Positional cloning of the APECED gene.

true 1998-07-15 2008-07-22 89 AIRE_HUMAN Autoimmune regulator Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy protein APECED protein Positional cloning of the APECED gene. Nagamine K. Peterson P. Scott H.S. Kudoh J. Minoshima S. Heino M. Krohn K.J.E. Lalioti M.D. Mullis P.E. Antonarakis S.E. Kawasaki K. Asakawa S. Ito F. Shimizu N. doi:10.1038/ng1297-393 1997 Nat. Genet. 17 393-398 NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1; 2 AND 3) VARIANT APECED GLU-83 Thymus An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Aaltonen J. Bjoerses P. Perheentupa J. Horelli-Kuitunen N. Palotie A. Peltonen L. Lee Y.S. Francis F. Hennig S. Thiel C. Lehrach H. Yaspo M.-L. 1997 Nat. Genet. 17 399-403 NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1) Thymus Lee Y.S. Francis F. Hennig S. Thiel C. Reinhard R. Lehrach H. Yaspo M.-L. 1998-07 EMBL/GenBank/DDBJ NUCLEOTIDE SEQUENCE [GENOMIC DNA] The DNA sequence of human chromosome 21. Hattori M. Fujiyama A. Taylor T.D. Watanabe H. Yada T. Park H.-S. Toyoda A. Ishii K. Totoki Y. Choi D.-K. Groner Y. Soeda E. Ohki M. Takagi T. Sakaki Y. Taudien S. Blechschmidt K. Polley A. Menzel U. Delabar J. Kumpf K. Lehmann R. Patterson D. Reichwald K. Rump A. Schillhabel M. Schudy A. Zimmermann W. Rosenthal A. Kudoh J. Shibuya K. Kawasaki K. Asakawa S. Shintani A. Sasaki T. Nagamine K. Mitsuyama S. Antonarakis S.E. Minoshima S. Shimizu N. Nordsiek G. Hornischer K. Brandt P. Scharfe M. Schoen O. Desario A. Reichelt J. Kauer G. Bloecker H. Ramser J. Beck A. Klages S. Hennig S. Riesselmann L. Dagand E. Wehrmeyer S. Borzym K. Gardiner K. Nizetic D. Francis F. Lehrach H. Reinhardt R. Yaspo M.-L. doi:10.1038/35012518 2000 Nature 405 311-319 NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] Localization of the APECED protein in distinct nuclear structures. Bjoerses P. Pelto-Huikko M. Kaukonen J. Aaltonen J. Peltonen L. Ulmanen I. doi:10.1093/hmg/8.2.259 1999 Hum. Mol. Genet. 8 259-266 SUBCELLULAR LOCATION The autoimmune regulator (AIRE) is a DNA-binding protein. Kumar P.G. Laloraya M. Wang C.-Y. Ruan Q.-G. Davoodi-Semiromi A. Kao K.-J. She J.-X. doi:10.1074/jbc.M104898200 2001 J. Biol. Chem. 276 41357-41364 PARTIAL PROTEIN SEQUENCE SUBUNIT STRUCTURE DNA-BINDING PHOSPHORYLATION Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein. Bjeorses P. Halonen M. Palvimo J.J. Kolmer M. Aaltonen J. Ellonen P. Perheentupa J. Ulmanen I. Peltonen L. doi:10.1086/302765 2000 Am. J. Hum. Genet. 66 378-392 SUBCELLULAR LOCATION VARIANTS APECED LEU-80; CYS-85; TYR-311 AND GLN-326 Subcellular localization of the autoimmune regulator protein. characterization of nuclear targeting and transcriptional activation domain. Pitkaenen J. Vaehaemurto P. Krohn K.J.E. Peterson P. doi:10.1074/jbc.M008322200 2001 J. Biol. Chem. 276 19597-19602 SUBCELLULAR LOCATION TRANSCRIPTION ACTIVATION MUTAGENESIS OF CYS-302 AND CYS-437 CHARACTERIZATION OF VARIANT APECED PRO-28 APECED-causing mutations in AIRE reveal the functional domains of the protein. Halonen M. Kangas H. Rueppell T. Ilmarinen T. Ollila J. Kolmer M. Vihinen M. Palvimo J. Saarela J. Ulmanen I. Eskelin P. doi:10.1002/humu.20003 2004 Hum. Mutat. 23 245-257 SUBCELLULAR LOCATION CHARACTERIZATION OF VARIANTS APECED LEU-15; MET-16; VAL-21; PRO-28; PRO-29; ARG-78; LEU-80; GLU-83; CYS-90; ARG-93; TRP-228 AND GLN-326 NMR structure of the first PHD finger of autoimmune regulator protein (AIRE1). Insights into autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) disease. Bottomley M.J. Stier G. Pennacchini D. Legube G. Simon B. Akhtar A. Sattler M. Musco G. doi:10.1074/jbc.M413959200 2005 J. Biol. Chem. 280 11505-11512 STRUCTURE BY NMR OF 293-354 IN COMPLEX WITH ZINC IONS CHARACTERIZATION OF APECED VARIANTS MET-301; TYR-311 AND GLN-326 Mutation analyses of North American APS-1 patients. Heino M. Scott H.S. Chen Q. Peterson P. Maeenpaeae U. Papasavvas M.-P. Mittaz L. Barras C. Rossier C. Chrousos G.P. Stratakis C.A. Nagamine K. Kudoh J. Shimizu N. Maclaren N. Antonarakis S.E. Krohn K.J.E. doi:10.1002/(SICI)1098-1004(1999)13:1<69::AID-HUMU8>3.0.CO;2-6 1999 Hum. Mutat. 13 69-74 VARIANT APECED PRO-28 Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins. Scott H.S. Heino M. Peterson P. Mittaz L. Lalioti M.D. Betterle C. Cohen A. Seri M. Lerone M. Romeo G. Collin P. Salo M. Metcalfe R. Weetman A. Papasavvas M.-P. Rossier C. Nagamine K. Kudoh J. Shimizu N. Krohn K.J.E. Antonarakis S.E. doi:10.1210/me.12.8.1112 1998 Mol. Endocrinol. 12 1112-1119 VARIANT ARG-278 Identification of a novel mutation in the autoimmune regulator (AIRE-1) gene in a French family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Saugier-Veber P. Drouot N. Wolf L.M. Kuhn J.M. Frebourg T. Lefebvre H. doi:10.1530/eje.0.1440347 2001 Eur. J. Endocrinol. 144 347-351 VARIANT APECED LEU-326 APECED mutations in the autoimmune regulator (AIRE) gene. Heino M. Peterson P. Kudoh J. Shimizu N. Antonarakis S.E. Scott H.S. Krohn K.J.E. doi:10.1002/humu.1176 2001 Hum. Mutat. 18 205-211 VARIANTS APECED LEU-15; MET-16; PRO-28; PR0-29; ARG-78; LEU-80; GLU-83; CYS-85; CYS-90; ARG-93; MET-301; TYR-311 AND GLN-326 VARIANT ARG-278 Novel AIRE mutations and P450 cytochrome autoantibodies in Central and Eastern European patients with APECED. Cihakova D. Trebusak K. Heino M. Fadeyev V. Tiulpakov A. Battelino T. Tar A. Halasz Z. Bluemel P. Tawfik S. Krohn K. Lebl J. Peterson P. The MEWPE-APECED study group doi:10.1002/humu.1178 2001 Hum. Mutat. 18 225-232 VARIANTS APECED MET-16 AND ARG-78 A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis. Cetani F. Barbesino G. Borsari S. Pardi E. Cianferotti L. Pinchera A. Marcocci C. doi:10.1210/jc.86.10.4747 2001 J. Clin. Endocrinol. Metab. 86 4747-4752 VARIANT APECED TRP-228 Distinct clinical phenotype and immunoreactivity in Japanese siblings with autoimmune polyglandular syndrome type 1 (APS-1) associated with compound heterozygous novel AIRE gene mutations. Kogawa K. Kudoh J. Nagafuchi S. Ohga S. Katsuta H. Ishibashi H. Harada M. Hara T. Shimizu N. doi:10.1006/clim.2002.5208 2002 Clin. Immunol. 103 277-283 VARIANT APECED PRO-29 A novel missense mutation of AIRE gene in a patient with autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED), accompanied with progressive muscular atrophy: case report and review of the literature in Japan. Sato K. Nakajima K. Imamura H. Deguchi T. Horinouchi S. Yamazaki K. Yamada E. Kanaji Y. Takano K. doi:10.1507/endocrj.49.625 2002 Endocr. J. 49 625-633 VARIANT APECED CYS-15 Delineation of the molecular defects in the AIRE gene in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients from Southern Italy. Meloni A. Perniola R. Faa V. Corvaglia E. Cao A. Rosatelli M.C. doi:10.1210/jc.87.2.841 2002 J. Clin. Endocrinol. Metab. 87 841-846 VARIANTS APECED ARG-78; LEU-252 AND LEU-539 AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype. Halonen M. Eskelin P. Myhre A.-G. Perheentupa J. Husebye E.S. Kaempe O. Rorsman F. Peltonen L. Ulmanen I. Partanen J. doi:10.1210/jc.87.6.2568 2002 J. Clin. Endocrinol. Metab. 87 2568-2574 VARIANTS APECED VAL-21; CYS-85 AND TYR-311 Two novel mutations of the AIRE protein affecting its homodimerization properties. Meloni A. Fiorillo E. Corda D. Perniola R. Cao A. Rosatelli M.C. doi:10.1002/humu.9309 2005 Hum. Mutat. 25 319 VARIANTS APECED 22-VAL-ASP-23 DEL; SER-77 AND ARG-78 CHARACTERIZATION OF VARIANTS APECED LEU-15; MET-16; 22-VAL-ASP-23 DEL; SER-77 AND ARG-78 Functional analysis of SAND mutations in AIRE supports dominant inheritance of the G228W mutation. Ilmarinen T. Eskelin P. Halonen M. Rueppell T. Kilpikari R. Torres G.D. Kangas H. Ulmanen I. doi:10.1002/humu.20224 2005 Hum. Mutat. 26 322-331 CHARACTERIZATION OF VARIANT APECED TRP-228 AIRE APECED Probable transcriptional regulator protein that binds to DNA as dimer and tetramer, but not as a monomer. Binds to G-doublets in an A/T-rich environment; the preferred motif is a tandem repeat of 5'-ATTGGTTA-3' combined with a 5'-TTATTA-3' box. May be involved in immune regulation. Homodimer and homotetramer. Interacts with CREBBP. Associated with tubular structures and in discrete nuclear dots resembling ND10 nuclear bodies. May shuttle between nucleus and cytoplasm. Additional isoforms seem to exist. Experimental confirmation may be lacking for some isoforms. Widely expressed. Expressed at higher level in thymus (medullary epithelial cells and monocyte-dendritic cells), pancreas, adrenal cortex, and testis. Expressed at lower level in the spleen, fetal liver and lymph nodes. Isoforms 2 and 3 seem to be less frequently expressed than isoform 1, if at all. The L-X-X-L-L repeats may be implicated in binding to nuclear receptors. The HSR domain is required for localization on tubular structures (N-terminal part) and for homodimerization. Disruption of the first PHD domain has been shown to lead to reduced transcriptional activity and to localization of the protein mainly in the cytoplasm in small granules. While the PHD zinc fingers are necessary for the transactivation capacity of the protein, other regions also modulate this function. Phosphorylated. Phosphorylation could trigger oligomerization. Defects in AIRE are a cause of autoimmune poly-endocrinopathy candidiasis ectodermal dystrophy (APECED) [MIM:240300]; also known as autoimmune polyglandular syndrome type I (APS-1). APECED is an autosomal recessive disease characterized by: (1) autoimmune polyendocrinopathies: hypoparathyroidism, adrenocortical failure, IDDM, gonadal failure, hypothyroidism, pernicious anemia, and hepatitis; (2) chronic mucocutaneous candidiasis; (3) ectodermal dystrophies: vitiligo, alopecia, keratopathy, dystrophy of dental enamel, nails and tympanic membranes. In addition, a high proportion of patients develop squamous cell carcinoma of the oral mucosa. The disease is reported worldwide but is exceptionally prevalent among the Finnish population (incidence 1:25000) and the Iranian jews (incidence 1:9000). Most of the mutations alter the nucleus-cytoplasm distribution of AIRE and disturb its association with nuclear dots and cytoplasmic filaments. Most of the mutations also decrease transactivation of the protein. The HSR domain is responsible for the homomultimerization activity of AIRE. All the missense mutations of the HSR and the SAND domains decrease this activity, but those in other domains do not. The AIRE protein is present in soluble high-molecular-weight complexes. Mutations in the HSR domain and deletion of PHD zinc fingers disturb the formation of these complexes. Contains 1 HSR domain. Contains 2 PHD-type zinc fingers. Contains 1 SAND domain. Autoimmune regulator 1 545 HSR 1 106 SAND 181 280 PHD-type 1 296 343 PHD-type 2 434 475 LXXLL motif 1 7 11 LXXLL motif 2 63 67 LXXLL motif 3 414 418 LXXLL motif 4 516 520 In isoform 2 and isoform 3. MWLVYSSGAPGTQQPARNRVFFPIGMAPGGVCWRPDGWGTGGQGRISGPGSMGAGQRLGSSGTQRCCWGSCFGKEVALRRVLHPS 1 292 In isoform 3. PRCQGWTPRPCTPYCVWVLRVSRTWLLVRVAGCAEMVRTCCGVLTAPLPSTGAATSQPAPPGPGRACAADPAQET 377 545 In APECED. C 15 15 In APECED; enzymatic activity of approximately 30% of that of the wild-type. L 15 15 In APECED; enzymatic activity of approximately 10% of that of the wild-type. M 16 16 In APECED. V 21 21 In APECED; lack of alpha-galactosidase enzymatic activity; lack of homodimerization. 22 23 In APECED; abolishes association with cytoplasmic tubular structures and homodimerization. P 28 28 In APECED. P 29 29 In APECED; lack of alpha-galactosidase enzymatic activity; lack of homodimerization. S 77 77 In APECED; lack of alpha-galactosidase enzymatic activity; lack of homodimerization. R 78 78 In APECED. L 80 80 In APECED. E 83 83 In APECED. C 85 85 In APECED. C 90 90 In APECED. R 93 93 In APECED; changes the subcellular localization and in addition disrupts the transactivating capacity of the wild-type AIRE; acts with a dominant negative effect by binding to the wild-type AIRE thus preventing the protein from forming the complexes needed for transactivation. W 228 228 In APECED. L 252 252 R 278 278 In APECED; no effect on protein structure. M 301 301 S 305 305 In APECED; impairs zinc binding and folding of the PHD-type 1 zinc finger. Y 311 311 In APECED. L 326 326 In APECED; alters folding of the PHD-type 1 zinc finger. Q 326 326 In APECED. L 539 539 Reduces transcription activation P 302 302 Reduces transcription activation P 437 437 W 437 467 298 303 320 322 323 325 338 342 AIREbase; AIRE mutation db GeneReviews EMBL EMBL EMBL EMBL EMBL EMBL EMBL EMBL EMBL RefSeq RefSeq UniGene PDB A=293-354 PDBsum PhosphoSite Ensembl Homo sapiens GeneID KEGG NMPDR H-InvDB HGNC AIRE MIM phenotype MIM phenotype MIM gene Orphanet Autoimmune polyendocrinopathy, type 1 PharmGKB HOGENOM HOVERGEN ArrayExpress CleanEx GermOnline Homo sapiens InterPro AIRE InterPro SAND InterPro Sp100 InterPro Znf_PHD InterPro Znf_RING/FYVE/PHD Gene3D Znf_RING/FYVE/PHD 2 Pfam PHD 2 Pfam SAND 1 Pfam Sp100 1 PRINTS AIREGULATOR SMART PHD 2 SMART SAND 1 PROSITE SAND 1 PROSITE ZF_PHD_1 2 PROSITE ZF_PHD_2 1 UniProtKB ProtInc ProtInc UniProtKB 1998-06-01 1 57727 1 AIRE-1 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 2 AIRE-2 3 AIRE-3