding.
FT MUTAGEN 38 38 Y->F: 25-fold reduction in IL4 binding.
FT MUTAGEN 39 39 M->A: No effect on IL4 binding.
FT MUTAGEN 40 40 S->A: No effect on IL4 binding.
FT MUTAGEN 64 64 L->A: 100-fold reduction in IL4 binding.
FT MUTAGEN 66 66 F->A: 45-fold reduction in IL4 binding.
FT MUTAGEN 67 67 L->A: No effect on IL4 binding.
FT MUTAGEN 68 68 L->A: No effect on IL4 binding.
FT MUTAGEN 91 91 D->A: Little effect on IL4 binding.
FT MUTAGEN 92 92 D->A: 50-fold reduction in IL4 binding.
FT MUTAGEN 93 93 V->A: Little effect on IL4 binding.
FT MUTAGEN 94 94 V->A: 35-fold reduction in IL4 binding.
FT MUTAGEN 95 95 S->A: No effect on IL4 binding.
FT MUTAGEN 97 97 D->A,N: >150-fold reduction in IL4
FT binding.
FT MUTAGEN 98 98 N->A: No effect on IL4 binding.
FT MUTAGEN 99 99 Y->A: 10-fold reduction in IL4 binding.
FT MUTAGEN 116 116 K->A: Little effect on IL4 binding.
FT MUTAGEN 117 117 P->A: Little effect on IL4 binding.
FT MUTAGEN 118 118 S->A: No effect on IL4 binding.
FT MUTAGEN 119 119 E->A: No effect on IL4 binding.
FT MUTAGEN 150 150 D->A: Little effect on IL4 binding.
FT MUTAGEN 151 151 N->A: Little effect on IL4 binding.
FT MUTAGEN 152 152 Y->A: 40-fold reduction in IL4 binding.
FT MUTAGEN 152 152 Y->F: No effect on IL4 binding.
FT MUTAGEN 153 153 L->A: Little effect on IL4 binding.
FT MUTAGEN 154 154 Y->A: Little effect on IL4 binding.
FT MUTAGEN 208 208 Y->A: 500-fold reduction in IL4 binding.
FT MUTAGEN 208 208 Y->F: 200-fold reduction in IL4 binding.
FT MUTAGEN 497 497 Y->F: Abolishes IRS1 tyrosine
FT phosphorylation. No cell proliferation.
FT MUTAGEN 575 575 Y->F: Loss of CD23 gene induction; when
FT associated with F-603 and F-631.
FT MUTAGEN 603 603 Y->F: Loss of CD23 gene induction; when
FT associated with F-575 and F-631.
FT MUTAGEN 631 631 Y->F: Loss of CD23 gene induction; when
FT associated with F-575 and F-603.
FT MUTAGEN 713 713 Y->F: Increased IL4-induced cell
FT proliferation and STAT6 activation.
FT STRAND 28 36
FT STRAND 38 50
FT HELIX 54 57
FT STRAND 58 68
FT STRAND 72 74
FT STRAND 77 89
FT STRAND 99 105
FT STRAND 108 115
FT HELIX 117 119
FT STRAND 127 132
FT TURN 135 137
FT STRAND 139 144
FT HELIX 154 156
FT STRAND 158 168
FT STRAND 172 177
FT STRAND 183 186
FT HELIX 188 190
FT STRAND 193 195
FT STRAND 197 204
FT HELIX 206 208
FT STRAND 219 221
FT HELIX 495 497
SQ SEQUENCE 825 AA; 89658 MW; 9F886DF5612297F8 CRC64;
MGWLCSGLLF PVSCLVLLQV ASSGNMKVLQ EPTCVSDYMS ISTCEWKMNG PTNCSTELRL
LYQLVFLLSE AHTCIPENNG GAGCVCHLLM DDVVSADNYT LDLWAGQQLL WKGSFKPSEH
VKPRAPGNLT VHTNVSDTLL LTWSNPYPPD NYLYNHLTYA VNIWSENDPA DFRIYNVTYL
EPSLRIAAST LKSGISYRAR VRAWAQCYNT TWSEWSPSTK WHNSYREPFE QHLLLGVSVS
CIVILAVCLL CYVSITKIKK EWWDQIPNPA RSRLVAIIIQ DAQGSQWEKR SRGQEPAKCP
HWKNCLTKLL PCFLEHNMKR DEDPHKAAKE MPFQGSGKSA WCPVEISKTV LWPESISVVR
CVELFEAPVE CEEEEEVEEE KGSFCASPES SRDDFQEGRE GIVARLTESL FLDLLGEENG
GFCQQDMGES CLLPPSGSTS AHMPWDEFPS AGPKEAPPWG KEQPLHLEPS PPASPTQSPD
NLTCTETPLV IAGNPAYRSF SNSLSQSPCP RELGPDPLLA RHLEEVEPEM PCVPQLSEPT
TVPQPEPETW EQILRRNVLQ HGAAAAPVSA PTSGYQEFVH AVEQGGTQAS AVVGLGPPGE
AGYKAFSSLL ASSAVSPEKC GFGASSGEEG YKPFQDLIPG CPGDPAPVPV PLFTFGLDRE
PPRSPQSSHL PSSSPEHLGL EPGEKVEDMP KPPLPQEQAT DPLVDSLGSG IVYSALTCHL
CGHLKQCHGQ EDGGQTPVMA SPCCGCCCGD RSSPPTTPLR APDPSPGGVP LEASLCPASL
APSGISEKSK SSSSFHPAPG NAQSSSQTPK IVNFVSVGPT YMRVS
//

MIM 147781
*RECORD*
*FIELD* NO
147781
*FIELD* TI
*147781 INTERLEUKIN 4 RECEPTOR; IL4R
;;INTERLEUKIN 4 RECEPTOR, ALPHA; IL4RA
*FIELD* TX
read more
DESCRIPTION

Interleukin-4 (IL4; 147780) plays a major role in immunoglobulin E (IgE)
production. Its signal is conferred to effector cells through binding to
the alpha chain of the IL4 receptor (IL4RA).

CLONING

IL4 is a cytokine produced by T cells that regulates proliferation and
differentiation of a variety of cells. It modulates the activity of
these cells following binding to cell surface receptors. By
cross-species hybridization using a cDNA encoding the murine
interleukin-4 receptor (IL4R), Idzerda et al. (1990) isolated cDNAs
encoding the human IL4R. The amino acid sequence of its extracellular
domain defined it as a member of the hematopoietin receptor superfamily.

Kruse et al. (1999) reported that membrane-bound IL4R is coded by exons
3 to 7 (extracellular domain), exon 9 (transmembrane domain), and exons
10 to 12 (intracellular domain). Alternative splicing leads to the
production of a soluble form of IL4R, which is coded by exons 3 to 8 and
lacks the exons for the transmembrane and intracellular regions. Soluble
IL4R has no signaling abilities and is believed to work as an antagonist
to the IL4 ligand (Bergin et al., 2006).

GENE STRUCTURE

Kruse et al. (1999) determined that the IL4R gene contains 12 exons.

GENE FUNCTION

Zurawski et al. (1993) presented data demonstrating that IL4R is a
complex of at least 2 components, one of which is a novel affinity
converting subunit that is critical for cellular signal transduction.
See also IL13RA1 (300119) and IL13RA2 (300130).

Ihle and Kerr (1995) reviewed the activation cascade involving
cytokines, IL4R and other cytokine receptors, the Janus kinases (see
JAK1; 147795), and the signal transducers and activators of
transcription, or STATs (see STAT1; 600555).

Kotanides and Reich (1996) identified a specific STAT6 (601512)
DNA-binding target site in the promoter of IL4R and showed that STAT6
activates IL4 gene expression via this site.

Because IL4 and IL13 (147683) and their specific signaling pathways are
considered attractive targets for the treatment of allergy and asthma,
Kelly-Welch et al. (2003) reviewed the signaling connections of these
cytokines. IL4 interacts with IL4R with high affinity, leading to
dimerization with either the common gamma chain (IL2RG; 308380), a
component of receptors for a number of cytokines, to create a type I
receptor, or with IL13RA1 to form a type II receptor. IL13, on the other
hand, binds with high affinity to IL13RA1, which induces
heterodimerization with IL4R to form a complex identical to the type II
receptor. Alternatively, IL13 may bind with even greater affinity to
IL13RA2, which fails to induce a signal, indicating that it acts as a
decoy receptor. The C-terminal tails of the IL4 and IL13 receptor
subunits interact with tyrosine kinases of the Janus kinase family,
leading to interaction with STAT6, which binds to consensus sequences in
the promoters of IL4- and IL13-regulated genes. Kelly-Welch et al.
(2003) proposed that subtle differences in IL4 and IL13 signaling due to
polymorphisms near docking sites in IL4R may have profound implications
for allergy and asthma.

The transcription factor NFATC2 (600490) controls myoblast fusion at a
specific stage of myogenesis after the initial formation of a myotube
and is necessary for further cell growth. By examining genes regulated
by NFATC2 in muscle, Horsley et al. (2003) identified the cytokine IL4
as a molecular signal that controls myoblast fusion with myotubes. Mouse
muscle cells lacking Il4 or the Il4 receptor alpha subunit formed
normally but were reduced in size and myonuclear number. Il4 was
expressed by a subset of mouse muscle cells in fusing muscle cultures
and required the Il4 receptor alpha subunit on myoblasts to promote
fusion and growth. These data demonstrated that following myotube
formation, myotubes recruit myoblast fusion by secretion of IL4, leading
to muscle growth.

Using confocal microscopy, Maldonado et al. (2004) found a random
distribution of Tcrb (see 186930), Il4r, and Ifngr1 (107470) in fixed
and permeabilized mouse naive T-helper lymphocytes (Thp) conjugated with
mouse mature splenic dendritic cells (DCs). In cells fixed and
permeabilized 30 minutes after conjugation of Thp and antigen-loaded
DCs, the authors observed a calcium- and Ifng (147570)-dependent
colocalization of Tcrb and Ifngr1, but not Il4r, at the Thp-DC
interface. This observation was more apparent in the Th1-prone C57Bl/6
mouse strain than in the Th2-prone BALB/c strain. In the presence of
Il4, but not Il10 (124092), Ifngr1 migration and copolarization was
completely inhibited. In mice lacking the Il4r signaling molecule, Stat6
, prevention of Tcrb/Ifngr1 copolarization was abolished. Maldonado et
al. (2004) proposed that strong TCR signaling leads to accentuated IFNGR
copolarization and the assembly of a Th1 signalosome, which is further
stabilized by secretion of IFNG, unless an inhibitory signal, such as
IL4 secretion and STAT6 activation, occurs and leads to the assembly of
a Th2 signalosome. They concluded that the immunologic synapse may be
involved in the control of cell fate decisions.

BIOCHEMICAL FEATURES

LaPorte et al. (2008) reported the crystal structures of the complete
set of IL4 and IL13 type I (IL4RA/IL2RG/IL4) and type II
(IL4RA/IL13RA1/IL4 and IL4RA/IL13RA1/IL13) ternary signaling complexes
at the 3.0-angstrom level. They noted that the type I receptor complex
is more active in regulating Th2 development, whereas the type II
receptor complex is not found on T cells and is more active in
regulating cells that mediate airway hypersensitivity and mucus
secretion. The type I complex revealed a structural basis for the
ability of IL2RG to recognize 6 different IL2RG cytokines.

MAPPING

Pritchard et al. (1991) localized the IL4R gene to 16p12.1-p11.2 by in
situ hybridization and Southern blot analysis of DNA from a panel of
mouse-human somatic cell lines. By interspecific backcross analysis,
they assigned the mouse homolog to the distal region of chromosome 7.
Thus, the IL4R locus is unlinked to other members of the hematopoietin
receptor family. Suzuki et al. (1991) demonstrated that the murine Il4r
gene is closely linked to the homolog of the ITGAL gene (153370) on
chromosome 7.

MOLECULAR GENETICS

- Association with Atopy

Khurana Hershey et al. (1997) noted that the interleukin-4 receptor is
composed of 2 subunits: a 140-kd alpha subunit, which binds
interleukin-4 and transduces its growth-promoting and
transcription-activating functions, and a gamma-c subunit, common to
several cytokine receptors, which amplifies signaling of interleukin-4
receptor alpha. The central role played by interleukin-4 receptor alpha
in regulating production of IgE prompted Khurana Hershey et al. (1997)
to investigate possible mutations in the gene that would enhance
receptor signaling and hence precipitate atopy. Using single-strand
conformation polymorphism (SSCP) analysis and DNA sequencing, they
searched for mutations in the alpha-subunit of the interleukin-4
receptor that might predispose persons to atopy. They examined the
prevalence of alleles among patients with allergic inflammatory
disorders and among 50 prospectively recruited adults. Subjects with
atopy were identified on the basis of elevated serum IgE level or a
positive radioimmunosorbent test in response to standard inhalant
allergens. An arg576 allele of IL4R (147781.0001) was found to be
strongly associated with atopy. It had previously been demonstrated that
gain-of-function polymorphisms in the interleukin-4 gene are associated
with increased output of interleukin-4, which in turn is associated with
asthma, skin-test positivity, and higher total concentrations of serum
IgE.

Caggana et al. (1999) examined the frequency of the IL4R sequence
variants gly551 to arg and ile50 to val in 4 anonymous New York state
populations defined by ethnic origin. These variants were studied
because they are associated with atopy or atopic asthma, the prevalence
of which varies in different populations. Methods were developed to
detect both polymorphisms in 855 newborn screening specimens. The arg551
allele was found most frequently in blacks (allele frequency of 68%),
whereas the ile50 allele was most common in whites (allele frequency of
87%). Significantly more blacks had chromosomes bearing both of the
'enhanced-signaling' variants (ile50/arg551). Since enhanced IL4R
signaling is associated with increased IgE production (atopy), Caggana
et al. (1999) interpreted their data as suggesting that African American
populations may be at increased risk for diseases, including asthma,
that are associated with atopy. The data pointed to the importance of
determining the frequencies of single-nucleotide polymorphisms in
different populations before drawing conclusions from allele association
studies, since the background allele frequencies may be disparate.

A genomewide screen for atopy susceptibility alleles in the Hutterites,
a founder population of European origin living mainly in Canada,
provided evidence for linkage to 16p (Ober et al., 1999). Ober et al.
(2000) examined the IL4RA gene as the 16p-linked susceptibility locus.
The Hutterites and outbred white, black, and Hispanic families all
showed evidence of association between variants in the IL4RA gene and
atopy or asthma; however, the alleles or haplotypes showing the
strongest evidence differed between the groups.

Bergin et al. (2006) identified a major and minor haplotype of 4 SNPs
flanking or within the alternatively-spliced exon 8 of the IL4R gene.
Using a minigene construct comprising exons 7 to 9 (exon 8+) in vitro,
the authors found that the minor haplotype expressed about 100 times
less of the exon 8+ transcript compared to the major haplotype. Analysis
of mRNA expression in peripheral blood mononuclear cells of asthma
patients and controls confirmed lower expression of sIL4R in those with
the minor haplotype. However, there was no association between the
haplotypes and asthma among 257 Swedish Caucasian patients.

- Association with HIV Infection and Progression to AIDS

By analysis of IL4R allele and genotype frequencies in individuals with
different risk factors for human immunodeficiency virus (HIV; see
609423) acquisition and different rates of progression to acquired
immunodeficiency syndrome (AIDS), Soriano et al. (2005) determined that
the V50 allele (147781.0002) predominated in HIV-positive long-term
nonprogressors (LTNPs), whereas the I50 allele predominated in healthy
controls, typical progressors, and those at risk for infection due to
sexual exposure or treatment of hemophilia. Homozygosity for V50 was
increased in LTNPs compared with other groups. Soriano et al. (2005)
concluded that V50 homozygosity appears to be associated with slow
progression to AIDS after HIV infection.

ANIMAL MODEL

The I4R motif of IL4R mediates association of IRS2 (600797) with IL4R
and transduces mitogenic signals in response to IL4. A polymorphism
within the I4R motif, ser503 to pro (S503P; 147781.003), is associated
with human allergic disorders. By targeted knockin mutagenesis, Blaeser
et al. (2003) created mice with a tyr500-to-phe (Y500F) mutation within
the I4R motif. Treatment of Y500F splenic T cells with IL4 resulted in
normal Jak1 kinase activation, but markedly decreased Il4r
phosphorylation, abrogation of tyr phosphorylation of Irs2, and impaired
Irs2 signaling cascade. CD4 T-cell proliferation was also impaired in
Y500F mice, but Stat6 activation and Th cell differentiation under Th2
polarizing conditions are unaffected. In vivo, the Y500F mutation was
associated with increased IgE production and allergic airway
inflammation. Blaeser et al. (2003) concluded that the I4R motif is
important in regulating allergic inflammation.

Chen et al. (2012) studied Th2-type immune responses in a mouse model of
intestinal nematode parasite infection in which parasite larvae migrate
transiently through lung. They found that acute lung injury occurred
shortly after worm inoculation and was associated with hemorrhaging,
inflammation, decreased lung function, and Ill7 (603149) expression.
Subsequent Il4r signaling reduced Il17 expression, enhanced expression
of Igf1 (147440) and Il10, and stimulated development of M2-type
macrophages, all of which contributed to rapid resolution of tissue
damage.

*FIELD* AV
.0001
ATOPY, SUSCEPTIBILITY TO
IL4R, GLN576ARG

Khurana Hershey et al. (1997) described a polymorphism of the IL4A gene
that occurred with increased frequency in patients with allergic
inflammatory disorders. The variant allele consisted of an A-to-G
transition at nucleotide 1902, causing a change from glutamine to
arginine at codon 576 (Q576R) in the cytoplasmic domain of the
interleukin-4 receptor alpha protein. The R576 allele was found in 3 of
3 patients with the hyper-IgE syndrome (147060) and in 4 of 7 patients
with severe atopic dermatitis. Among 50 prospectively recruited adults,
it was found in 13 of 20 subjects with atopy (147050) and in 5 of 30
without atopy; the relative risk of atopy among those with a mutant
allele was 9.3. The R576 allele was associated with higher levels of
expression of CD23 (151445) by interleukin-4 than was the wildtype
allele. This enhanced signaling was associated with a change in the
binding specificity of the adjacent tyrosine residue at position 575 to
signal-transducing molecules.

Deichmann et al. (1998) confirmed the association of IL4R alleles with
atopy; however, they found reduced total IgE concentrations in patients
with Q576R (Kruse et al., 1999). Kruse et al. (1999) also found that the
Q576R allele is in direct linkage disequilibrium with another
polymorphism, S503P (147781.0003). Grimbacher et al. (1998) investigated
the frequency of Q576R in 25 control subjects and 20 unrelated patients
with the hyper-IgE syndrome who were followed at the National Institutes
of Health Clinical Center. Only 4 of the 20 patients had the Q576R
mutation (allelic frequency, 10%), which was not significantly different
from the frequency of 12% (6 of 25) in the control subjects.

Patuzzo et al. (2000) could find no evidence of linkage or association
of atopic asthma with this mutation in 851 Italian subjects with atopic
asthma.

.0002
ASTHMA, ATOPIC
ACQUIRED IMMUNODEFICIENCY SYNDROME, SLOW PROGRESSION TO, INCLUDED
IL4R, ILE50VAL

An ile50-to-val (numbering for mature peptide) variant of human
IL4R-alpha was identified by Idzerda et al. (1990) and Galizzi et al.
(1990). Up to 1998, it was the only known extracellular variant of human
IL4R. To test whether the ile50-to-val variant promotes dysregulation of
IgE synthesis, Mitsuyasu et al. (1998) conducted a genetic association
study for serum IgE levels in a Japanese population. A significant
difference in ile/val genotype frequencies was found between control and
atopic subjects; ile50 associated with atopic asthma but not with
non-atopic asthma; ile50 specifically and significantly associated with
raised total serum IgE levels and mite-specific IgE. The association
with atopy was especially strong in children. The high frequency of
ile50 homozygotes (approximately 60%) in the childhood atopic asthma
group and the significant skewing from Hardy-Weinberg equilibrium (P
less than 0.0001) suggested a largely recessive genetic effect for ile50
on atopy. (The effect of the previously reported arg576-to-gln variant
(147781.0001) appeared to be mainly dominant.)

To investigate the functional aspects of the ile50 and val50 variants of
IL4R, Mitsuyasu et al. (1998) transfected complete cDNAs for these
variants into mouse and human B-lymphocyte lines. In response to human
IL4, the ile50-transfected mouse cells showed almost 3 times greater
cell growth and approximately 3 times greater induction of luciferase
activity (expression under the control of the IgE promoter) compared
with val50-transfected cells (15.5- vs 5.4-fold increase, respectively).
These augmented responses of ile50-transfected mouse cells to IL4 were
not due to higher expression of ile50 than val50 transfectants.
Furthermore, no difference between ile50- and val50-transfected cells in
binding assays was detected. Similar results were obtained with the
transfected human B-lymphocyte clones. Mitsuyasu et al. (1998) found
that the ile50 variant augmented STAT6 (601512) activation 1.8-fold
compared with the val50 variant in both mouse and human cells. These
data suggested that the ile50 variant significantly upregulates receptor
response to IL4, with resultant increased activation of STAT6, and hence
increased cell proliferation and increased IgE production. The data on
this and the arg576-to-gln variant provide compelling evidence that IL4R
is a major atopy locus.

By analysis of IL4R allele and genotype frequencies in individuals with
different risk factors for human immunodeficiency virus (HIV; see
609423) acquisition and different rates of progression to acquired
immunodeficiency syndrome (AIDS), Soriano et al. (2005) determined that
the V50 allele predominated in HIV-positive long-term nonprogressors
(LTNPs), whereas the I50 allele predominated in healthy controls,
typical progressors, and those at risk for infection due to sexual
exposure or treatment of hemophilia. Homozygosity for V50 was increased
in LTNPs compared with other groups. Soriano et al. (2005) concluded
that V50 homozygosity appears to be associated with slow progression to
AIDS after HIV infection.

.0003
ATOPY, RESISTANCE TO
ASTHMA, SUSCEPTIBILITY TO
IL4R, SER503PRO

Kruse et al. (1999) detected low total IgE concentrations (147050) in
individuals with a ser503-to-pro substitution in the IL4R gene. They
found direct linkage disequilibrium of S503P with Q576R (147781.0001);
76% of R576 carriers were also P503 carriers. Individuals with both
polymorphisms had significantly (p less than 0.0008) lower total IgE
concentrations.

Howard et al. (2002) investigated 5 IL4RA single-nucleotide
polymorphisms in a population of Dutch families ascertained through a
proband with asthma (600807). They observed significant associations of
atopy and asthma-related phenotypes with several IL4RA polymorphisms,
including S503P, which they referred to as SER478PRO (S478P), and total
serum IgE levels. A significant gene-gene interaction between S503P in
IL4RA and the -1112C-T promoter variation (147683.0001) in IL13,
previously shown to be associated with bronchial hyperresponsiveness,
was detected. Individuals with the risk genotype for both genes were at
almost 5 times greater risk for the development of asthma compared to
individuals with both nonrisk genotypes.

*FIELD* RF
1. Bergin, A.-M.; Balder, B.; Kishore, S.; Sward, K.; Hahn-Zoric,
M.; Lowhagen, O.; Hanson, L. A.; Padyukov, L.: Common variations
in the IL4R gene affect splicing and influence natural expression
of the soluble isoform. Hum. Mutat. 27: 990-998, 2006.

2. Blaeser, F.; Bryce, P. J.; Ho, N.; Raman, V.; Dedeoglu, F.; Donaldson,
D. D.; Geha, R. S.; Oettgen, H. C.; Chatila, T. A.: Targeted inactivation
of the IL-4 receptor alpha chain I4R motif promotes allergic airway
inflammation. J. Exp. Med. 198: 1189-1200, 2003.

3. Caggana, M.; Walker, K.; Reilly, A. A.; Conroy, J. M.; Duva, S.;
Walsh, A. C.: Population-based studies reveal differences in the
allelic frequencies of two functionally significant human interleukin-4
receptor polymorphisms in several ethnic groups. Genet. Med. 1:
267-271, 1999.

4. Chen, F.; Liu, Z.; Wu, W.; Rozo, C.; Bowdridge, S.; Millman, A.;
Van Rooijen, N.; Urban, J. F., Jr.; Wynn, T. A.; Gause, W. C.: An
essential role for TH2-type responses in limiting acute tissue damage
during experimental helminth infection. Nature Med. 18: 260-266,
2012.

5. Deichmann, K. A.; Heinzmann, A.; Forster, J.; Dischinger, S.; Mehl,
C.; Brueggenolte, E.; Hildebrandt, F.; Moseler, M.; Kuehr, J.: Linkage
and allelic association of atopy and markers flanking the IL4-receptor
gene. Clin. Exp. Allergy 28: 151-155, 1998.

6. Galizzi, J.-P.; Zuber, C. E.; Harada, N.; Gorman, D. M.; Kastelein,
R.; Banchereau, J.; Howard, M.; Miyajima, A.: Molecular cloning of
a cDNA encoding the human interleukin 4 receptor. Int. Immun. 2:
669-675, 1990.

7. Grimbacher, B.; Holland, S. M.; Puck, J. M.: The interleukin-4
receptor variant Q576R in hyper-IgE syndrome. (Letter) New Eng. J.
Med. 338: 1073-1074, 1998.

8. Horsley, V.; Jansen, K. M.; Mills, S. T.; Pavlath, G. K.: IL-4
acts as a myoblast recruitment factor during mammalian muscle growth. Cell 113:
483-494, 2003.

9. Howard, T. D.; Koppelman, G. H.; Xu, J.; Zheng, S. L.; Postma,
D. S.; Meyers, D. A.; Bleecker, E. R.: Gene-gene interaction in asthma:
IL4RA and IL13 in a Dutch population with asthma. Am. J. Hum. Genet. 70:
230-236, 2002.

10. Idzerda, R. L.; March, C. J.; Mosley, B.; Lyman, S. D.; VandenBos,
T.; Gimpel, S. D.; Din, W. S.; Grabstein, K. H.; Widmer, M. B.; Park,
L. S.; Cosman, D.; Beckmann, M. P.: Human interleukin-4 receptor
confers biological responsiveness and defines a novel receptor superfamily. J.
Exp. Med. 171: 861-873, 1990.

11. Ihle, J. N.; Kerr, I. M.: Jaks and Stats in signaling by the
cytokine receptor superfamily. Trends Genet. 11: 69-74, 1995.

12. Kelly-Welch, A. E.; Hanson, E. M.; Boothby, M. R.; Keegan, A.
D.: Interleukin-4 and interleukin-13 signaling connections maps. Science 300:
1527-1528, 2003.

13. Khurana Hershey, G. K.; Friedrich, M. F.; Esswein, L. A.; Thomas,
M. L.; Chatila, T. A.: The association of atopy with a gain-of-function
mutation in the alpha subunit of the interleukin-4 receptor. New
Eng. J. Med. 337: 1720-1725, 1997.

14. Kotanides, H.; Reich, N. C.: Interleukin-4-induced STAT6 recognizes
and activates a target site in the promoter of the interleukin-4 receptor
gene. J. Biol. Chem. 271: 25555-25561, 1996.

15. Kruse, S.; Forster, J.; Kuehr, J.; Deichmann, K. A.: Characterization
of the membrane-bound and a soluble form of human IL-4 receptor alpha
produced by alternative splicing. Int. Immun. 11: 1965-1970, 1999.

16. Kruse, S.; Japha, T.; Tedner, M.; Sparholt, S. H.; Forster, J.;
Kuehr, J.; Deichmann, K. A.; Abello, A.: The polymorphisms S503P
and Q576R in the interleukin-4 receptor alpha gene are associated
with atopy and influence the signal transduction. Immunology 96:
365-371, 1999.

17. LaPorte, S. L.; Juo, Z. S.; Vaclavikova, J.; Colf, L. A.; Qi,
X.; Heller, N. M.; Keegan, A. D.; Garcia, K. C.: Molecular and structural
basis of cytokine receptor pleiotropy in the interleukin-4/13 system. Cell 132:
259-272, 2008.

18. Maldonado, R. A.; Irvine, D. J.; Schreiber, R.; Glimcher, L. H.
: A role for the immunological synapse in lineage commitment of CD4
lymphocytes. Nature 431: 527-532, 2004.

19. Mitsuyasu, H.; Izuhara, K.; Mao, X.-Q.; Gao, P.-S.; Arinobu, Y.;
Enomoto, T.; Kawai, M.; Sasaki, S.; Dake, Y.; Hamasaki, N.; Shirakawa,
T.; Hopkin, J. M.: Ile50val variant of IL4R-alpha upregulates IgE
synthesis and associates with atopic asthma. (Letter) Nature Genet. 19:
119-120, 1998.

20. Ober, C.; Leavitt, S. A.; Tsalenko, A.; Howard, T. D.; Hoki, D.
M.; Daniel, R.; Newman, D. L.; Wu, X.; Parry, R.; Lester, L. A.; Solway,
J.; Blumenthal, M.; King, R. A.; Xu, J.; Meyers, D. A.; Bleecker,
E. R.; Cox, N. J.: Variation in the interleukin 4-receptor alpha
gene confers susceptibility to asthma and atopy in ethnically diverse
populations. Am. J. Hum. Genet. 66: 517-526, 2000.

21. Ober, C.; Tsalenko, A.; Willadsen, S.; Newman, D.; Daniel, R.;
Wu, X.; Andal, J.; Hoki, D.; Schneider, D.; True, K.; Schou, C.; Parry,
R.; Cox, N.: Genome-wide screen for atopy susceptibility alleles
in the Hutterites. Clin. Exp. Allergy 29 (suppl. 4): 11-15, 1999.

22. Patuzzo, C.; Trabetti, E.; Malerba, G.; Martinati, L. C.; Boner,
A. L.; Pescollderungg, L.; Zanoni, G.; Pignatti, P. F.: No linkage
or association of the IL-4R-alpha gene Q576R mutation with atopic
asthma in Italian families. (Letter) J. Med. Genet. 37: 382-384,
2000.

23. Pritchard, M. A.; Baker, E.; Whitmore, S. A.; Sutherland, G. R.;
Idzerda, R. L.; Park, L. S.; Cosman, D.; Jenkins, N. A.; Gilbert,
D. J.; Copeland, N. G.; Beckmann, M. P.: The interleukin-4 receptor
gene (IL4R) maps to 16p11.2-16p12.1 in human and to the distal region
of mouse chromosome 7. Genomics 10: 801-806, 1991.

24. Soriano, A.; Lozano, F.; Oliva, H.; Garcia, F.; Nomdedeu, M.;
De Lazzari, E.; Rodriguez, C.; Barrasa, A.; Lorenzo, J. I.; del Romero,
J.; Plana, M.; Miro, J. M.; Gatell, J. M.; Vives, J.; Gallart, T.
: Polymorphisms in the interleukin-4 receptor alpha chain gene influence
susceptibility to HIV-1 infection and its progression to AIDS. Immunogenetics 57:
644-654, 2005.

25. Suzuki, H.; Chung, F.; Palmer, E.; Sasaki, T.; Ohara, N.; Taylor,
B. A.; Ohara, J.-I.: Gene mapping of mouse IL-4 receptor: the loci
of interleukin 4 (IL-4) receptor gene and lymphocyte function associated
antigen 1 (LFA-1) gene are closely linked on chromosome 7. Immunogenetics 34:
252-256, 1991.

26. Zurawski, S. M.; Vega, F., Jr.; Huyghe, B.; Zurawski, G.: Receptors
for interleukin-13 and interleukin-4 are complex and share a novel
component that functions in signal transduction. EMBO J. 12: 2663-2670,
1993.

*FIELD* CN
Paul J. Converse - updated: 3/8/2012
Paul J. Converse - updated: 3/21/2008
Cassandra L. Kniffin - updated: 10/12/2006
Paul J. Converse - updated: 4/3/2006
Paul J. Converse - updated: 1/6/2006
Paul J. Converse - updated: 9/30/2004
Stylianos E. Antonarakis - updated: 7/3/2003
Paul J. Converse - updated: 6/12/2003
Victor A. McKusick - updated: 1/22/2002
Paul J. Converse - updated: 5/15/2000
Victor A. McKusick - updated: 3/31/2000
Victor A. McKusick - updated: 2/16/2000
Victor A. McKusick - updated: 5/27/1998
Victor A. McKusick - updated: 4/15/1998
Victor A. McKusick - updated: 12/19/1997
Jennifer P. Macke - updated: 4/24/1997

*FIELD* CD
Victor A. McKusick: 6/4/1991

*FIELD* ED
mgross: 10/07/2013
mgross: 3/9/2012
terry: 3/8/2012
carol: 10/15/2009
mgross: 3/21/2008
terry: 3/21/2008
carol: 5/16/2007
terry: 11/3/2006
wwang: 10/20/2006
ckniffin: 10/12/2006
wwang: 10/5/2006
terry: 7/26/2006
mgross: 4/4/2006
terry: 4/3/2006
mgross: 1/6/2006
alopez: 10/29/2004
mgross: 9/30/2004
tkritzer: 10/24/2003
tkritzer: 10/20/2003
mgross: 7/3/2003
mgross: 6/12/2003
carol: 2/5/2002
carol: 2/4/2002
mcapotos: 1/31/2002
terry: 1/22/2002
alopez: 7/27/2001
terry: 7/20/2001
mcapotos: 8/1/2000
carol: 5/31/2000
carol: 5/15/2000
mgross: 4/12/2000
terry: 3/31/2000
mgross: 3/14/2000
terry: 2/16/2000
dholmes: 7/9/1998
alopez: 6/1/1998
terry: 5/27/1998
psherman: 5/20/1998
dholmes: 5/11/1998
carol: 4/17/1998
terry: 4/15/1998
mark: 1/10/1998
terry: 12/19/1997
alopez: 7/18/1997
alopez: 7/14/1997
alopez: 4/24/1997
mark: 2/8/1996
carol: 3/21/1994
supermim: 3/16/1992
carol: 11/27/1991
carol: 6/7/1991
carol: 6/6/1991
supermim: 6/4/1991