RBCC Red Blood Cell Collection

NFKBIA (IKBA, MAD3, NFKBI) [Confidence: low (only semi-automatic identification from reviews)]
NF-kappa-B inhibitor alpha (I-kappa-B-alpha; IkB-alpha; IkappaBalpha; Major histocompatibility complex enhancer-binding protein MAD3)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P25963
ID IKBA_HUMAN Reviewed; 317 AA.
AC P25963; B2R8L6;
DT 01-MAY-1992, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-1992, sequence version 1.
DT 22-JAN-2014, entry version 159.
DE RecName: Full=NF-kappa-B inhibitor alpha;
DE AltName: Full=I-kappa-B-alpha;
DE Short=IkB-alpha;
DE Short=IkappaBalpha;
DE AltName: Full=Major histocompatibility complex enhancer-binding protein MAD3;
GN Name=NFKBIA; Synonyms=IKBA, MAD3, NFKBI;
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].
RC TISSUE=Monocyte;
RX PubMed=1829648; DOI=10.1016/0092-8674(91)90022-Q;
RA Haskill S., Beg A.A., Tompkins S.M., Morris J.S., Yurochko A.D.,
RA Sampson-Johannes A., Mondal K., Ralph P., Baldwin A.S. Jr.;
RT "Characterization of an immediate-early gene induced in adherent
RT monocytes that encodes I kappa B-like activity.";
RL Cell 65:1281-1289(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Lymph node;
RX PubMed=10637284; DOI=10.1084/jem.191.2.395;
RA Jungnickel B., Staratschek-Jox A., Braeuninger A., Spieker T.,
RA Wolf J., Diehl V., Hansmann M.-L., Rajewsky K., Kueppers R.;
RT "Clonal deleterious mutations in the IkappaB alpha gene in the
RT malignant cells in Hodgkin's lymphoma.";
RL J. Exp. Med. 191:395-402(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Liu B., Huang A.;
RT "Homo sapiens IkBa mRNA.";
RL Submitted (APR-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cerebellum;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S.,
RA Sun H., Du H., Pepin K., Artiguenave F., Robert C., Cruaud C.,
RA Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P.,
RA Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N.,
RA Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C.,
RA Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S.,
RA Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B.,
RA Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M.,
RA Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S.,
RA Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D.,
RA Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A.,
RA Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L.,
RA Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J.,
RA Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W.,
RA Quetier F., Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Kidney;
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 [10]
RP INTERACTION WITH RELA.
RX PubMed=1493333; DOI=10.1091/mbc.3.12.1339;
RA Ganchi P.A., Sun S.C., Greene W.C., Ballard D.W.;
RT "I kappa B/MAD-3 masks the nuclear localization signal of NF-kappa B
RT p65 and requires the transactivation domain to inhibit NF-kappa B p65
RT DNA binding.";
RL Mol. Biol. Cell 3:1339-1352(1992).
RN [11]
RP UBIQUITINATION AT LYS-21 AND LYS-22, FUNCTION, AND MUTAGENESIS OF
RP LYS-21; LYS-22; LYS-38 AND LYS-47.
RX PubMed=7479976; DOI=10.1073/pnas.92.24.11259;
RA Scherer D.C., Brockman J.A., Chen Z., Maniatis T., Ballard D.W.;
RT "Signal-induced degradation of IkappaB alpha requires site-specific
RT ubiquitination.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:11259-11263(1995).
RN [12]
RP PHOSPHORYLATION AT TYR-42, AND MUTAGENESIS OF TYR-42.
RX PubMed=8797825; DOI=10.1016/S0092-8674(00)80153-1;
RA Imbert V., Rupec R.A., Livolsi A., Pahl H.L., Traenckner E.B.-M.,
RA Mueller-Dieckmann C., Farahifar D., Rossi B., Auberger P.,
RA Baeuerle P.A., Peyron J.-F.;
RT "Tyrosine phosphorylation of IkappaB-alpha activates NF-kappaB without
RT proteolytic degradation of IkappaB-alpha.";
RL Cell 86:787-798(1996).
RN [13]
RP PHOSPHORYLATION AT SER-283; SER-288; SER-293 AND THR-291.
RX PubMed=8622692;
RA McElhinny J.A., Trushin S.A., Bren G.D., Chester N., Paya C.V.;
RT "Casein kinase II phosphorylates I kappa B alpha at S-283, S-289, S-
RT 293, and T-291 and is required for its degradation.";
RL Mol. Cell. Biol. 16:899-906(1996).
RN [14]
RP MUTAGENESIS OF LYS-21; LYS-22; ASP-31; SER-32; ASP-35; SER-36;
RP SER-234; SER-262 AND THR-263.
RX PubMed=8657102;
RA DiDonato J.A., Mercurio F., Rosette C., Wu-Li J., Suyang H., Ghosh S.,
RA Karin M.;
RT "Mapping of the inducible IkappaB phosphorylation sites that signal
RT its ubiquitination and degradation.";
RL Mol. Cell. Biol. 16:1295-1304(1996).
RN [15]
RP PHOSPHORYLATION AT THR-291; SER-283 AND THR-299.
RX PubMed=8657113;
RA Lin R., Beauparlant P., Makris C., Meloche S., Hiscott J.;
RT "Phosphorylation of IkappaBalpha in the C-terminal PEST domain by
RT casein kinase II affects intrinsic protein stability.";
RL Mol. Cell. Biol. 16:1401-1409(1996).
RN [16]
RP SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, AND MUTAGENESIS OF
RP 115-LEU--ILE-120.
RX PubMed=9566872;
RA Sachdev S., Hoffmann A., Hannink M.;
RT "Nuclear localization of IkappaB alpha is mediated by the second
RT ankyrin repeat: the IkappaB alpha ankyrin repeats define a novel class
RT of cis-acting nuclear import sequences.";
RL Mol. Cell. Biol. 18:2524-2534(1998).
RN [17]
RP UBIQUITINATION BY THE SCF(FBXW11) COMPLEX.
RX PubMed=10437795; DOI=10.1016/S0014-5793(99)00895-9;
RA Vuillard L., Nicholson J., Hay R.T.;
RT "A complex containing betaTrCP recruits Cdc34 to catalyse
RT ubiquitination of IkappaBalpha.";
RL FEBS Lett. 455:311-314(1999).
RN [18]
RP PHOSPHORYLATION AT SER-32 AND SER-36, MUTAGENESIS OF SER-32 AND
RP SER-36, AND UBIQUITINATION BY UBE2D2 AND UBE2D3.
RX PubMed=10329681; DOI=10.1074/jbc.274.21.14823;
RA Gonen H., Bercovich B., Orian A., Carrano A., Takizawa C.,
RA Yamanaka K., Pagano M., Iwai K., Ciechanover A.;
RT "Identification of the ubiquitin carrier proteins, E2s, involved in
RT signal-induced conjugation and subsequent degradation of
RT IkappaBalpha.";
RL J. Biol. Chem. 274:14823-14830(1999).
RN [19]
RP INTERACTION WITH HBV PROTEIN X.
RX PubMed=10454581;
RA Weil R., Sirma H., Giannini C., Kremsdorf D., Bessia C., Dargemont C.,
RA Brechot C., Israel A.;
RT "Direct association and nuclear import of the hepatitis B virus X
RT protein with the NF-kappaB inhibitor IkappaBalpha.";
RL Mol. Cell. Biol. 19:6345-6354(1999).
RN [20]
RP PHOSPHORYLATION AT SER-32 AND SER-36.
RX PubMed=10882136; DOI=10.1016/S1097-2765(00)80445-1;
RA Peters R.T., Liao S.-M., Maniatis T.;
RT "IKK epsilon is part of a novel PMA-inducible IkappaB kinase
RT complex.";
RL Mol. Cell 5:513-522(2000).
RN [21]
RP PHOSPHORYLATION BY TBK1.
RX PubMed=10783893; DOI=10.1038/35008109;
RA Tojima Y., Fujimoto A., Delhase M., Chen Y., Hatakeyama S.,
RA Nakayama K., Kaneko Y., Nimura Y., Motoyama N., Ikeda K., Karin M.,
RA Nakanishi M.;
RT "NAK is an IkappaB kinase-activating kinase.";
RL Nature 404:778-782(2000).
RN [22]
RP INTERACTION WITH NKIRAS1 AND NKIRAS2.
RX PubMed=10657303; DOI=10.1126/science.287.5454.869;
RA Fenwick C., Na S.-Y., Voll R.E., Zhong H., Im S.-Y., Lee J.W.,
RA Ghosh S.;
RT "A subclass of Ras proteins that regulate the degradation of
RT IkappaB.";
RL Science 287:869-873(2000).
RN [23]
RP SUBCELLULAR LOCATION, NUCLEAR EXPORT SIGNAL, AND MUTAGENESIS OF
RP 45-MET--ILE-52.
RX PubMed=10655476; DOI=10.1073/pnas.97.3.1014;
RA Huang T.T., Kudo N., Yoshida M., Miyamoto S.;
RT "A nuclear export signal in the N-terminal regulatory domain of
RT IkappaBalpha controls cytoplasmic localization of inactive NF-
RT kappaB/IkappaBalpha complexes.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:1014-1019(2000).
RN [24]
RP SUMOYLATION AT LYS-21, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-21
RP AND LYS-22.
RX PubMed=11124955; DOI=10.1074/jbc.M009476200;
RA Rodriguez M.S., Dargemont C., Hay R.T.;
RT "SUMO-1 conjugation in vivo requires both a consensus modification
RT motif and nuclear targeting.";
RL J. Biol. Chem. 276:12654-12659(2001).
RN [25]
RP INTERACTION WITH PRKACA.
RX PubMed=20356841; DOI=10.1074/jbc.M109.077602;
RA Gambaryan S., Kobsar A., Rukoyatkina N., Herterich S., Geiger J.,
RA Smolenski A., Lohmann S.M., Walter U.;
RT "Thrombin and collagen induce a feedback inhibitory signaling pathway
RT in platelets involving dissociation of the catalytic subunit of
RT protein kinase A from an NFkappaB-IkappaB complex.";
RL J. Biol. Chem. 285:18352-18363(2010).
RN [26]
RP INTERACTION WITH PRMT2, AND SUBCELLULAR LOCATION.
RX PubMed=16648481; DOI=10.1128/MCB.26.10.3864-3874.2006;
RA Ganesh L., Yoshimoto T., Moorthy N.C., Akahata W., Boehm M.,
RA Nabel E.G., Nabel G.J.;
RT "Protein methyltransferase 2 inhibits NF-kappaB function and promotes
RT apoptosis.";
RL Mol. Cell. Biol. 26:3864-3874(2006).
RN [27]
RP INTERACTION WITH HIF1AN, HYDROXYLATION AT ASN-210 AND ASN-244, AND
RP MUTAGENESIS OF ASN-210 AND ASN-244.
RX PubMed=17003112; DOI=10.1073/pnas.0606877103;
RA Cockman M.E., Lancaster D.E., Stolze I.P., Hewitson K.S.,
RA McDonough M.A., Coleman M.L., Coles C.H., Yu X., Hay R.T., Ley S.C.,
RA Pugh C.W., Oldham N.J., Masson N., Schofield C.J., Ratcliffe P.J.;
RT "Posttranslational hydroxylation of ankyrin repeats in IkappaB
RT proteins by the hypoxia-inducible factor (HIF) asparaginyl
RT hydroxylase, factor inhibiting HIF (FIH).";
RL Proc. Natl. Acad. Sci. U.S.A. 103:14767-14772(2006).
RN [28]
RP INTERACTION WITH RWDD3, SUMOYLATION, AND MUTAGENESIS OF LYS-21 AND
RP LSY-22.
RX PubMed=17956732; DOI=10.1016/j.cell.2007.07.044;
RA Carbia-Nagashima A., Gerez J., Perez-Castro C., Paez-Pereda M.,
RA Silberstein S., Stalla G.K., Holsboer F., Arzt E.;
RT "RSUME, a small RWD-containing protein, enhances SUMO conjugation and
RT stabilizes HIF-1alpha during hypoxia.";
RL Cell 131:309-323(2007).
RN [29]
RP UBIQUITINATION AT LYS-21 AND LYS-22.
RX PubMed=20347421; DOI=10.1016/j.molcel.2010.02.025;
RA Wu K., Kovacev J., Pan Z.Q.;
RT "Priming and extending: a UbcH5/Cdc34 E2 handoff mechanism for
RT polyubiquitination on a SCF substrate.";
RL Mol. Cell 37:784-796(2010).
RN [30]
RP DEUBIQUITINATION BY PORCINE REPRODUCTIVE AND RESPIRATORY SYNDROME
RP VIRUS NSP2 PROTEIN.
RX PubMed=20504922; DOI=10.1128/JVI.00217-10;
RA Sun Z., Chen Z., Lawson S.R., Fang Y.;
RT "The cysteine protease domain of porcine reproductive and respiratory
RT syndrome virus nonstructural protein 2 possesses deubiquitinating and
RT interferon antagonism functions.";
RL J. Virol. 84:7832-7846(2010).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 70-282.
RX PubMed=9865693; DOI=10.1016/S0092-8674(00)81698-0;
RA Jacobs M.D., Harrison S.C.;
RT "Structure of an IkappaBalpha/NF-kappaB complex.";
RL Cell 95:749-758(1998).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 73-302.
RX PubMed=9865694; DOI=10.1016/S0092-8674(00)81699-2;
RA Huxford T., Huang D.B., Malek S., Ghosh G.;
RT "The crystal structure of the IkappaBalpha/NF-kappaB complex reveals
RT mechanisms of NF-kappaB inactivation.";
RL Cell 95:759-770(1998).
RN [33]
RP VARIANT ADEDAID ILE-32.
RX PubMed=14523047; DOI=10.1172/JCI200318714;
RA Courtois G., Smahi A., Reichenbach J., Doffinger R., Cancrini C.,
RA Bonnet M., Puel A., Chable-Bessia C., Yamaoka S., Feinberg J.,
RA Dupuis-Girod S., Bodemer C., Livadiotti S., Novelli F., Rossi P.,
RA Fischer A., Israel A., Munnich A., Le Deist F., Casanova J.L.;
RT "A hypermorphic IkappaBalpha mutation is associated with autosomal
RT dominant anhidrotic ectodermal dysplasia and T cell
RT immunodeficiency.";
RL J. Clin. Invest. 112:1108-1115(2003).
RN [34]
RP INVOLVEMENT IN ADEDAID.
RX PubMed=18412279; DOI=10.1002/humu.20740;
RA Lopez-Granados E., Keenan J.E., Kinney M.C., Leo H., Jain N., Ma C.A.,
RA Quinones R., Gelfand E.W., Jain A.;
RT "A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-
RT truncated protein and is associated with ectodermal dysplasia with
RT immunodeficiency.";
RL Hum. Mutat. 29:861-868(2008).
CC -!- FUNCTION: Inhibits the activity of dimeric NF-kappa-B/REL
CC complexes by trapping REL dimers in the cytoplasm through masking
CC of their nuclear localization signals. On cellular stimulation by
CC immune and proinflammatory responses, becomes phosphorylated
CC promoting ubiquitination and degradation, enabling the dimeric
CC RELA to translocate to the nucleus and activate transcription.
CC -!- SUBUNIT: Interacts with RELA; the interaction requires the nuclear
CC import signal. Interacts with NKIRAS1 and NKIRAS2. Part of a 70-90
CC kDa complex at least consisting of CHUK, IKBKB, NFKBIA, RELA,
CC IKBKAP and MAP3K14. Interacts with HBV protein X. Interacts with
CC RWDD3; the interaction enhances sumoylation. Interacts (when
CC phosphorylated at the 2 serine residues in the destruction motif
CC D-S-G-X(2,3,4)-S) with BTRC. Associates with the SCF(BTRC)
CC complex, composed of SKP1, CUL1 and BTRC; the association is
CC mediated via interaction with BTRC. Part of a SCF(BTRC)-like
CC complex lacking CUL1, which is associated with RELA; RELA
CC interacts directly with NFKBIA. Interacts with PRMT2. Interacts
CC with PRKACA in platelets; this interaction is disrupted by
CC thrombin and collagen. Interacts with HIF1AN.
CC -!- INTERACTION:
CC Self; NbExp=2; IntAct=EBI-307386, EBI-307386;
CC O15111:CHUK; NbExp=13; IntAct=EBI-307386, EBI-81249;
CC Q60680-2:Chuk (xeno); NbExp=2; IntAct=EBI-307386, EBI-646264;
CC Q8N668:COMMD1; NbExp=3; IntAct=EBI-307386, EBI-1550112;
CC O14920:IKBKB; NbExp=11; IntAct=EBI-307386, EBI-81266;
CC Q9Y6K9:IKBKG; NbExp=4; IntAct=EBI-307386, EBI-81279;
CC P19838:NFKB1; NbExp=2; IntAct=EBI-307386, EBI-300010;
CC Q04206:RELA; NbExp=13; IntAct=EBI-307386, EBI-73886;
CC P0CG48:UBC; NbExp=3; IntAct=EBI-307386, EBI-3390054;
CC Q9J0X9:UL54 (xeno); NbExp=3; IntAct=EBI-307386, EBI-7967856;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Shuttles between
CC the nucleus and the cytoplasm by a nuclear localization signal
CC (NLS) and a CRM1-dependent nuclear export (By similarity).
CC -!- INDUCTION: Induced in adherent monocytes.
CC -!- PTM: Phosphorylated; disables inhibition of NF-kappa-B DNA-binding
CC activity. Phosphorylation at positions 32 and 36 is prerequisite
CC to recognition by UBE2D3 leading to polyubiquitination and
CC subsequent degradation.
CC -!- PTM: Sumoylated; sumoylation requires the presence of the nuclear
CC import signal.
CC -!- PTM: Monoubiquitinated at Lys-21 and/or Lys-22 by UBE2D3.
CC Ubiquitin chain elongation is then performed by CDC34 in
CC cooperation with the SCF(FBXW11) E3 ligase complex, building
CC ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin.
CC The resulting polyubiquitination leads to protein degradation.
CC Also ubiquitinated by SCF(BTRC) following stimulus-dependent
CC phosphorylation at Ser-32 and Ser-36.
CC -!- PTM: Deubiquitinated by porcine reproductive and respiratory
CC syndrome virus Nsp2 protein, which thereby interferes with NFKBIA
CC degradation and impairs subsequent NF-kappa-B activation.
CC -!- DISEASE: Ectodermal dysplasia, anhidrotic, with T-cell
CC immunodeficiency autosomal dominant (ADEDAID) [MIM:612132]: A form
CC of ectoderma dysplasia, a heterogeneous group of disorders due to
CC abnormal development of two or more ectodermal structures. This
CC form of ectodermal dysplasia is associated with decreased
CC production of pro-inflammatory cytokines and certain interferons,
CC rendering patients susceptible to infection. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the NF-kappa-B inhibitor family.
CC -!- SIMILARITY: Contains 5 ANK repeats.
CC -!- WEB RESOURCE: Name=NFKBIAbase; Note=NFKBIA mutation db;
CC URL="http://bioinf.uta.fi/NFKBIAbase/";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/nfkbia/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M69043; AAA16489.1; -; mRNA.
DR EMBL; AJ249294; CAB65556.2; -; Genomic_DNA.
DR EMBL; AJ249295; CAB65556.2; JOINED; Genomic_DNA.
DR EMBL; AJ249283; CAB65556.2; JOINED; Genomic_DNA.
DR EMBL; AJ249284; CAB65556.2; JOINED; Genomic_DNA.
DR EMBL; AJ249285; CAB65556.2; JOINED; Genomic_DNA.
DR EMBL; AJ249286; CAB65556.2; JOINED; Genomic_DNA.
DR EMBL; AY033600; AAK51149.1; -; mRNA.
DR EMBL; BT007091; AAP35754.1; -; mRNA.
DR EMBL; AY496422; AAR29599.1; -; Genomic_DNA.
DR EMBL; AK313421; BAG36213.1; -; mRNA.
DR EMBL; AL133163; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471078; EAW65875.1; -; Genomic_DNA.
DR EMBL; BC002601; AAH02601.1; -; mRNA.
DR EMBL; BC004983; AAH04983.1; -; mRNA.
DR PIR; A39935; A39935.
DR RefSeq; NP_065390.1; NM_020529.2.
DR UniGene; Hs.81328; -.
DR PDB; 1IKN; X-ray; 2.30 A; D=67-302.
DR PDB; 1NFI; X-ray; 2.70 A; E/F=70-282.
DR PDBsum; 1IKN; -.
DR PDBsum; 1NFI; -.
DR DisProt; DP00468; -.
DR ProteinModelPortal; P25963; -.
DR SMR; P25963; 40-281.
DR DIP; DIP-139N; -.
DR IntAct; P25963; 35.
DR MINT; MINT-120458; -.
DR STRING; 9606.ENSP00000216797; -.
DR BindingDB; P25963; -.
DR ChEMBL; CHEMBL2898; -.
DR PhosphoSite; P25963; -.
DR DMDM; 126682; -.
DR PaxDb; P25963; -.
DR PeptideAtlas; P25963; -.
DR PRIDE; P25963; -.
DR DNASU; 4792; -.
DR Ensembl; ENST00000216797; ENSP00000216797; ENSG00000100906.
DR GeneID; 4792; -.
DR KEGG; hsa:4792; -.
DR UCSC; uc001wtf.4; human.
DR CTD; 4792; -.
DR GeneCards; GC14M035870; -.
DR HGNC; HGNC:7797; NFKBIA.
DR HPA; CAB003815; -.
DR HPA; HPA029207; -.
DR MIM; 164008; gene.
DR MIM; 612132; phenotype.
DR neXtProt; NX_P25963; -.
DR Orphanet; 251579; Giant cell glioblastoma.
DR Orphanet; 251576; Gliosarcoma.
DR Orphanet; 98813; Hypohidrotic ectodermal dysplasia with immunodeficiency.
DR PharmGKB; PA31601; -.
DR eggNOG; COG0666; -.
DR HOGENOM; HOG000059576; -.
DR HOVERGEN; HBG018875; -.
DR InParanoid; P25963; -.
DR KO; K04734; -.
DR OMA; SIHGYLA; -.
DR OrthoDB; EOG7W154S; -.
DR PhylomeDB; P25963; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR SABIO-RK; P25963; -.
DR SignaLink; P25963; -.
DR ChiTaRS; NFKBIA; human.
DR EvolutionaryTrace; P25963; -.
DR GeneWiki; I%CE%BAB%CE%B1; -.
DR GenomeRNAi; 4792; -.
DR NextBio; 18466; -.
DR PMAP-CutDB; P25963; -.
DR PRO; PR:P25963; -.
DR ArrayExpress; P25963; -.
DR Bgee; P25963; -.
DR CleanEx; HS_NFKBIA; -.
DR Genevestigator; P25963; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0033256; C:I-kappaB/NF-kappaB complex; TAS:BHF-UCL.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0051059; F:NF-kappaB binding; IDA:MGI.
DR GO; GO:0008139; F:nuclear localization sequence binding; IPI:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:0070417; P:cellular response to cold; NAS:BHF-UCL.
DR GO; GO:0007253; P:cytoplasmic sequestering of NF-kappaB; IMP:BHF-UCL.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:Reactome.
DR GO; GO:0043392; P:negative regulation of DNA binding; NAS:UniProtKB.
DR GO; GO:0010888; P:negative regulation of lipid storage; IMP:BHF-UCL.
DR GO; GO:0010745; P:negative regulation of macrophage derived foam cell differentiation; IMP:BHF-UCL.
DR GO; GO:0045638; P:negative regulation of myeloid cell differentiation; IEA:Ensembl.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:MGI.
DR GO; GO:0045746; P:negative regulation of Notch signaling pathway; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0070427; P:nucleotide-binding oligomerization domain containing 1 signaling pathway; IEA:Ensembl.
DR GO; GO:0070431; P:nucleotide-binding oligomerization domain containing 2 signaling pathway; IEA:Ensembl.
DR GO; GO:0032270; P:positive regulation of cellular protein metabolic process; IMP:BHF-UCL.
DR GO; GO:0010875; P:positive regulation of cholesterol efflux; IMP:BHF-UCL.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; TAS:Reactome.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
DR GO; GO:0032481; P:positive regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0000060; P:protein import into nucleus, translocation; IEA:Ensembl.
DR GO; GO:0042127; P:regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0043330; P:response to exogenous dsRNA; IEA:Ensembl.
DR GO; GO:0032495; P:response to muramyl dipeptide; IEA:Ensembl.
DR GO; GO:0050852; P:T cell receptor signaling pathway; TAS:Reactome.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR Gene3D; 1.25.40.20; -; 1.
DR InterPro; IPR002110; Ankyrin_rpt.
DR InterPro; IPR020683; Ankyrin_rpt-contain_dom.
DR Pfam; PF00023; Ank; 4.
DR PRINTS; PR01415; ANKYRIN.
DR SMART; SM00248; ANK; 5.
DR SUPFAM; SSF48403; SSF48403; 1.
DR PROSITE; PS50297; ANK_REP_REGION; 1.
DR PROSITE; PS50088; ANK_REPEAT; 3.
PE 1: Evidence at protein level;
KW 3D-structure; ANK repeat; Complete proteome; Cytoplasm;
KW Disease mutation; Ectodermal dysplasia; Host-virus interaction;
KW Hydroxylation; Isopeptide bond; Nucleus; Phosphoprotein;
KW Reference proteome; Repeat; Ubl conjugation.
FT CHAIN 1 317 NF-kappa-B inhibitor alpha.
FT /FTId=PRO_0000066999.
FT REPEAT 73 103 ANK 1.
FT REPEAT 110 139 ANK 2.
FT REPEAT 143 172 ANK 3.
FT REPEAT 182 211 ANK 4.
FT REPEAT 216 245 ANK 5.
FT MOTIF 30 36 Destruction motif.
FT MOTIF 45 54 Nuclear export signal.
FT MOTIF 110 120 Nuclear import signal.
FT MOD_RES 32 32 Phosphoserine; by IKKA and IKKE.
FT MOD_RES 36 36 Phosphoserine; by IKKA, IKKB, IKKE and
FT TBK1.
FT MOD_RES 42 42 Phosphotyrosine; by Tyr-kinases.
FT MOD_RES 210 210 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 244 244 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 283 283 Phosphoserine; by CK2.
FT MOD_RES 288 288 Phosphoserine; by CK2.
FT MOD_RES 291 291 Phosphothreonine; by CK2.
FT MOD_RES 293 293 Phosphoserine; by CK2.
FT MOD_RES 299 299 Phosphothreonine; by CK2.
FT CROSSLNK 21 21 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO or
FT ubiquitin).
FT CROSSLNK 22 22 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VARIANT 32 32 S -> I (in ADEDAID; dbSNP:rs28933100).
FT /FTId=VAR_034871.
FT MUTAGEN 21 21 K->R: Little change in Tax-stimulated
FT transactivation. No sumoylation. Greatly
FT reduced Tax- or cytokine-stimulated
FT transactivation and decrease in
FT ubiquitination and degradation; when
FT associated with R-22.
FT MUTAGEN 22 22 K->R: Little change in Tax-stimulated
FT transactivation. No sumoylation. Greatly
FT reduced Tax- or cytokine-stimulated
FT transactivation and decrease in
FT ubiquitination and degradation; when
FT associated with R-21.
FT MUTAGEN 31 31 D->A: Loss of phosphorylation; when
FT associated with A-35.
FT MUTAGEN 32 32 S->A: Loss of phosphorylation,
FT ubiquitination and degradation; when
FT associated with A-36.
FT MUTAGEN 32 32 S->T: Decrease in phosphorylation and
FT degradation; when associated with T-36.
FT MUTAGEN 35 35 D->A: Loss in phosphorylation; when
FT associated with A-31.
FT MUTAGEN 35 35 D->G: No change neither in
FT phosphorylation, nor on degradation.
FT MUTAGEN 36 36 S->A: Loss of phosphorylation,
FT ubiquitination, and degradation; when
FT associated with A-32.
FT MUTAGEN 36 36 S->T: Decrease in phosphorylation and
FT degradation; when associated with T-32.
FT MUTAGEN 38 38 K->R: No change in Tax-stimulated
FT transactivation. No change in Tax-
FT stimulated transactivation; when
FT associated with R-47.
FT MUTAGEN 42 42 Y->F: No phosphorylation.
FT MUTAGEN 45 52 MVKELQEI->AAKEAQEA: No nuclear export.
FT MUTAGEN 47 47 K->R: Little change in Tax-stimulated
FT transactivation. No change in Tax-
FT stimulated transactivation; when
FT associated with R-38.
FT MUTAGEN 115 120 LHLAVI->AHAAVA: Greatly reduced nuclear
FT localization. Great reduction in its
FT ability to inhibit DNA binding of RELA.
FT MUTAGEN 210 210 N->A: Almost abolished ability to inhibit
FT NF-kappa-B DNA-binding activity; when
FT associated with A-244.
FT MUTAGEN 234 234 S->A: No inducible ubiquitination nor
FT protein degradation.
FT MUTAGEN 244 244 N->A: Almost abolished ability to inhibit
FT NF-kappa-B DNA-binding activity; when
FT associated with A-210.
FT MUTAGEN 262 262 S->A: No inducible ubiquitination nor
FT protein degradation.
FT MUTAGEN 263 263 T->A: No inducible ubiquitination nor
FT protein degradation.
FT TURN 72 74
FT HELIX 79 83
FT STRAND 87 91
FT HELIX 101 104
FT HELIX 114 120
FT HELIX 124 128
FT HELIX 147 154
FT HELIX 157 165
FT TURN 167 170
FT STRAND 171 173
FT HELIX 175 177
FT HELIX 186 192
FT HELIX 196 205
FT TURN 214 216
FT HELIX 220 226
FT HELIX 230 237
FT TURN 238 240
FT HELIX 253 256
FT HELIX 263 270
FT HELIX 275 277
FT TURN 285 287
SQ SEQUENCE 317 AA; 35609 MW; 088B313226786395 CRC64;
MFQAAERPQE WAMEGPRDGL KKERLLDDRH DSGLDSMKDE EYEQMVKELQ EIRLEPQEVP
RGSEPWKQQL TEDGDSFLHL AIIHEEKALT MEVIRQVKGD LAFLNFQNNL QQTPLHLAVI
TNQPEIAEAL LGAGCDPELR DFRGNTPLHL ACEQGCLASV GVLTQSCTTP HLHSILKATN
YNGHTCLHLA SIHGYLGIVE LLVSLGADVN AQEPCNGRTA LHLAVDLQNP DLVSLLLKCG
ADVNRVTYQG YSPYQLTWGR PSTRIQQQLG QLTLENLQML PESEDEESYD TESEFTEFTE
DELPYDDCVF GGQRLTL
//

MIM 164008
*RECORD*
*FIELD* NO
164008
*FIELD* TI
*164008 NUCLEAR FACTOR OF KAPPA LIGHT CHAIN GENE ENHANCER IN B CELLS INHIBITOR,
ALPHA; NFKBIA
read more;;NUCLEAR FACTOR OF KAPPA LIGHT CHAIN GENE ENHANCER IN B CELLS INHIBITOR;
NFKBI;;
NUCLEAR FACTOR KAPPA-B INHIBITOR;;
INHIBITOR OF KAPPA LIGHT CHAIN GENE ENHANCER IN B CELLS, ALPHA;;
I-KAPPA-B-ALPHA; IKBA
*FIELD* TX

DESCRIPTION

NFKB1 (164011) or NFKB2 (164012) is bound to REL (164910), RELA
(164014), or RELB (604758) to form the NFKB complex. The NFKB complex is
inhibited by I-kappa-B proteins (NFKBIA or NFKBIB, 604495), which
inactivate NF-kappa-B by trapping it in the cytoplasm. Phosphorylation
of serine residues on the I-kappa-B proteins by kinases (IKBKA, 600664,
or IKBKB, 603258) marks them for destruction via the ubiquitination
pathway, thereby allowing activation of the NF-kappa-B complex.
Activated NFKB complex translocates into the nucleus and binds DNA at
kappa-B-binding motifs such as 5-prime GGGRNNYYCC 3-prime or 5-prime
HGGARNYYCC 3-prime (where H is A, C, or T; R is an A or G purine; and Y
is a C or T pyrimidine).

CLONING

Haskill et al. (1991) cloned 1 form of I-kappa-B (referred to as
I-kappa-B-alpha by them) and showed that it is a protein with multiple
ankyrin (612641) repeats.

Cells from patients with ataxia-telangiectasia (208900) are
hypersensitive to ionizing radiation and are defective in the regulation
of DNA synthesis. By expression cloning, Jung et al. (1995) isolated a
cDNA that corrected the radiation sensitivity in DNA synthesis defects
in fibroblasts from an ataxia-telangiectasia group D patient. They
showed that the cDNA encoded a truncated form of I-kappa-B-alpha. The
parental AT1 fibroblast expressed large amounts of the I-kappa-B-alpha
transcript and showed constitutive activation of NF-kappa-B. AT1
fibroblasts transfected with the truncated NFKBI gene expressed normal
amounts of the NFKBI transcript and showed regulated activation of
NF-kappa-B. These results suggested that aberrant regulation of these 2
genes contribute to the cellular defect in ataxia-telangiectasia since
the NFKBI gene is localized to chromosome 14. Whereas genetic linkage
analysis has mapped the putative AT1 gene to 11q, Jung et al. (1995)
hypothesized that the contribution of the NFKB and inhibitor complex to
the ataxia-telangiectasia phenotype must act downstream of the gene
representing the primary defect.

Rupec et al. (1999) cloned the mouse Ikba gene and determined its
structure.

GENE FUNCTION

Glucocorticoids are among the most potent antiinflammatory and
immunosuppressive agents known. They inhibit synthesis of almost all
cytokines and of several cell-surface molecules required for immune
function. Scheinman et al. (1995) and Auphan et al. (1995) showed that
the synthetic glucocorticoid dexamethasone induces transcription of the
I-kappa-B-alpha gene, which results in an increased rate of synthesis of
the inhibitor protein. The inhibitory protein traps activated NF-kappa-B
in inactive cytoplasmic complexes. Because NF-kappa-B activates many
immunoregulatory genes in response to proinflammatory stimuli, the
inhibition of its activity can be a major component of the
antiinflammatory activity of glucocorticoids.

The mucosal lining of the intestine coexists with diverse luminal
prokaryotic microflora by maintaining a state of tolerance or
inflammatory hyporesponsiveness. However, enteropathogens that cause
acute inflammatory colitis do activate the NFKB pathway, resulting in
the secretion of chemokines such as IL8 (146930). Using a model system
of intestinal epithelia and live nonpathogenic Salmonella bacteria,
Neish et al. (2000) found that IL8 secretion and mRNA expression, as
well as IKBA expression, was attenuated compared to the response
elicited by proinflammatory Salmonella strains and proinflammatory
stimuli such as TNFA (191160), calcium-mobilizing carbachol, and phorbol
ester. Attenuation of IL8 secretion and IKBA expression also occurred if
the model epithelia were colonized with the nonvirulent Salmonella
before proinflammatory stimulation. Immunofluorescence analysis revealed
that the NFKB complex did not translocate to the nucleus in epithelial
cells colonized with the antiinflammatory organisms. Western blot
analysis confirmed that in epithelial cells exposed to the avirulent
Salmonella, IKBA, in spite of becoming phosphorylated via the JNK (see
601158) pathway, was stabilized; challenge with virulent organisms or
TNFA alone resulted in degradation of IKBA. The same results were not
achieved with monocytic or endothelial cells. Immunoblot analysis
further showed that the antiinflammatory strains block the
ubiquitination of phosphorylated IKBA, induced by the inflammatory
Salmonella strains or inflammatory stimuli. Neish et al. (2000) also
observed abrogation of ubiquitination of beta-catenin (CTNNB1; 116806)
but not of other proteins in this model, suggesting that the effect of
the nonpathogenic bacteria is specific to the SCF complex (see BTRC,
603482) substrates CTNNB1 and IKBA. Neish et al. (2000) noted that their
model may help to explain the beneficial effects of treatment of
inflammatory bowel disease with nonpathogenic probiotic enteric
organisms.

Using electrophoretic mobility shift analysis (EMSA), Hoffmann et al.
(2002) showed that persistent stimulation of T cells, monocytes, or
fibroblasts with TNFA resulted in the coordinated degradation,
synthesis, and localization of IKBA, IKBB, and IKBE (604548) necessary
to generate the characteristic NFKB activation profile.

Because therapeutics inhibiting RAS (190020) and NFKB pathways are used
to treat human cancer, experiments assessing the effects of altering
these regulators have been performed in mice. The medical relevance of
murine studies is limited, however, by differences between mouse and
human skin, and by the greater ease of transforming murine cells. To
study RAS and NFKB in a setting more relevant to human tumorigenesis,
Dajee et al. (2003) expressed the active HRAS gly12-to-val mutation
(190020.0001), NFKB p65 (164014), and a stable NFKB repressor mutant of
IKBA in human skin tissue. Primary human keratinocytes were retrovirally
transduced and used to regenerate human skin on immune-deficient mice.
Tissue expressing IKBA alone showed mild hyperplasia, whereas expression
of oncogenic RAS induced growth arrest with graft failure. Although
implicated in promoting features of neoplasia in other settings, the
coexpression of oncogenic RAS with NFKB subunits failed to support
proliferation. Coexpression of RAS and IKBA produced large neoplasms
with deep invasion through fat into underlying muscle and fascia,
similar to human squamous cell carcinomas (SCC), in 3 weeks. These
tumors showed more than 10-fold increase in mitotic index, preserved
telomeres, and increased amounts of TERT (187270) protein. Human
keratinocytes lacking laminin-5 (LAMB3; 150310) and ITGB4 (147557)
failed to form tumors on coexpression with RAS and IKBA; however,
introduction of wildtype LAMB3 and ITGB4 restored tumor-forming
capacity, suggesting that these 2 proteins are required for SCC
tumorigenesis. Dajee et al. (2003) demonstrated that growth arrest
triggered by oncogenic RAS can be bypassed by IKBA-mediated blockade of
NFKB and that RAS opposed the increased susceptibility to apoptosis
caused by NFKB blockade. Thus, IKBA circumvents restraints on growth
promotion induced by oncogenic RAS and can act with RAS to induce
invasive human tissue neoplasia.

Sigala et al. (2004) identified ELKS (607127) as an essential regulatory
subunit of the IKK complex. Silencing ELKS expression by RNA
interference blocked induced expression of NF-kappa-B target genes,
including the NF-kappa-B inhibitor IKBA and proinflammatory genes such
as cyclooxygenase-2 (COX2; 600262) and interleukin-8 (IL8; 146930).
These cells were also not protected from apoptosis in response to
cytokines. Sigala et al. (2004) concluded that ELKS likely functions by
recruiting IKBA to the IKK complex and thus serves a regulatory function
in IKK activation.

BIOCHEMICAL FEATURES

Jacobs and Harrison (1998) and Huxford et al. (1998) determined the
structure of the IKBA ankyrin repeat domain, bound to a partially
truncated NFKB heterodimer (p50/p65), by x-ray crystallography at 2.7-
and 2.3-angstrom resolution, respectively. It shows a stack of 6 IKBA
ankyrin repeats facing the C-terminal domains of the NFKB rel homology
regions. Contacts occur in discontinuous patches, suggesting a
combinatorial quality for ankyrin repeat specificity. The first 2
repeats cover an alpha helically ordered segment containing the p65
nuclear localization signal. The position of the sixth ankyrin repeat
shows that full-length IKBA will occlude the NFKB DNA-binding cleft. The
orientation of IKBA in the complex places its N- and C-terminal regions
in appropriate locations for their known regulatory functions. Baeuerle
(1998) discussed the model of interactions between IKBA and NFKB.

GENE STRUCTURE

The IKBA gene was shown by Ito et al. (1995) to have 6 exons spanning
about 3.5-kb of genomic DNA. The organization of the gene is similar to
that of other members of the ankyrin family including BCL3 (109560) and
NFKB2.

MAPPING

Le Beau et al. (1992) mapped the NFKBI gene to 14q13 by fluorescence in
situ hybridization. Rupec et al. (1999) mapped the Nfkbi gene to mouse
chromosome 12 in a region of conserved synteny with human chromosome 14.

MOLECULAR GENETICS

- Anhidrotic Ectodermal Dysplasia with T-cell Immunodeficiency

X-linked anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID;
300291) is caused by hypomorphic mutations in the gene encoding
IKK-gamma (IKBKG; 300248), the regulatory subunit of the IKK complex.
IKK normally phosphorylates the I-kappa-B inhibitors of NF-kappa-B at
specific serine residues, thereby promoting their ubiquitination and
degradation by the proteasome. This in turn allows NF-kappa-B complexes
to translocate into the nucleus where they activate their target genes.
In patients with X-linked EDA-ID, impaired immunity and EDA result from
impaired NF-kappa-B activation. Courtois et al. (2003) described a
patient with an autosomal dominant form of EDA-ID (612132) associated
with a heterozygous mutation in the NFKBIA gene (S32I; 164008.0001).
This gain-of-function mutation enhanced the inhibitory capacity of
I-kappa-B-alpha by preventing its phosphorylation and degradation, and
resulted in impaired NF-kappa-B activation. Developmental, immunologic,
and infectious phenotypes associated with hypomorphic IKBKG mutations
and hypermorphic IKBA mutations largely overlap; however, autosomal
dominant EDA-ID, but not X-linked EDA-ID, was associated with a severe
and unique T-cell immunodeficiency. Despite marked blood lymphocytosis,
there were no detectable memory T cells in vivo, and naive T cells did
not respond to CD3-TCR activation in vitro. The report highlighted both
the diversity of genotypes associated with EDA-ID and the diversity of
immunologic phenotypes associated with mutations in different components
of the NF-kappa-B signaling pathway.

McDonald et al. (2007) identified a heterozygous mutation in the NFKBIA
gene (164008.0002) in a girl with anhidrotic ectodermal dysplasia and
immunodeficiency.

In a male infant with anhidrotic ectodermal dysplasia and T-cell
immunodeficiency, Lopez-Granados et al. (2008) identified a mutation in
the NFKBIA gene (164008.0003). In vitro studies indicated a
gain-of-function mutation resulting in impaired NFKB1 activity.

- Somatic Mutations in Glioblastoma

Bredel et al. (2011) analyzed 790 human glioblastomas (see 137800) for
deletions, mutations, or expression of NFKBIA and EGFR (131550). They
further studied the tumor suppressor activity of NFKBIA in tumor cell
culture and compared the molecular results with the outcome of
glioblastoma in 570 affected individuals. Bredel et al. (2011) found
that NFKBIA is often deleted but not mutated in glioblastomas; most
deletions occur in nonclassical subtypes of the disease. Deletion of
NFKBIA and amplification of EGFR show a pattern of mutual exclusivity.
Restoration of the expression of NFKBIA attenuated the malignant
phenotype and increased the vulnerability to chemotherapy of cells
cultured from tumors with NFKBIA deletion; it also reduced the viability
of cells with EGFR amplification but not of cells with normal gene
dosages of both NFKBIA and EGFR. Deletion and low expression of NFKBIA
were associated with unfavorable outcomes. Patients who had tumors with
NFKBIA deletion had outcomes that were similar to those in patients with
tumors harboring EGFR amplification. These outcomes were poor as
compared with the outcomes in patients with tumors that had normal gene
dosages of NFKBIA and EGFR. Bredel et al. (2011) suggested a 2-gene
model that was based on expression of NFKBIA and O(6)-methylguanine DNA
methyltransferase (156569) being strongly associated with the clinical
course of the disease, and concluded that deletion of NFKBIA has an
effect that is similar to the effect of EGFR amplification in the
pathogenesis of glioblastoma and is associated with comparatively short
survival.

- Other Associations

Ali et al. (2013) evaluated the impact of 3 NFKBIA promoter SNPs, dbSNP
rs3138053, dbSNP rs2233406, and dbSNP rs2233409, on NFKBIA mRNA
expression, NFKBIA protein expression, and TLR (see 603030)
responsiveness. They detected enhanced NFKBIA mRNA and protein
expression in individuals homozygous for the haplotype comprising the
common promoter variants (ACC) compared with those heterozygous for the
haplotype comprising the minor promoter variants (GTT). Cord blood from
ACC/GTT heterozygous neonates had higher production of TNF in response
to lipopolysaccharide. Systems biology and functional analyses
identified NFKBIA as a candidate gene in asthma, respiratory syncytial
virus infection, and bronchopulmonary dysplasia. Ali et al. (2013)
concluded that negative innate immune regulators are important in
pediatric lung disease.

ANIMAL MODEL

Hoffmann et al. (2002) generated mice deficient in Ikbb and Ikbe by
homologous recombination and intercrossed them with Ikba-deficient mice
to yield embryonic fibroblasts containing only 1 Ikb isoform. TNFA
stimulation of the Ikba fibroblasts resulted in a highly oscillatory
Nfkb response, whereas in Ikbb and Ikbe fibroblasts nuclear Nfkb
increased monotonically. Hoffmann et al. (2002) concluded that IKBA
mediates rapid NFKB activation and strong negative feedback regulation,
while IKBB and IKBE respond more slowly to IKK activation and act to
dampen long-term oscillations of the NFKB response. Computational and
EMSA analyses revealed bimodal signal-processing characteristics with
respect to the duration of the stimulus, enabling the generation of
specificity in gene expression of IP10 (CXCL10; 147310) and RANTES
(CCL5; 187011). In a commentary, Ting and Endy (2002) compared the
duration of signaling to the creation of an audible tone by pressing a
piano key, which causes a hammer to hit a string. How hard the string is
hit, and whether or not string vibration is sustained after the key is
released, can be modified by depressing a foot pedal, much as signal
transduction pathways are activated and modified by information in the
environment.

Cai et al. (2004) created transgenic mice with Nfkb either activated or
inhibited selectively in skeletal muscle through expression of
constitutively active IKKB (603258) or a dominant inhibitory form of
IKBA, respectively. They referred to these mice as MIKK (muscle-specific
expression of IKKB) or MISR (muscle-specific expression of IKBA
superrepressor), respectively. MIKK mice showed profound muscle wasting
that resembled clinical cachexia, whereas MISR mice showed no overt
phenotype. Muscle loss in MIKK mice was due to accelerated protein
breakdown through ubiquitin-dependent proteolysis. Expression of the E3
ligase Murf1 (RNF28; 606131), a mediator of muscle atrophy, was
increased in MIKK mice. Pharmacologic or genetic inhibition of the
Ikkb/Nfkb/Murf1 pathway in MIKK mice reversed the muscle atrophy. The
Nfkb inhibition in MISR mice substantially reduced denervation- and
tumor-induced muscle loss and improved survival rates. The results were
consistent with a critical role for NFKB in the pathology of muscle
wasting and established NFKB as an important clinical target for the
treatment of muscle atrophy.

*FIELD* AV
.0001
ECTODERMAL DYSPLASIA, ANHIDROTIC, WITH T-CELL IMMUNODEFICIENCY, AUTOSOMAL
DOMINANT
NFKBIA, SER32ILE

In a 7-year-old boy with autosomal dominant anhidrotic ectodermal
dysplasia and T-cell immunodeficiency (612132), Courtois et al. (2003)
identified a 94G-T transversion in the NFKBIA gene, resulting in a
ser32-to-ile (S32I) change. Ser32 is a key phospho-acceptor site of
I-kappa-B-alpha, and is conserved in the other 2 I-kappa-B proteins. The
mutation appeared to be a de novo event. The patient was born to
unrelated parents. Since 2 months of age he had chronic diarrhea,
recurrent bronchopneumonitis, hepatosplenomegaly, and failure to thrive.
Bone marrow transplantation was performed at 1 year of age. A diagnosis
of ectodermal dysplasia with immunodeficiency was made at the age of 3
years on the basis of a dry, rough skin, moderately sparse scalp hair,
and conical teeth. The patient had no other overt developmental defects.

Janssen et al. (2004) identified heterozygosity for the S32I mutation in
a boy with anhidrotic ectodermal dysplasia and T-cell immunodeficiency.
The father had a less severe phenotype and was found to be mosaic for
the mutation. Monocytes from both father and son showed impaired
function, but T cells from the father showed relatively normal function
and displayed the wildtype allele. Ser32 is 1 of the 2 serines that is
phosphorylated on NFKBIA, leading to ubiquitin-related degradation of
NFKBIA and allowing NFKB1 to be translocated to the nucleus for
activation of downstream targets.

.0002
ECTODERMAL DYSPLASIA, ANHIDROTIC, WITH T-CELL IMMUNODEFICIENCY, AUTOSOMAL
DOMINANT
NFKBIA, TRP11TER

In a girl with anhidrotic ectodermal dysplasia with T-cell
immunodeficiency (612132), McDonald et al. (2007) identified a
heterozygous 32G-A transition in exon 1 of the NFKBIA gene, resulting in
a trp11-to-ter (W11X) substitution. Studies of patient fibroblasts
showed that a downstream initiation sequence resulted in the translation
of an N-terminally truncated protein. The mutant protein did not undergo
ligand-induced phosphorylation or degradation, and retained NFKB in the
cytoplasm. This led to roughly a 50% decrease in NFKB DNA-binding
activity and functional haploinsufficiency of NFKB activation. Unlike
S32I NFKBIA mutant also associated with ectodermal dysplasia with immune
deficiency (164008.0001), the W11X mutation did not exert a
dominant-negative effect but rather a 'persistence-of-function' mutant,
resulting in functional NFKB haploinsufficiency.

.0003
ECTODERMAL DYSPLASIA, ANHIDROTIC, WITH T-CELL IMMUNODEFICIENCY, AUTOSOMAL
DOMINANT
NFKBIA, GLU14TER

In a male infant with anhidrotic ectodermal dysplasia and T-cell
immunodeficiency (612132), Lopez-Granados et al. (2008) identified a de
novo heterozygous 40G-T transversion in exon 1 of the NFKB1A gene,
resulting in a glu14-to-ter (E14X) substitution. He had failure to
thrive, developed multiple infections including gastrointestinal and
respiratory infections, and died from complications of a cord blood
transplant. Skin biopsy showed absence of sweat glands, and laboratory
studies showed normal serum immunoglobulin levels but impaired
production of NFKB1-regulated cytokines. In vitro studies showed that an
in-frame methionine downstream of the G14X mutation allowed for
reinitiation of translation. The resulting N-terminally truncated
protein lacked both serine phosphorylation sites and inhibited NFKB1
signaling by functioning as a dominant negative on NFKB1 activity in
lymphocytes and monocytes. These findings supported the scanning model
for translation initiation in eukaryotes and confirmed the critical role
of NFKB1 in human immune response.

*FIELD* RF
1. Ali, S.; Hirschfeld, A. F.; Mayer, M. L.; Fortuno, E. S., III;
Corbett, N.; Kaplan, M.; Wang, S.; Schneidermann, J.; Fjell, C. D.;
Yan, J.; Akhabir, L.; Aminuddin, F.; and 11 others: Functional
genetic variation in NFKBIA and susceptibility to childhood asthma,
bronchiolitis, and bronchopulmonary dysplasia. J. Immun. 190: 3949-3958,
2013.

2. Auphan, N.; DiDonato, J.A.; Rosette, C.; Helmberg, A.; Karin, M.
: Immunosuppression by glucocorticoids: inhibition of NF-kappa-B activity
through induction of I-kappa-B synthesis. Science 270: 286-290,
1995.

3. Baeuerle, P. A.: I-kappa-B--NF-kappa-B structures: at the interface
of inflammation control. Cell 95: 729-731, 1998.

4. Bredel, M.; Scholtens, D. M.; Yadav, A. K.; Alvarez, A. A.; Renfrow,
J. J.; Chandler, J. P.; Yu, I. L. Y.; Carro, M. S.; Dai, F.; Tagge,
M. J.; Ferrarese, R.; Bredel, C.; and 13 others: NFKBIA deletion
in glioblastomas. New Eng. J. Med. 364: 627-637, 2011.

5. Cai, D.; Frantz, J. D.; Tawa, N. E., Jr.; Melendez, P. A.; Oh,
B.-C.; Lidov, H. G. W.; Hasselgren, P.-O.; Frontera, W. R.; Lee, J.;
Glass, D. J.; Shoelson, S. E.: IKK-beta/NF-kappa-B activation causes
severe muscle wasting in mice. Cell 119: 285-298, 2004.

6. Courtois, G.; Smahi, A.; Reichenbach, J.; Doffinger, R.; Cancrini,
C.; Bonnet, M.; Puel, A.; Chable-Bessia, C.; Yamaoka, S.; Feinberg,
J.; Dupuis-Girod, S.; Bodemer, C.; Livadiotti, S.; Novelli, F.; Rossi,
P.; Fischer, A.; Israel, A.; Munnich, A.; Le Deist, F.; Casanova,
J.-L.: A hypermorphic I-kappa-B-alpha mutation is associated with
autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J.
Clin. Invest. 112: 1108-1115, 2003.

7. Dajee, M.; Lazarov, M.; Zhang, J. Y.; Cai, T.; Green, C. L.; Russell,
A. J.; Marinkovich, M. P.; Tao, S.; Lin, Q.; Kubo, Y.; Khavari, P.
A.: NF-kappa-B blockade and oncogenic Ras trigger invasive human
epidermal neoplasia. Nature 421: 639-643, 2003.

8. Haskill, S.; Beg, A. A.; Tompkins, S. M.; Morris, J. S.; Yurochko,
A. D.; Sampson-Johannes, A.; Mondal, K.; Ralph, P.; Baldwin, A. S.,
Jr.: Characterization of an immediate-early gene induced in adherent
monocytes that encodes I-kappa-B-like activity. Cell 65: 1281-1289,
1991.

9. Hoffmann, A.; Levchenko, A.; Scott, M. L.; Baltimore, D.: The
I-kappa-B-NF-kappa-B signaling module: temporal control and selective
gene activation. Science 298: 1241-1245, 2002. Note: Erratum: Science
318: 1550 only, 2007.

10. Huxford, T.; Huang, D.-B.; Malek, S.; Ghosh, G.: The crystal
structure of the I-kappa-B-alpha/NF-kappa-B complex reveals mechanisms
of NF-kappa-B inactivation. Cell 95: 759-770, 1998.

11. Ito, C. Y.; Adey, N.; Bautch, V. L.; Baldwin, A. S., Jr.: Structure
and evolution of the human IKBA gene. Genomics 29: 490-495, 1995.

12. Jacobs, M. D.; Harrison, S. C.: Structure of an I-kappa-B-alpha/NF-kappa-B
complex. Cell 95: 749-758, 1998.

13. Janssen, R.; van Wengen, A.; Hoeve, M. A.; ten Dam, M.; van der
Burg, M.; van Dongen, J.; van de Vosse, E.; van Tol, M.; Bredius,
R.; Ottenhoff, T. H.; Weemaes, C.; van Dissel, J. T.; Lankester, A.
: The same I-kappa-B-alpha mutation in two related individuals leads
to completely different clinical symptoms. J. Exp. Med. 200: 559-568,
2004.

14. Jung, M.; Zhang, Y.; Lee, S.; Dritschilo, A.: Correction of radiation
sensitivity in ataxia telangiectasia cells by a truncated I-kappa-B-alpha. Science 268:
1619-1621, 1995.

15. Le Beau, M. M.; Ito, C.; Cogswell, P.; Espinosa, R., III; Fernald,
A. A.; Baldwin, A. S., Jr.: Chromosomal localization of the genes
encoding the p50/p105 subunits of NF-kappa-B (NFKB2) and the I-kappa-B/MAD-3
(NFKBI) inhibitor of NF-kappa-B to 4q24 and 14q13, respectively. Genomics 14:
529-531, 1992.

16. Lopez-Granados, E.; Keenan, J. E.; Kinney, M. C.; Leo, H.; Jain,
N.; Ma, C. A.; Quinones, R.; Gelfand, E. W.; Jain, A.: A novel mutation
in NFKBIA/IKBA results in a degradation-resistant N-truncated protein
and is associated with ectodermal dysplasia with immunodeficiency. Hum.
Mutat. 29: 861-868, 2008.

17. McDonald, D. R.; Mooster, J. L.; Reddy, M.; Bawle, E.; Secord,
E.; Geha, R. S.: Heterozygous N-terminal deletion of I-kappa-B-alpha
results in functional nuclear factor kappa-B haploinsufficiency, ectodermal
dysplasia, and immune deficiency. J. Allergy Clin. Immun. 120: 900-907,
2007.

18. Neish, A. S..; Gewirtz, A. T.; Zeng, H.; Young, A. N.; Hobert,
M. E.; Karmali, V.; Rao, A. S.; Madara, J. L.: Prokaryotic regulation
of epithelial responses by inhibition of I-kappa-B-alpha ubiquitination. Science 289:
1560-1563, 2000.

19. Rupec, R. A.; Poujol, D.; Grosgeorge, J.; Carle, G. F.; Livolsi,
A.; Peyron, J.-F.; Schmid, R. M.; Baeuerle, P. A.; Messer, G.: Structural
analysis, expression, and chromosomal localization of the mouse ikba
gene. Immunogenetics 49: 395-403, 1999.

20. Scheinman, R. I.; Cogswell, P. C.; Lofquist, A. K.; Baldwin, A.
S., Jr.: Role of transcriptional activation of I-kappa-B-alpha in
mediation of immunosuppression by glucocorticoids. Science 270:
283-286, 1995.

21. Sigala, J. L. D.; Bottero, V.; Young, D. B.; Shevchenko, A.; Mercurio,
F.; Verma, I. M.: Activation of transcription factor NF-kappa-B requires
ELKS, an I-kappa-B kinase regulatory subunit. Science 304: 1963-1967,
2004.

22. Ting, A. Y.; Endy, D.: Decoding NF-kappa-B signaling. Science 298:
1189-1190, 2002.

*FIELD* CN
Paul J. Converse - updated: 1/23/2014
Ada Hamosh - updated: 6/19/2012
Cassandra L. Kniffin - updated: 6/26/2008
Ada Hamosh - updated: 4/24/2008
Stylianos E. Antonarakis - updated: 3/30/2005
Ada Hamosh - updated: 7/26/2004
Victor A. McKusick - updated: 11/18/2003
Ada Hamosh - updated: 2/4/2003
Paul J. Converse - updated: 11/14/2002
Paul J. Converse - updated: 8/31/2000
Paul J. Converse - updated: 2/15/2000
Victor A. McKusick - updated: 6/8/1999
Stylianos E. Antonarakis - updated: 12/22/1998
Alan F. Scott - updated: 11/8/1995

*FIELD* CD
Victor A. McKusick: 10/4/1993

*FIELD* ED
mgross: 01/24/2014
mcolton: 1/23/2014
alopez: 6/26/2012
terry: 6/19/2012
carol: 2/26/2009
wwang: 7/3/2008
ckniffin: 6/26/2008
alopez: 5/6/2008
terry: 4/24/2008
wwang: 12/20/2006
terry: 12/18/2006
terry: 7/26/2006
wwang: 3/28/2006
terry: 3/24/2006
mgross: 3/30/2005
alopez: 7/26/2004
mgross: 3/17/2004
tkritzer: 11/20/2003
terry: 11/18/2003
alopez: 2/5/2003
terry: 2/4/2003
mgross: 11/14/2002
alopez: 8/31/2000
alopez: 4/14/2000
carol: 2/15/2000
alopez: 2/4/2000
alopez: 7/12/1999
terry: 6/8/1999
alopez: 4/12/1999
carol: 12/22/1998
alopez: 11/6/1998
alopez: 11/5/1998
alopez: 11/4/1998
alopez: 8/21/1998
dkim: 7/30/1998
joanna: 5/8/1998
terry: 11/11/1997
alopez: 7/10/1997
mark: 1/17/1996
mark: 11/8/1995
mark: 6/30/1995
carol: 10/11/1993
carol: 10/4/1993

MIM 612132
*RECORD*
*FIELD* NO
612132
*FIELD* TI
#612132 ECTODERMAL DYSPLASIA, ANHIDROTIC, WITH T-CELL IMMUNODEFICIENCY, AUTOSOMAL
DOMINANT
read more*FIELD* TX
A number sign (#) is used with this entry because autosomal dominant
anhidrotic ectodermal dysplasia with T-cell immunodeficiency is caused
by mutation in the NFKBIA gene (164008).

See also 300291 for an X-linked form of the disorder.

DESCRIPTION

Mutations in the NFKBIA gene result in functional impairment of NFKB1
(164011), a master transcription factor required for normal activation
of immune responses. Interruption of NFKB1 signaling results in
decreased production of proinflammatory cytokines and certain
interferons, rendering patients susceptible to infection (McDonald et
al., 2007).

CLINICAL FEATURES

Courtois et al. (2003) reported a 7-year-old boy with autosomal dominant
anhidrotic ectodermal dysplasia and T-cell immunodeficiency. His parents
were unaffected and not related. Since 2 months of age he had chronic
diarrhea, recurrent bronchopneumonitis, hepatosplenomegaly, and failure
to thrive. Bone marrow transplantation was performed at 1 year of age. A
diagnosis of ectodermal dysplasia with immunodeficiency was made at the
age of 3 years on the basis of dry, rough skin, moderately sparse scalp
hair, and conical teeth. The patient had no other overt developmental
defects. Dupuis-Girod et al. (2006) reported on the successful bone
marrow transplant in the patient reported by Courtois et al. (2003). At
8 years of age, the patient had total donor chimerism in his blood
cells, which restored innate and adaptive immune responses. However, he
continued to receive occasional immunoglobulin substitutions.

Janssen et al. (2004) reported a male infant with multiple recurrent
infections. Laboratory studies showed agammaglobulinemia, increased IgM,
and persistent leukocytosis composed mainly of naive T cells. During the
first years of life, he was noted to have conical teeth, dry skin,
periorbital wrinkling, speech delay, and growth retardation. The
patient's father was diagnosed with juvenile arthritis at age 6 years
and was treated with corticosteroids. He had repeated infections as a
teen which were managed by antibiotics. At the time of this report, he
had no health complaints and had normal serum Ig and lymphocyte counts.
T cells derived from the patient showed impaired proliferative
responses, but those from the father were much less severely affected.
Monocytes from both patients showed defective signaling.

McDonald et al. (2007) reported a 10-year-old girl with a history of
multiple episodes of pneumonia since 2 months of age and evidence of
bronchiectasis. Physical examination showed slightly thin hair, recessed
hairline, pegged teeth, and coarse skin. She was noted to be heat
intolerant and unable to sweat, and was diagnosed with ectodermal
dysplasia. Her parents were unaffected. Immunologic studies showed
markedly increased serum IgA and low serum IgM. Serum levels of IgG and
IgG subclasses were normal. She also had lymphocytosis, with normal
percentages of T and B lymphocytes and natural killer cells. T-cell
proliferation studies were normal. The patient had protective titers to
immunization with tetanus toxoid; however, she had no specific antibody
response after immunization to any of the 14 polysaccharide antigens
contained in the pneumococcal polysaccharide vaccine. Stimulation
studies showed defects in the production of NFKB-dependent cytokines.

Lopez-Granados et al. (2008) reported a male infant with anhidrotic
ectodermal dysplasia and T-cell immunodeficiency. He had failure to
thrive, developed multiple infections including gastrointestinal and
respiratory infections, and died at age 9 months from complications of a
cord blood transplant. Skin biopsy showed absence of sweat glands, and
laboratory studies showed normal serum immunoglobulin levels but
impaired production of NFKB1-regulated cytokines. In vitro studies
showed that the mutant NFKBIA protein inhibited NFKB signaling by
functioning as a dominant negative on NFKB activity in lymphocytes and
monocytes.

MOLECULAR GENETICS

In a 7-year-old boy with autosomal dominant anhidrotic ectodermal
dysplasia and T-cell immunodeficiency, Courtois et al. (2003) identified
a heterozygous mutation in the NFKBIA gene (S32I; 164008.0001). Janssen
et al. (2004) identified the S32I mutation in a father and son with the
disorder. However, the father had a much less severe phenotype and was
found to be mosaic for the mutation.

In a patient with anhidrotic ectodermal dysplasia and immune deficiency,
McDonald et al. (2007) identified a heterozygous mutation in the NFKBIA
gene (164008.0002).

In a male infant with anhidrotic ectodermal dysplasia and T-cell
immunodeficiency, Lopez-Granados et al. (2008) identified a de novo
heterozygous mutation in the NFKB1A gene (164008.0003).

*FIELD* RF
1. Courtois, G.; Smahi, A.; Reichenbach, J.; Doffinger, R.; Cancrini,
C.; Bonnet, M.; Puel, A.; Chable-Bessia, C.; Yamaoka, S.; Feinberg,
J.; Dupuis-Girod, S.; Bodemer, C.; Livadiotti, S.; Novelli, F.; Rossi,
P.; Fischer, A.; Israel, A.; Munnich, A.; Le Deist, F.; Casanova,
J.-L.: A hypermorphic I-kappa-B-alpha mutation is associated with
autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J.
Clin. Invest. 112: 1108-1115, 2003.

2. Dupuis-Girod, S.; Cancrini, C.; Le Deist, F.; Palma, P.; Bodemer,
C.; Puel, A.; Livadiotti, S.; Picard, C.; Bossuyt, X.; Rossi, P.;
Fischer, A.; Casanova, J.-L.: Successful allogeneic hemopoietic stem
cell transplantation in a child who had anhidrotic ectodermal dysplasia
with immunodeficiency. Pediatrics 118: e205-e211, 2006.

3. Janssen, R.; van Wengen, A.; Hoeve, M. A.; ten Dam, M.; van der
Burg, M.; van Dongen, J.; van de Vosse, E.; van Tol, M.; Bredius,
R.; Ottenhoff, T. H.; Weemaes, C.; van Dissel, J. T.; Lankester, A.
: The same I-kappa-B-alpha mutation in two related individuals leads
to completely different clinical symptoms. J. Exp. Med. 200: 559-568,
2004.

4. Lopez-Granados, E.; Keenan, J. E.; Kinney, M. C.; Leo, H.; Jain,
N.; Ma, C. A.; Quinones, R.; Gelfand, E. W.; Jain, A.: A novel mutation
in NFKBIA/IKBA results in a degradation-resistant N-truncated protein
and is associated with ectodermal dysplasia with immunodeficiency. Hum.
Mutat. 29: 861-868, 2008.

5. McDonald, D. R.; Mooster, J. L.; Reddy, M.; Bawle, E.; Secord,
E.; Geha, R. S.: Heterozygous N-terminal deletion of I-kappa-B-alpha
results in functional nuclear factor kappa-B haploinsufficiency, ectodermal
dysplasia, and immune deficiency. J. Allergy Clin. Immun. 120: 900-907,
2007.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Face];
Frontal bossing;
[Nose];
Saddle nose;
[Teeth];
Hypodontia;
Conical teeth

RESPIRATORY:
Respiratory infections, recurrent

ABDOMEN:
[Gastrointestinal];
Gastrointestinal infections, recurrent

SKIN, NAILS, HAIR:
[Skin];
Anhidrosis;
Hypohidrosis;
Lack of sweat glands;
Heat intolerance;
Cutaneous candidiasis;
[Hair];
Light, sparse hair

IMMUNOLOGY:
Recurrent infections;
Low or normal serum immunoglobulins;
Defective production of NFKB1-dependent cytokines by white blood cells;
Impaired immune responses

MISCELLANEOUS:
Onset in infancy;
See also the X-linked form (300291)

MOLECULAR BASIS:
Caused by mutation in the nuclear factor of kappa light chain gene
enhancer in B cells inhibitor alpha gene (NFKBIA, 164008.0001).

*FIELD* CD
Cassandra L. Kniffin: 6/26/2008

*FIELD* ED
joanna: 01/28/2009
ckniffin: 6/26/2008

*FIELD* CD
Cassandra L. Kniffin: 6/26/2008

*FIELD* ED
carol: 11/05/2009
carol: 7/3/2008
wwang: 7/3/2008
ckniffin: 6/26/2008