ID AIRE_HUMAN Reviewed; 545 AA. AC O43918; B2RP50; O43922; O43932; O75745; DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-1998, sequence version 1. DT 28-JAN-2026, entry version 236. DE RecName: Full=Autoimmune regulator; DE AltName: Full=Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy protein; DE Short=APECED protein; GN Name=AIRE; Synonyms=APECED; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1; 2 AND 3), AND VARIANT RP APS1 GLU-83. RC TISSUE=Thymus; RX PubMed=9398839; DOI=10.1038/ng1297-393; RA Nagamine K., Peterson P., Scott H.S., Kudoh J., Minoshima S., Heino M., RA Krohn K.J.E., Lalioti M.D., Mullis P.E., Antonarakis S.E., Kawasaki K., RA Asakawa S., Ito F., Shimizu N.; RT "Positional cloning of the APECED gene."; RL Nat. Genet. 17:393-398(1997). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1). RC TISSUE=Thymus; RX PubMed=9398840; DOI=10.1038/ng1297-399; RA Aaltonen J., Bjoerses P., Perheentupa J., Horelli-Kuitunen N., Palotie A., RA Peltonen L., Lee Y.S., Francis F., Hennig S., Thiel C., Lehrach H., RA Yaspo M.-L.; RT "An autoimmune disease, APECED, caused by mutations in a novel gene RT featuring two PHD-type zinc-finger domains."; RL Nat. Genet. 17:399-403(1997). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Lee Y.S., Francis F., Hennig S., Thiel C., Reinhard R., Lehrach H., RA Yaspo M.-L.; RL Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=10830953; DOI=10.1038/35012518; RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S., RA Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M., RA Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U., RA Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A., RA Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J., RA Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K., RA Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G., RA Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J., RA Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S., RA Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K., RA Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.; RT "The DNA sequence of human chromosome 21."; RL Nature 405:311-319(2000). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4). 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 project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP SUBCELLULAR LOCATION. RX PubMed=9931333; DOI=10.1093/hmg/8.2.259; RA Bjoerses P., Pelto-Huikko M., Kaukonen J., Aaltonen J., Peltonen L., RA Ulmanen I.; RT "Localization of the APECED protein in distinct nuclear structures."; RL Hum. Mol. Genet. 8:259-266(1999). RN [8] RP PARTIAL PROTEIN SEQUENCE, SUBUNIT STRUCTURE, DNA-BINDING, AND RP PHOSPHORYLATION. RX PubMed=11533054; DOI=10.1074/jbc.m104898200; RA Kumar P.G., Laloraya M., Wang C.-Y., Ruan Q.-G., Davoodi-Semiromi A., RA Kao K.-J., She J.-X.; RT "The autoimmune regulator (AIRE) is a DNA-binding protein."; RL J. Biol. Chem. 276:41357-41364(2001). RN [9] RP SUBCELLULAR LOCATION, AND VARIANTS APS1 LEU-80; CYS-85; TYR-311 AND RP GLN-326. RX PubMed=10677297; DOI=10.1086/302765; RA Bjeorses P., Halonen M., Palvimo J.J., Kolmer M., Aaltonen J., Ellonen P., RA Perheentupa J., Ulmanen I., Peltonen L.; RT "Mutations in the AIRE gene: effects on subcellular location and RT transactivation function of the autoimmune polyendocrinopathy-candidiasis- RT ectodermal dystrophy protein."; RL Am. J. Hum. Genet. 66:378-392(2000). RN [10] RP SUBCELLULAR LOCATION, FUNCTION, MUTAGENESIS OF CYS-302 AND CYS-437, AND RP CHARACTERIZATION OF VARIANT APS1 PRO-28. RX PubMed=11274163; DOI=10.1074/jbc.m008322200; RA Pitkaenen J., Vaehaemurto P., Krohn K.J.E., Peterson P.; RT "Subcellular localization of the autoimmune regulator protein. RT characterization of nuclear targeting and transcriptional activation RT domain."; RL J. Biol. Chem. 276:19597-19602(2001). RN [11] RP SUBCELLULAR LOCATION, HOMOOLIGOMERIZATION, AND CHARACTERIZATION OF VARIANTS RP APS1 LEU-15; MET-16; VAL-21; PRO-28; PRO-29; ARG-78; LEU-80; GLU-83; RP CYS-90; ARG-93; TRP-228 AND GLN-326. RX PubMed=14974083; DOI=10.1002/humu.20003; RA Halonen M., Kangas H., Rueppell T., Ilmarinen T., Ollila J., Kolmer M., RA Vihinen M., Palvimo J., Saarela J., Ulmanen I., Eskelin P.; RT "APECED-causing mutations in AIRE reveal the functional domains of the RT protein."; RL Hum. Mutat. 23:245-257(2004). RN [12] RP INTERACTION WITH HISTONE H3 NON-METHYLATED OR MONO-METHYLATED AT LYS-4, RP FUNCTION, MUTAGENESIS OF ASP-297 AND ASP-312, AND CHARACTERIZATION OF RP VARIANTS APS1 MET-301 AND TYR-311. RX PubMed=18292755; DOI=10.1038/sj.embor.2008.11; RA Org T., Chignola F., Hetenyi C., Gaetani M., Rebane A., Liiv I., Maran U., RA Mollica L., Bottomley M.J., Musco G., Peterson P.; RT "The autoimmune regulator PHD finger binds to non-methylated histone H3K4 RT to activate gene expression."; RL EMBO Rep. 9:370-376(2008). RN [13] RP REVIEW OF FUNCTION IN SELF-TOLERANCE. RX PubMed=19302042; DOI=10.1146/annurev.immunol.25.022106.141532; RA Mathis D., Benoist C.; RT "Aire."; RL Annu. Rev. Immunol. 27:287-312(2009). RN [14] RP TISSUE SPECIFICITY. RX PubMed=23993652; DOI=10.1016/j.immuni.2013.08.005; RA Gardner J.M., Metzger T.C., McMahon E.J., Au-Yeung B.B., Krawisz A.K., RA Lu W., Price J.D., Johannes K.P., Satpathy A.T., Murphy K.M., Tarbell K.V., RA Weiss A., Anderson M.S.; RT "Extrathymic Aire-expressing cells are a distinct bone marrow-derived RT population that induce functional inactivation of CD4[?] T cells."; RL Immunity 39:560-572(2013). RN [15] RP REVIEW OF FUNCTION IN SELF-TOLERANCE. RX PubMed=26972725; DOI=10.1038/nri.2016.9; RA Anderson M.S., Su M.A.; RT "AIRE expands: new roles in immune tolerance and beyond."; RL Nat. Rev. Immunol. 16:247-258(2016). RN [16] RP STRUCTURE BY NMR OF 293-354 IN COMPLEX WITH ZINC IONS, AND CHARACTERIZATION RP OF VARIANTS APS1 MET-301; TYR-311 AND GLN-326. RX PubMed=15649886; DOI=10.1074/jbc.m413959200; RA Bottomley M.J., Stier G., Pennacchini D., Legube G., Simon B., Akhtar A., RA Sattler M., Musco G.; RT "NMR structure of the first PHD finger of autoimmune regulator protein RT (AIRE1). Insights into autoimmune polyendocrinopathy-candidiasis-ectodermal RT dystrophy (APECED) disease."; RL J. Biol. Chem. 280:11505-11512(2005). RN [17] RP STRUCTURE BY NMR OF 293-354 IN COMPLEX WITH ZINC IONS AND UNMETHYLATED RP HISTONE H3 N-TERMINUS, IDENTIFICATION BY MASS SPECTROMETRY, MUTAGENESIS OF RP ASN-295; GLU-298; ARG-303; ASP-304 AND GLU-307, AND INTERACTION WITH RP HISTOME H3. RX PubMed=19293276; DOI=10.1093/nar/gkp166; RA Chignola F., Gaetani M., Rebane A., Org T., Mollica L., Zucchelli C., RA Spitaleri A., Mannella V., Peterson P., Musco G.; RT "The solution structure of the first PHD finger of autoimmune regulator in RT complex with non-modified histone H3 tail reveals the antagonistic role of RT H3R2 methylation."; RL Nucleic Acids Res. 37:2951-2961(2009). RN [18] RP STRUCTURE BY NMR OF 294-347 IN COMPLEX WITH ZINC IONS AND UNMETHYLATED RP HISTONE H3 N-TERMINUS, AND CHARACTERIZATION OF VARIANTS APS1 MET-301; RP TYR-311; LEU-326 AND GLN-326. RX PubMed=19446523; DOI=10.1016/j.str.2009.02.017; RA Chakravarty S., Zeng L., Zhou M.-M.; RT "Structure and site-specific recognition of histone H3 by the PHD finger of RT human autoimmune regulator."; RL Structure 17:670-679(2009). RN [19] RP VARIANT APS1 PRO-28. RX PubMed=9888391; RX DOI=10.1002/(sici)1098-1004(1999)13:1<69::aid-humu8>3.0.co;2-6; RA Heino M., Scott H.S., Chen Q., Peterson P., Maeenpaeae U., RA Papasavvas M.-P., Mittaz L., Barras C., Rossier C., Chrousos G.P., RA Stratakis C.A., Nagamine K., Kudoh J., Shimizu N., Maclaren N., RA Antonarakis S.E., Krohn K.J.E.; RT "Mutation analyses of North American APS-1 patients."; RL Hum. Mutat. 13:69-74(1999). RN [20] RP VARIANT ARG-278. RX PubMed=9717837; DOI=10.1210/mend.12.8.0143; RA Scott H.S., Heino M., Peterson P., Mittaz L., Lalioti M.D., Betterle C., RA Cohen A., Seri M., Lerone M., Romeo G., Collin P., Salo M., Metcalfe R., RA Weetman A., Papasavvas M.-P., Rossier C., Nagamine K., Kudoh J., RA Shimizu N., Krohn K.J.E., Antonarakis S.E.; RT "Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal RT dystrophy patients of different origins."; RL Mol. Endocrinol. 12:1112-1119(1998). RN [21] RP VARIANT APS1 LEU-326. RX PubMed=11275943; DOI=10.1530/eje.0.1440347; RA Saugier-Veber P., Drouot N., Wolf L.M., Kuhn J.M., Frebourg T., RA Lefebvre H.; RT "Identification of a novel mutation in the autoimmune regulator (AIRE-1) RT gene in a French family with autoimmune polyendocrinopathy-candidiasis- RT ectodermal dystrophy."; RL Eur. J. Endocrinol. 144:347-351(2001). RN [22] RP VARIANTS APS1 LEU-15; MET-16; PRO-28; PRO-29; ARG-78; LEU-80; GLU-83; RP CYS-85; CYS-90; ARG-93; MET-301; TYR-311 AND GLN-326, AND VARIANT ARG-278. RX PubMed=11524731; DOI=10.1002/humu.1176; RA Heino M., Peterson P., Kudoh J., Shimizu N., Antonarakis S.E., Scott H.S., RA Krohn K.J.E.; RT "APECED mutations in the autoimmune regulator (AIRE) gene."; RL Hum. Mutat. 18:205-211(2001). RN [23] RP VARIANTS APS1 MET-16 AND ARG-78. RX PubMed=11524733; DOI=10.1002/humu.1178; RG The MEWPE-APECED study group; RA Cihakova D., Trebusak K., Heino M., Fadeyev V., Tiulpakov A., Battelino T., RA Tar A., Halasz Z., Bluemel P., Tawfik S., Krohn K., Lebl J., Peterson P.; RT "Novel AIRE mutations and P450 cytochrome autoantibodies in Central and RT Eastern European patients with APECED."; RL Hum. Mutat. 18:225-232(2001). RN [24] RP VARIANT APS1 TRP-228. RX PubMed=11600535; DOI=10.1210/jcem.86.10.7884; RA Cetani F., Barbesino G., Borsari S., Pardi E., Cianferotti L., Pinchera A., RA Marcocci C.; RT "A novel mutation of the autoimmune regulator gene in an Italian kindred RT with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting RT in a dominant fashion and strongly cosegregating with hypothyroid RT autoimmune thyroiditis."; RL J. Clin. Endocrinol. Metab. 86:4747-4752(2001). RN [25] RP VARIANT APS1 PRO-29. RX PubMed=12173302; DOI=10.1006/clim.2002.5208; RA Kogawa K., Kudoh J., Nagafuchi S., Ohga S., Katsuta H., Ishibashi H., RA Harada M., Hara T., Shimizu N.; RT "Distinct clinical phenotype and immunoreactivity in Japanese siblings with RT autoimmune polyglandular syndrome type 1 (APS-1) associated with compound RT heterozygous novel AIRE gene mutations."; RL Clin. Immunol. 103:277-283(2002). RN [26] RP VARIANT APS1 CYS-15, AND VARIANT ARG-278. RX PubMed=12625412; DOI=10.1507/endocrj.49.625; RA Sato K., Nakajima K., Imamura H., Deguchi T., Horinouchi S., Yamazaki K., RA Yamada E., Kanaji Y., Takano K.; RT "A novel missense mutation of AIRE gene in a patient with autoimmune RT polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED), RT accompanied with progressive muscular atrophy: case report and review of RT the literature in Japan."; RL Endocr. J. 49:625-633(2002). RN [27] RP VARIANTS APS1 ARG-78; LEU-252 AND LEU-539. RX PubMed=11836330; DOI=10.1210/jcem.87.2.8209; RA Meloni A., Perniola R., Faa V., Corvaglia E., Cao A., Rosatelli M.C.; RT "Delineation of the molecular defects in the AIRE gene in autoimmune RT polyendocrinopathy-candidiasis-ectodermal dystrophy patients from Southern RT Italy."; RL J. Clin. Endocrinol. Metab. 87:841-846(2002). RN [28] RP VARIANTS APS1 VAL-21; CYS-85 AND TYR-311. RX PubMed=12050215; DOI=10.1210/jcem.87.6.8564; RA Halonen M., Eskelin P., Myhre A.-G., Perheentupa J., Husebye E.S., RA Kaempe O., Rorsman F., Peltonen L., Ulmanen I., Partanen J.; RT "AIRE mutations and human leukocyte antigen genotypes as determinants of RT the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy RT phenotype."; RL J. Clin. Endocrinol. Metab. 87:2568-2574(2002). RN [29] RP VARIANTS APS1 22-VAL-ASP-23 DEL; SER-77 AND ARG-78, AND CHARACTERIZATION OF RP VARIANTS APS1 LEU-15; MET-16; 22-VAL-ASP-23 DEL; SER-77 AND ARG-78. RX PubMed=15712268; DOI=10.1002/humu.9309; RA Meloni A., Fiorillo E., Corda D., Perniola R., Cao A., Rosatelli M.C.; RT "Two novel mutations of the AIRE protein affecting its homodimerization RT properties."; RL Hum. Mutat. 25:319-319(2005). RN [30] RP CHARACTERIZATION OF VARIANTS APS1 PRO-28; CYS-85; TRP-228 AND LEU-252. RX PubMed=16114041; DOI=10.1002/humu.20224; RA Ilmarinen T., Eskelin P., Halonen M., Rueppell T., Kilpikari R., RA Torres G.D., Kangas H., Ulmanen I.; RT "Functional analysis of SAND mutations in AIRE supports dominant RT inheritance of the G228W mutation."; RL Hum. Mutat. 26:322-331(2005). RN [31] RP INVOLVEMENT IN APS1, FUNCTION, SUBCELLULAR LOCATION, VARIANTS APS1 PRO-28; RP CYS-90; MET-301; TYR-311 AND LEU-326, CHARACTERIZATION OF VARIANTS PRO-28; RP CYS-90; MET-301; TYR-311 AND LEU-326, MUTAGENESIS OF 28-LEU-LEU-29; LEU-97; RP ASP-297; ARG-303; ASP-312; CYS-446 AND ARG-471, VARIANTS LYS-298; TRP-299; RP TYR-302; GLN-303; TRP-303; SER-305; ARG-306; MET-309; GLN-316; TRP-316; RP PRO-319; GLN-328; TRP-328; ARG-332 AND ALA-484, AND CHARACTERIZATION OF RP VARIANTS LYS-298; TYR-302; SER-305 AND GLN-328. RX PubMed=26084028; DOI=10.1016/j.immuni.2015.04.021; RA Oftedal B.E., Hellesen A., Erichsen M.M., Bratland E., Vardi A., RA Perheentupa J., Kemp E.H., Fiskerstrand T., Viken M.K., Weetman A.P., RA Fleishman S.J., Banka S., Newman W.G., Sewell W.A., Sozaeva L.S., RA Zayats T., Haugarvoll K., Orlova E.M., Haavik J., Johansson S., RA Knappskog P.M., Loevaas K., Wolff A.S., Abramson J., Husebye E.S.; RT "Dominant mutations in the autoimmune regulator AIRE are associated with RT common organ-specific autoimmune diseases."; RL Immunity 42:1185-1196(2015). RN [32] RP INVOLVEMENT IN APS1, AND FUNCTION. RX PubMed=27426947; DOI=10.1016/j.cell.2016.06.024; RG APECED patient collaborative; RA Meyer S., Woodward M., Hertel C., Vlaicu P., Haque Y., Kaerner J., RA Macagno A., Onuoha S.C., Fishman D., Peterson H., Metskuela K., Uibo R., RA Jaentti K., Hokynar K., Wolff A.S., Krohn K., Ranki A., Peterson P., RA Kisand K., Hayday A.; RT "AIRE-deficient patients harbor unique high-affinity disease-ameliorating RT autoantibodies."; RL Cell 166:582-595(2016). CC -!- FUNCTION: Transcription factor playing an essential role to promote CC self-tolerance in the thymus by regulating the expression of a wide CC array of self-antigens that have the commonality of being tissue- CC restricted in their expression pattern in the periphery, called tissue CC restricted antigens (TRA) (PubMed:26084028). Binds to G-doublets in an CC A/T-rich environment; the preferred motif is a tandem repeat of 5'- CC ATTGGTTA-3' combined with a 5'-TTATTA-3' box. Binds to nucleosomes (By CC similarity). Binds to chromatin and interacts selectively with histone CC H3 that is not methylated at 'Lys-4', not phosphorylated at 'Thr-3' and CC not methylated at 'Arg-2'. Functions as a sensor of histone H3 CC modifications that are important for the epigenetic regulation of gene CC expression. Mainly expressed by medullary thymic epithelial cells CC (mTECs), induces the expression of thousands of tissue-restricted CC proteins, which are presented on major histocompatibility complex class CC I (MHC-I) and MHC-II molecules to developing T-cells percolating CC through the thymic medulla (PubMed:26084028). Also induces self- CC tolerance through other mechanisms such as the regulation of the CC mTEC differentiation program. Controls the medullary accumulation of CC thymic dendritic cells and the development of regulatory T-cell through CC the regulation of XCL1 expression. Regulates the production of CCR4 and CC CCR7 ligands in medullary thymic epithelial cells and alters the CC coordinated maturation and migration of thymocytes. In thimic B-cells, CC allows the presentation of licensing-dependent endogenous self-anitgen CC for negative selection. In secondary lymphoid organs, induces CC functional inactivation of CD4(+) T-cells. Expressed by a distinct bone CC marrow-derived population, induces self-tolerance through a mechanism CC that does not require regulatory T-cells and is resitant to innate CC inflammatory stimuli (By similarity). {ECO:0000250|UniProtKB:Q9Z0E3, CC ECO:0000269|PubMed:11274163, ECO:0000269|PubMed:18292755, CC ECO:0000269|PubMed:26084028, ECO:0000305|PubMed:19302042, CC ECO:0000305|PubMed:26972725}. CC -!- SUBUNIT: Homodimer and homotetramer. Interacts with CREBBP. Interacts CC preferentially with histone H3 that is not methylated at 'Lys-4'. Binds CC with lower affinity to histone H3 that is monomethylated at 'Lys-4'. CC Trimethylation of histone H3 at 'Lys-4' or phosphorylation at 'Thr-3' CC abolish the interaction. Binds with lower affinity to histone H3 that CC is acetylated at 'Lys-4', or that is acetylated at 'Lys-9' or CC trimethylated at 'Lys-9'. Binds histone H3 that is dimethylated at CC 'Arg-2' with very low affinity. {ECO:0000269|PubMed:11533054, CC ECO:0000269|PubMed:15649886, ECO:0000269|PubMed:18292755, CC ECO:0000269|PubMed:19293276, ECO:0000269|PubMed:19446523}. CC -!- INTERACTION: CC O43918; O43918: AIRE; NbExp=3; IntAct=EBI-1753081, EBI-1753081; CC O43918; Q9UER7: DAXX; NbExp=5; IntAct=EBI-1753081, EBI-77321; CC O43918; P68431: H3C12; NbExp=20; IntAct=EBI-1753081, EBI-79722; CC O43918; P16333: NCK1; NbExp=2; IntAct=EBI-1753081, EBI-389883; CC O43918; P78527: PRKDC; NbExp=2; IntAct=EBI-1753081, EBI-352053; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:14974083, CC ECO:0000269|PubMed:26084028}. Cytoplasm {ECO:0000269|PubMed:11274163, CC ECO:0000269|PubMed:14974083}. Note=Predominantly nuclear but also CC cytoplasmic (PubMed:11274163, PubMed:14974083). Found in nuclear body- CC like structures (dots) and in a filamentous vimentin-like pattern CC (PubMed:11274163, PubMed:14974083, PubMed:26084028). Associated with CC tubular structures (PubMed:11274163, PubMed:14974083). CC {ECO:0000269|PubMed:11274163, ECO:0000269|PubMed:14974083, CC ECO:0000269|PubMed:26084028}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Comment=Additional isoforms seem to exist. Experimental confirmation CC may be lacking for some isoforms.; CC Name=1; Synonyms=AIRE-1; CC IsoId=O43918-1; Sequence=Displayed; CC Name=2; Synonyms=AIRE-2; CC IsoId=O43918-2; Sequence=VSP_004089; CC Name=3; Synonyms=AIRE-3; CC IsoId=O43918-3; Sequence=VSP_004089, VSP_004090; CC Name=4; CC IsoId=O43918-4; Sequence=VSP_004089, VSP_043529; CC -!- TISSUE SPECIFICITY: Widely expressed. Expressed at higher level in CC thymus (medullary epithelial cells and monocyte-dendritic cells), CC pancreas, adrenal cortex and testis. Expressed at lower level in the CC spleen, fetal liver and lymph nodes. In secondary lymphoid organs, CC expressed in a discrete population of bone marrow-derived toleregenic CC antigen presenting cells (APCs) called extrathymic AIRE expressing CC cells (eTAC)(at protein level) (PubMed:23993652). Isoform 2 and isoform CC 3 seem to be less frequently expressed than isoform 1, if at all. CC {ECO:0000269|PubMed:23993652}. CC -!- DOMAIN: The L-X-X-L-L repeats may be implicated in binding to nuclear CC receptors. CC -!- DOMAIN: The HSR domain is required for localization on tubular CC structures (N-terminal part) and for homodimerization. CC -!- DOMAIN: Interacts via the first PHD domain with the N-terminus of CC histone H3 that is not methylated at 'Lys-4'. Disruption of the first CC PHD domain has been shown to lead to reduced transcriptional activity CC and to localization of the protein mainly in the cytoplasm in small CC granules. While the PHD zinc fingers are necessary for the CC transactivation capacity of the protein, other regions also modulate CC this function. CC -!- PTM: Phosphorylated. Phosphorylation could trigger oligomerization. CC {ECO:0000269|PubMed:11533054}. CC -!- DISEASE: Autoimmune polyendocrine syndrome 1, with or without CC reversible metaphyseal dysplasia (APS1) [MIM:240300]: A rare disease CC characterized by the combination of chronic mucocutaneous candidiasis, CC hypoparathyroidism and Addison disease. Symptoms of mucocutaneous CC candidiasis manifest first, followed by hypotension or fatigue CC occurring as a result of Addison disease. APS1 is associated with other CC autoimmune disorders including diabetes mellitus, vitiligo, alopecia, CC hepatitis, pernicious anemia and primary hypothyroidism. CC {ECO:0000269|PubMed:10677297, ECO:0000269|PubMed:11274163, CC ECO:0000269|PubMed:11275943, ECO:0000269|PubMed:11524731, CC ECO:0000269|PubMed:11524733, ECO:0000269|PubMed:11600535, CC ECO:0000269|PubMed:11836330, ECO:0000269|PubMed:12050215, CC ECO:0000269|PubMed:12173302, ECO:0000269|PubMed:12625412, CC ECO:0000269|PubMed:14974083, ECO:0000269|PubMed:15649886, CC ECO:0000269|PubMed:15712268, ECO:0000269|PubMed:16114041, CC ECO:0000269|PubMed:18292755, ECO:0000269|PubMed:19446523, CC ECO:0000269|PubMed:26084028, ECO:0000269|PubMed:27426947, CC ECO:0000269|PubMed:9398839, ECO:0000269|PubMed:9888391}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. Most of the mutations alter the nucleus-cytoplasm distribution CC of AIRE and disturb its association with nuclear dots and cytoplasmic CC filaments. Most of the mutations also decrease transactivation of the CC protein. The HSR domain is responsible for the homomultimerization CC activity of AIRE. All the missense mutations of the HSR and the SAND CC domains decrease this activity, but those in other domains do not. The CC AIRE protein is present in soluble high-molecular-weight complexes. CC Mutations in the HSR domain and deletion of PHD zinc fingers disturb CC the formation of these complexes (PubMed:14974083). Heterozygous CC mutations within the PHD1 domain have dominant-negative effects and CC cause organ-specific autoimmune diseases (PubMed:26084028). Patients CC harbor extremely high-affinity, neutralizing autoantibodies, CC particularly against specific cytokines such as type I interferons CC which could protect them from some types of autoimmune diseases, like CC type I diabetes (PubMed:27426947). {ECO:0000269|PubMed:14974083, CC ECO:0000269|PubMed:26084028, ECO:0000269|PubMed:27426947}. CC -!- WEB RESOURCE: Name=Mendelian genes autoimmune regulator (AIRE); CC Note=Leiden Open Variation Database (LOVD); CC URL="https://databases.lovd.nl/shared/genes/AIRE"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB006682; BAA23988.1; -; mRNA. DR EMBL; AB006683; BAA23989.1; -; mRNA. DR EMBL; AB006684; BAA23990.1; -; Genomic_DNA. DR EMBL; AB006684; BAA23991.1; -; Genomic_DNA. DR EMBL; AB006684; BAA23992.1; -; Genomic_DNA. DR EMBL; AB006685; BAA23993.1; -; mRNA. DR EMBL; Z97990; CAB10790.1; -; mRNA. DR EMBL; AJ009610; CAA08759.1; -; Genomic_DNA. DR EMBL; AP001754; BAA95560.1; -; Genomic_DNA. DR EMBL; AP001060; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471079; EAX09443.1; -; Genomic_DNA. DR EMBL; BC137268; AAI37269.1; -; mRNA. DR EMBL; BC137270; AAI37271.1; -; mRNA. DR CCDS; CCDS13706.1; -. [O43918-1] DR RefSeq; NP_000374.1; NM_000383.4. [O43918-1] DR PDB; 1XWH; NMR; -; A=293-354. DR PDB; 2KE1; NMR; -; A=293-354. DR PDB; 2KFT; NMR; -; A=294-347. DR PDB; 2LRI; NMR; -; C=423-485. DR PDBsum; 1XWH; -. DR PDBsum; 2KE1; -. DR PDBsum; 2KFT; -. DR PDBsum; 2LRI; -. DR AlphaFoldDB; O43918; -. DR BMRB; O43918; -. DR SMR; O43918; -. DR BioGRID; 106823; 104. DR CORUM; O43918; -. DR DIP; DIP-47504N; -. DR FunCoup; O43918; 730. DR IntAct; O43918; 39. DR MINT; O43918; -. DR STRING; 9606.ENSP00000291582; -. DR iPTMnet; O43918; -. DR PhosphoSitePlus; O43918; -. DR BioMuta; AIRE; -. DR jPOST; O43918; -. DR MassIVE; O43918; -. DR PaxDb; 9606-ENSP00000291582; -. DR PeptideAtlas; O43918; -. DR Antibodypedia; 10157; 632 antibodies from 41 providers. DR DNASU; 326; -. DR Ensembl; ENST00000291582.6; ENSP00000291582.5; ENSG00000160224.18. [O43918-1] DR GeneID; 326; -. DR KEGG; hsa:326; -. DR MANE-Select; ENST00000291582.6; ENSP00000291582.5; NM_000383.4; NP_000374.1. DR UCSC; uc002zei.4; human. [O43918-1] DR AGR; HGNC:360; -. DR ClinPGx; PA24654; -. DR CTD; 326; -. DR DisGeNET; 326; -. DR GeneCards; AIRE; -. DR HGNC; HGNC:360; AIRE. DR HPA; ENSG00000160224; Tissue enhanced (lymphoid). DR MalaCards; AIRE; -. DR MIM; 109100; phenotype. DR MIM; 240300; phenotype. DR MIM; 607358; gene. DR OpenTargets; ENSG00000160224; -. DR Orphanet; 3453; Autoimmune polyendocrinopathy type 1. DR Orphanet; 189466; Familial isolated hypoparathyroidism due to impaired PTH secretion. DR VEuPathDB; HostDB:ENSG00000160224; -. DR eggNOG; KOG0383; Eukaryota. DR GeneTree; ENSGT00940000161104; -. DR HOGENOM; CLU_042233_1_0_1; -. DR InParanoid; O43918; -. DR OMA; DVLRCTH; -. DR OrthoDB; 787137at2759; -. DR PAN-GO; O43918; 11 GO annotations based on evolutionary models. DR PhylomeDB; O43918; -. DR PathwayCommons; O43918; -. DR SignaLink; O43918; -. DR SIGNOR; O43918; -. DR Agora; ENSG00000160224; -. DR BioGRID-ORCS; 326; 11 hits in 1166 CRISPR screens. DR EvolutionaryTrace; O43918; -. DR GeneWiki; Autoimmune_regulator; -. DR GenomeRNAi; 326; -. DR Pharos; O43918; Tbio. DR PRO; PR:O43918; -. DR Proteomes; UP000005640; Chromosome 21. DR RNAct; O43918; protein. DR Bgee; ENSG00000160224; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 78 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0001674; C:female germ cell nucleus; IEA:Ensembl. DR GO; GO:0001673; C:male germ cell nucleus; IEA:Ensembl. DR GO; GO:0016604; C:nuclear body; ISS:UniProtKB. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0003682; F:chromatin binding; IDA:UniProtKB. DR GO; GO:0042393; F:histone binding; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IDA:NTNU_SB. DR GO; GO:0045182; F:translation regulator activity; IEA:InterPro. DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB. DR GO; GO:0002509; P:central tolerance induction to self antigen; IMP:UniProtKB. DR GO; GO:0006959; P:humoral immune response; IBA:GO_Central. DR GO; GO:0006955; P:immune response; TAS:ProtInc. DR GO; GO:0045060; P:negative thymic T cell selection; IBA:GO_Central. DR GO; GO:0002458; P:peripheral T cell tolerance induction; ISS:UniProtKB. DR GO; GO:0032722; P:positive regulation of chemokine production; ISS:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IMP:NTNU_SB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:2000410; P:regulation of thymocyte migration; ISS:UniProtKB. DR GO; GO:0097536; P:thymus epithelium morphogenesis; ISS:UniProtKB. DR GO; GO:0006366; P:transcription by RNA polymerase II; IEA:Ensembl. DR CDD; cd15539; PHD1_AIRE; 1. DR CDD; cd15540; PHD2_AIRE; 1. DR FunFam; 3.10.390.10:FF:000006; Autoimmune regulator; 1. DR FunFam; 3.30.40.10:FF:000374; Autoimmune regulator; 1. DR FunFam; 3.30.40.10:FF:000446; Autoimmune regulator; 1. DR Gene3D; 3.10.390.10; SAND domain-like; 1. DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 2. DR InterPro; IPR008087; AIRE. DR InterPro; IPR042580; AIRE_PHD2. DR InterPro; IPR004865; HSR_dom. DR InterPro; IPR010919; SAND-like_dom_sf. DR InterPro; IPR000770; SAND_dom. DR InterPro; IPR043563; Sp110/Sp140/Sp140L-like. DR InterPro; IPR019786; Zinc_finger_PHD-type_CS. DR InterPro; IPR011011; Znf_FYVE_PHD. DR InterPro; IPR001965; Znf_PHD. DR InterPro; IPR019787; Znf_PHD-finger. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR PANTHER; PTHR46386:SF11; AUTOIMMUNE REGULATOR; 1. DR PANTHER; PTHR46386; NUCLEAR BODY PROTEIN SP140; 1. DR Pfam; PF03172; HSR; 1. DR Pfam; PF00628; PHD; 1. DR Pfam; PF01342; SAND; 1. DR PRINTS; PR01711; AIREGULATOR. DR SMART; SM00249; PHD; 2. DR SMART; SM00258; SAND; 1. DR SUPFAM; SSF57903; FYVE/PHD zinc finger; 2. DR SUPFAM; SSF63763; SAND domain-like; 1. DR PROSITE; PS51414; HSR; 1. DR PROSITE; PS50864; SAND; 1. DR PROSITE; PS01359; ZF_PHD_1; 2. DR PROSITE; PS50016; ZF_PHD_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Activator; Alternative splicing; Cytoplasm; KW Direct protein sequencing; Disease variant; DNA-binding; Metal-binding; KW Nucleus; Phosphoprotein; Proteomics identification; Reference proteome; KW Repeat; Transcription; Transcription regulation; Zinc; Zinc-finger. FT CHAIN 1..545 FT /note="Autoimmune regulator" FT /id="PRO_0000064513" FT DOMAIN 1..105 FT /note="HSR" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00747" FT DOMAIN 181..280 FT /note="SAND" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00185" FT ZN_FING 296..343 FT /note="PHD-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00146" FT ZN_FING 434..475 FT /note="PHD-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00146" FT REGION 101..178 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 234..290 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 295..298 FT /note="Interaction with histone H3 not methylated at 'Lys- FT 4'" FT REGION 304..312 FT /note="Interaction with histone H3 not methylated at 'Lys- FT 4'" FT REGION 331..335 FT /note="Interaction with histone H3 not methylated at 'Lys- FT 4'" FT REGION 348..382 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 489..508 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 7..11 FT /note="LXXLL motif 1" FT MOTIF 63..67 FT /note="LXXLL motif 2" FT MOTIF 414..418 FT /note="LXXLL motif 3" FT MOTIF 516..520 FT /note="LXXLL motif 4" FT COMPBIAS 116..128 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 140..152 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 358..368 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VAR_SEQ 1..292 FT /note="MATDAALRRLLRLHRTEIAVAVDSAFPLLHALADHDVVPEDKFQETLHLKEK FT EGCPQAFHALLSWLLTQDSTAILDFWRVLFKDYNLERYGRLQPILDSFPKDVDLSQPRK FT GRKPPAVPKALVPPPRLPTKRKASEEARAAAPAALTPRGTASPGSQLKAKPPKKPESSA FT EQQRLPLGNGIQTMSASVQRAVAMSSGDVPGARGAVEGILIQQVFESGGSKKCIQVGGE FT FYTPSKFEDSGSGKNKARSSSGPKPLVRAKGAQGAAPGGGEARLGQQGSVPAPLALPSD FT PQLH -> MWLVYSSGAPGTQQPARNRVFFPIGMAPGGVCWRPDGWGTGGQGRISGPGS FT MGAGQRLGSSGTQRCCWGSCFGKEVALRRVLHPS (in isoform 2, isoform 3 FT and isoform 4)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:9398839" FT /id="VSP_004089" FT VAR_SEQ 293 FT /note="Q -> PVCMGVSCLCQ (in isoform 4)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_043529" FT VAR_SEQ 377..545 FT /note="VRGPPGEPLAGMDTTLVYKHLPAPPSAAPLPGLDSSALHPLLCVGPEGQQNL FT APGARCGVCGDGTDVLRCTHCAAAFHWRCHFPAGTSRPGTGLRCRSCSGDVTPAPVEGV FT LAPSPARLAPGPAKDDTASHEPALHRDDLESLLSEHTFDGILQWAIQSMARPAAPFPS FT -> PRCQGWTPRPCTPYCVWVLRVSRTWLLVRVAGCAEMVRTCCGVLTAPLPSTGAATS FT QPAPPGPGRACAADPAQET (in isoform 3)" FT /evidence="ECO:0000303|PubMed:9398839" FT /id="VSP_004090" FT VARIANT 15 FT /note="R -> C (in APS1; dbSNP:rs179363875)" FT /evidence="ECO:0000269|PubMed:12625412" FT /id="VAR_026480" FT VARIANT 15 FT /note="R -> L (in APS1; prevents homooligomerization; FT slightly alters subcellular localization; no effect on the FT transcriptional transactivation activity; FT dbSNP:rs179363876)" FT /evidence="ECO:0000269|PubMed:11524731, FT ECO:0000269|PubMed:14974083, ECO:0000269|PubMed:15712268" FT /id="VAR_013713" FT VARIANT 16 FT /note="T -> M (in APS1; prevents homooligomerization; FT slightly alters subcellular localization; no effect on the FT transcriptional transactivation activity; FT dbSNP:rs179363877)" FT /evidence="ECO:0000269|PubMed:11524731, FT ECO:0000269|PubMed:11524733, ECO:0000269|PubMed:14974083, FT ECO:0000269|PubMed:15712268" FT /id="VAR_013714" FT VARIANT 21 FT /note="A -> V (in APS1; no effect on homooligomerization; FT no effect on subcellular localization; no effect on the FT transcriptional transactivation activity; FT dbSNP:rs179363886)" FT /evidence="ECO:0000269|PubMed:12050215, FT ECO:0000269|PubMed:14974083" FT /id="VAR_026481" FT VARIANT 22..23 FT /note="Missing (in APS1; prevents homodimerization)" FT /evidence="ECO:0000269|PubMed:15712268" FT /id="VAR_026482" FT VARIANT 28 FT /note="L -> P (in APS1; abolishes association with FT cytoplasmic tubular structures and homodimerization; loss FT of doted nuclear localization; nuclear smear; severe FT decrease of transcriptional transactivation activity; FT dbSNP:rs179363878)" FT /evidence="ECO:0000269|PubMed:11274163, FT ECO:0000269|PubMed:11524731, ECO:0000269|PubMed:14974083, FT ECO:0000269|PubMed:16114041, ECO:0000269|PubMed:26084028, FT ECO:0000269|PubMed:9888391" FT /id="VAR_005004" FT VARIANT 29 FT /note="L -> P (in APS1; dbSNP:rs179363879)" FT /evidence="ECO:0000269|PubMed:12173302, FT ECO:0000269|PubMed:14974083" FT /id="VAR_013715" FT VARIANT 77 FT /note="F -> S (in APS1; loss of homooligomerization; FT dbSNP:rs179363887)" FT /evidence="ECO:0000269|PubMed:15712268" FT /id="VAR_026483" FT VARIANT 78 FT /note="W -> R (in APS1; loss of homooligomerization; FT dbSNP:rs179363880)" FT /evidence="ECO:0000269|PubMed:11524731, FT ECO:0000269|PubMed:11524733, ECO:0000269|PubMed:11836330, FT ECO:0000269|PubMed:14974083, ECO:0000269|PubMed:15712268" FT /id="VAR_013716" FT VARIANT 80 FT /note="V -> L (in APS1; dbSNP:rs179363881)" FT /evidence="ECO:0000269|PubMed:10677297, FT ECO:0000269|PubMed:11524731, ECO:0000269|PubMed:14974083" FT /id="VAR_013717" FT VARIANT 83 FT /note="K -> E (in APS1; dbSNP:rs121434255)" FT /evidence="ECO:0000269|PubMed:11524731, FT ECO:0000269|PubMed:14974083, ECO:0000269|PubMed:9398839" FT /id="VAR_005005" FT VARIANT 85 FT /note="Y -> C (in APS1; no significant effect on FT transcriptional transactivation activity; FT dbSNP:rs179363882)" FT /evidence="ECO:0000269|PubMed:10677297, FT ECO:0000269|PubMed:11524731, ECO:0000269|PubMed:12050215, FT ECO:0000269|PubMed:16114041" FT /id="VAR_013718" FT VARIANT 90 FT /note="Y -> C (in APS1; decreases doted nuclear FT localization; dbSNP:rs179363883)" FT /evidence="ECO:0000269|PubMed:11524731, FT ECO:0000269|PubMed:14974083, ECO:0000269|PubMed:26084028" FT /id="VAR_013719" FT VARIANT 93 FT /note="L -> R (in APS1; dbSNP:rs179363884)" FT /evidence="ECO:0000269|PubMed:11524731, FT ECO:0000269|PubMed:14974083" FT /id="VAR_013720" FT VARIANT 228 FT /note="G -> W (in APS1; changes the subcellular FT localization and in addition disrupts the transactivating FT capacity of the wild-type AIRE; acts with a dominant FT negative effect by binding to the wild-type AIRE thus FT preventing the protein from forming the complexes needed FT for transactivation; dbSNP:rs121434257)" FT /evidence="ECO:0000269|PubMed:11600535, FT ECO:0000269|PubMed:14974083, ECO:0000269|PubMed:16114041" FT /id="VAR_014422" FT VARIANT 252 FT /note="P -> L (in APS1; benign; does not affect FT transcriptional transactivation activity; FT dbSNP:rs34397615)" FT /evidence="ECO:0000269|PubMed:11836330, FT ECO:0000269|PubMed:16114041" FT /id="VAR_026484" FT VARIANT 278 FT /note="S -> R (in dbSNP:rs1800520)" FT /evidence="ECO:0000269|PubMed:11524731, FT ECO:0000269|PubMed:12625412, ECO:0000269|PubMed:9717837" FT /id="VAR_005006" FT VARIANT 298 FT /note="E -> K (in dbSNP:rs763636007)" FT /evidence="ECO:0000269|PubMed:26084028" FT /id="VAR_076940" FT VARIANT 299 FT /note="C -> W (in dbSNP:rs751066946)" FT /evidence="ECO:0000269|PubMed:26084028" FT /id="VAR_076941" FT VARIANT 301 FT /note="V -> M (in APS1; no effect on protein structure or FT on interaction with histone H3; no effect on doted nuclear FT localization; dominant-negative effect on regulation of FT target gene transcription; dbSNP:rs150634562)" FT /evidence="ECO:0000269|PubMed:11524731, FT ECO:0000269|PubMed:15649886, ECO:0000269|PubMed:18292755, FT ECO:0000269|PubMed:19446523, ECO:0000269|PubMed:26084028" FT /id="VAR_013721" FT VARIANT 302 FT /note="C -> Y (found in patients with hypothyroidism and FT organ- and cytokine-specific autoantibodies; no effect on FT doted nuclear localization; dominant-negative effect on FT regulation of target gene transcription)" FT /evidence="ECO:0000269|PubMed:26084028" FT /id="VAR_076942" FT VARIANT 303 FT /note="R -> Q (in dbSNP:rs139808903)" FT /evidence="ECO:0000269|PubMed:26084028" FT /id="VAR_076943" FT VARIANT 303 FT /note="R -> W (in dbSNP:rs778929451)" FT /evidence="ECO:0000269|PubMed:26084028" FT /id="VAR_076944" FT VARIANT 305 FT /note="G -> S (found in a patient with pernicious anemia FT and neuropathy; uncertain significance; no effect on doted FT nuclear localization; dominant-negative effect on FT regulation of target gene transcription)" FT /evidence="ECO:0000269|PubMed:26084028" FT /id="VAR_013722" FT VARIANT 306 FT /note="G -> R (in dbSNP:rs754932526)" FT /evidence="ECO:0000269|PubMed:26084028" FT /id="VAR_076945" FT VARIANT 309 FT /note="I -> M (in dbSNP:rs74162062)" FT /evidence="ECO:0000269|PubMed:26084028" FT /id="VAR_076946" FT VARIANT 311 FT /note="C -> Y (in APS1; impairs zinc binding and folding of FT the PHD-type 1 zinc finger; dominant-negative effect on the FT regulation of target gene transcription; no effect on doted FT nuclear localization; dominant-negative effect on FT regulation of target gene transcription; FT dbSNP:rs386833674)" FT /evidence="ECO:0000269|PubMed:10677297, FT ECO:0000269|PubMed:11524731, ECO:0000269|PubMed:12050215, FT ECO:0000269|PubMed:15649886, ECO:0000269|PubMed:18292755, FT ECO:0000269|PubMed:19446523, ECO:0000269|PubMed:26084028" FT /id="VAR_013723" FT VARIANT 316 FT /note="R -> Q (in dbSNP:rs202027254)" FT /evidence="ECO:0000269|PubMed:26084028" FT /id="VAR_076947" FT VARIANT 316 FT /note="R -> W (found in a patient with pernicious anemia; FT uncertain significance; dbSNP:rs139874934)" FT /evidence="ECO:0000269|PubMed:26084028" FT /id="VAR_076948" FT VARIANT 319 FT /note="H -> P (in dbSNP:rs776951380)" FT /evidence="ECO:0000269|PubMed:26084028" FT /id="VAR_076949" FT VARIANT 326 FT /note="P -> L (in APS1; no significant effect on structure, FT but may alter protein interactions; no effect on doted FT nuclear localization; dominant-negative effect on FT regulation of target gene transcription; FT dbSNP:rs179363885)" FT /evidence="ECO:0000269|PubMed:11275943, FT ECO:0000269|PubMed:19446523, ECO:0000269|PubMed:26084028" FT /id="VAR_026485" FT VARIANT 326 FT /note="P -> Q (in APS1; alters folding of the PHD-type 1 FT zinc finger; dbSNP:rs179363885)" FT /evidence="ECO:0000269|PubMed:10677297, FT ECO:0000269|PubMed:11524731, ECO:0000269|PubMed:14974083, FT ECO:0000269|PubMed:15649886, ECO:0000269|PubMed:19446523" FT /id="VAR_013724" FT VARIANT 328 FT /note="R -> Q (found in a patient with acrofacial vitiligo FT and gastric parietal cell autoantibodies; no effect on FT doted nuclear localization; dominant-negative effect on FT regulation of target gene transcription; FT dbSNP:rs775921321)" FT /evidence="ECO:0000269|PubMed:26084028" FT /id="VAR_076950" FT VARIANT 328 FT /note="R -> W (in dbSNP:rs74162063)" FT /evidence="ECO:0000269|PubMed:26084028" FT /id="VAR_076951" FT VARIANT 332 FT /note="S -> R (in dbSNP:rs766901260)" FT /evidence="ECO:0000269|PubMed:26084028" FT /id="VAR_076952" FT VARIANT 484 FT /note="V -> A (found in a patient with acrofacial vitiligo FT and gastric parietal cell autoantibodies; uncertain FT significance; dbSNP:rs769470638)" FT /evidence="ECO:0000269|PubMed:26084028" FT /id="VAR_076953" FT VARIANT 539 FT /note="P -> L (in APS1; dbSNP:rs179363889)" FT /evidence="ECO:0000269|PubMed:11836330" FT /id="VAR_026486" FT MUTAGEN 28..29 FT /note="LL->PP: Loss of doted nuclear location, forms FT nuclear smears. Loss of transactivation activity on target FT genes transcription." FT /evidence="ECO:0000269|PubMed:26084028" FT MUTAGEN 97 FT /note="L->P: Loss of transactivation activity on target FT gene transcription; no dominant-negative effect on target FT gene transcription. Loss of doted nuclear localization." FT /evidence="ECO:0000269|PubMed:26084028" FT MUTAGEN 295 FT /note="N->A: Abolishes interaction with histone H3." FT /evidence="ECO:0000269|PubMed:19293276" FT MUTAGEN 297 FT /note="D->A: Strongly reduces interaction with unmethylated FT histone H3 and abolishes interaction with histone H3 FT trimethylated at 'Lys-4'. No effect on doted nuclear FT localization. Dominant-negative effect on target gene FT transcription." FT /evidence="ECO:0000269|PubMed:18292755, FT ECO:0000269|PubMed:26084028" FT MUTAGEN 298 FT /note="E->A: Reduces interaction with histone H3." FT /evidence="ECO:0000269|PubMed:19293276" FT MUTAGEN 302 FT /note="C->P: Reduces transcriptional activation." FT /evidence="ECO:0000269|PubMed:11274163" FT MUTAGEN 303 FT /note="R->P: Alters protein folding and abolishes FT interaction with histone H3. No effect on doted nuclear FT localization. Dominant-negative effect on target gene FT transcription." FT /evidence="ECO:0000269|PubMed:19293276, FT ECO:0000269|PubMed:26084028" FT MUTAGEN 304 FT /note="D->A: Strongly reduces interaction with histone H3." FT /evidence="ECO:0000269|PubMed:19293276" FT MUTAGEN 307 FT /note="E->A: Reduces interaction with histone H3." FT /evidence="ECO:0000269|PubMed:19293276" FT MUTAGEN 312 FT /note="D->A: Abolishes interaction with histone H3." FT /evidence="ECO:0000269|PubMed:18292755" FT MUTAGEN 312 FT /note="D->N: No effect on doted nuclear localization. FT Dominant-negative effect on target gene transcription." FT /evidence="ECO:0000269|PubMed:26084028" FT MUTAGEN 437 FT /note="C->P: Reduces transcription activation." FT /evidence="ECO:0000269|PubMed:11274163" FT MUTAGEN 446 FT /note="C->G: Dominant-negative effect on regulation of FT target gene transcription." FT /evidence="ECO:0000269|PubMed:26084028" FT MUTAGEN 471 FT /note="R->C: No effect on regulation of target gene FT transcription." FT /evidence="ECO:0000269|PubMed:26084028" FT CONFLICT 437..467 FT /note="CGDGTDVLRCTHCAAAFHWRCHFPAGTSRPG -> W (in Ref. 3; FT CAA08759)" FT /evidence="ECO:0000305" FT STRAND 298..303 FT /evidence="ECO:0007829|PDB:1XWH" FT STRAND 306..310 FT /evidence="ECO:0007829|PDB:2KE1" FT STRAND 312..314 FT /evidence="ECO:0007829|PDB:2KE1" FT STRAND 317..319 FT /evidence="ECO:0007829|PDB:2KE1" FT TURN 320..322 FT /evidence="ECO:0007829|PDB:1XWH" FT STRAND 323..325 FT /evidence="ECO:0007829|PDB:1XWH" FT HELIX 338..342 FT /evidence="ECO:0007829|PDB:1XWH" FT TURN 423..426 FT /evidence="ECO:0007829|PDB:2LRI" FT TURN 435..437 FT /evidence="ECO:0007829|PDB:2LRI" FT STRAND 447..449 FT /evidence="ECO:0007829|PDB:2LRI" FT HELIX 455..458 FT /evidence="ECO:0007829|PDB:2LRI" FT TURN 460..462 FT /evidence="ECO:0007829|PDB:2LRI" FT STRAND 467..469 FT /evidence="ECO:0007829|PDB:2LRI" FT TURN 473..476 FT /evidence="ECO:0007829|PDB:2LRI" SQ SEQUENCE 545 AA; 57727 MW; 8CF703F8C9411BC5 CRC64; MATDAALRRL LRLHRTEIAV AVDSAFPLLH ALADHDVVPE DKFQETLHLK EKEGCPQAFH ALLSWLLTQD STAILDFWRV LFKDYNLERY GRLQPILDSF PKDVDLSQPR KGRKPPAVPK ALVPPPRLPT KRKASEEARA AAPAALTPRG TASPGSQLKA KPPKKPESSA EQQRLPLGNG IQTMSASVQR AVAMSSGDVP GARGAVEGIL IQQVFESGGS KKCIQVGGEF YTPSKFEDSG SGKNKARSSS GPKPLVRAKG AQGAAPGGGE ARLGQQGSVP APLALPSDPQ LHQKNEDECA VCRDGGELIC CDGCPRAFHL ACLSPPLREI PSGTWRCSSC LQATVQEVQP RAEEPRPQEP PVETPLPPGL RSAGEEVRGP PGEPLAGMDT TLVYKHLPAP PSAAPLPGLD SSALHPLLCV GPEGQQNLAP GARCGVCGDG TDVLRCTHCA AAFHWRCHFP AGTSRPGTGL RCRSCSGDVT PAPVEGVLAP SPARLAPGPA KDDTASHEPA LHRDDLESLL SEHTFDGILQ WAIQSMARPA APFPS //