ID FOXI3_HUMAN Reviewed; 420 AA. AC A8MTJ6; B5RI09; DT 10-JUN-2008, integrated into UniProtKB/Swiss-Prot. DT 24-MAR-2009, sequence version 3. DT 27-MAR-2024, entry version 113. DE RecName: Full=Forkhead box protein I3 {ECO:0000305}; GN Name=FOXI3 {ECO:0000303|PubMed:36260083, ECO:0000312|HGNC:HGNC:35123}; 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 [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [2] RP IDENTIFICATION. RX PubMed=18787161; DOI=10.1126/science.1162525; RA Droegemueller C., Karlsson E.K., Hytoenen M.K., Perloski M., Dolf G., RA Sainio K., Lohi H., Lindblad-Toh K., Leeb T.; RT "A mutation in hairless dogs implicates FOXI3 in ectodermal development."; RL Science 321:1462-1462(2008). RN [3] RP VARIANTS CFM2 TRP-236 AND CYS-240. RX PubMed=36260083; DOI=10.1016/j.gim.2022.09.005; RA Quiat D., Timberlake A.T., Curran J.J., Cunningham M.L., McDonough B., RA Artunduaga M.A., DePalma S.R., Duenas-Roque M.M., Gorham J.M., RA Gustafson J.A., Hamdan U., Hing A.V., Hurtado-Villa P., Nicolau Y., RA Osorno G., Pachajoa H., Porras-Hurtado G.L., Quintanilla-Dieck L., RA Serrano L., Tumblin M., Zarante I., Luquetti D.V., Eavey R.D., Heike C.L., RA Seidman J.G., Seidman C.E.; RT "Damaging variants in FOXI3 cause microtia and craniofacial microsomia."; RL Genet. Med. 25:143-150(2023). RN [4] RP FUNCTION, SUBCELLULAR LOCATION, VARIANTS CFM2 TYR-102; 119-SER--ALA-124 RP DEL; THR-147; ASN-169; PHE-199; ARG-225; LEU-234; VAL-234; CYS-235; RP GLN-236; TRP-236; GLN-238; CYS-240; HIS-240; LEU-355; 373-SER--THR-376 DEL RP AND 415-ARG--VAL-420 DEL, AND CHARACTERIZATION OF VARIANTS CFM2 TYR-102; RP 119-SER--ALA-124 DEL; THR-147; ASN-169; PHE-199; ARG-225; LEU-234; VAL-234; RP CYS-235; GLN-236; TRP-236; GLN-238; CYS-240; HIS-240; LEU-355; RP 373-SER--THR-376 DEL AND 415-ARG--VAL-420 DEL. RX PubMed=37041148; DOI=10.1038/s41467-023-37703-6; RA Mao K., Borel C., Ansar M., Jolly A., Makrythanasis P., Froehlich C., RA Iwaszkiewicz J., Wang B., Xu X., Li Q., Blanc X., Zhu H., Chen Q., Jin F., RA Ankamreddy H., Singh S., Zhang H., Wang X., Chen P., Ranza E., RA Paracha S.A., Shah S.F., Guida V., Piceci-Sparascio F., Melis D., RA Dallapiccola B., Digilio M.C., Novelli A., Magliozzi M., Fadda M.T., RA Streff H., Machol K., Lewis R.A., Zoete V., Squeo G.M., Prontera P., RA Mancano G., Gori G., Mariani M., Selicorni A., Psoni S., Fryssira H., RA Douzgou S., Marlin S., Biskup S., De Luca A., Merla G., Zhao S., Cox T.C., RA Groves A.K., Lupski J.R., Zhang Q., Zhang Y.B., Antonarakis S.E.; RT "FOXI3 pathogenic variants cause one form of craniofacial microsomia."; RL Nat. Commun. 14:2026-2026(2023). CC -!- FUNCTION: Transcription factor required for pharyngeal arch CC development, which is involved in hair, ear, jaw and dental development CC (PubMed:37041148). May act as a pioneer transcription factor during CC pharyngeal arch development (By similarity). Required for epithelial CC cell differentiation within the epidermis (By similarity). Acts at CC multiple stages of otic placode induction: necessary for preplacodal CC ectoderm to execute an inner ear program (By similarity). Required for CC hair follicle stem cell specification (By similarity). Acts downstream CC of TBX1 for the formation of the thymus and parathyroid glands from the CC third pharyngeal pouch (By similarity). {ECO:0000250|UniProtKB:D3Z120, CC ECO:0000269|PubMed:37041148}. CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:37041148}. CC -!- DOMAIN: The 9aaTAD motif is a transactivation domain present in a large CC number of yeast and animal transcription factors. CC {ECO:0000250|UniProtKB:D3Z120}. CC -!- PTM: Phosphorylation promotes the transcription factor activity. CC Dephosphorylation by protein phosphatase 2A (PP2A) reduces its CC activity. {ECO:0000250|UniProtKB:D3Z120}. CC -!- DISEASE: Craniofacial microsomia 2 (CFM2) [MIM:620444]: A form of CC craniofacial microsomia, a disorder characterized by a spectrum of CC craniofacial malformations ranging from isolated microtia with or CC without aural atresia to underdevelopment of the mandible, maxilla, CC orbit, facial soft tissue, and/or facial nerve. Most CFM2 patients CC exhibit isolated unilateral or bilateral grade II/III microtia, with or CC without atresia, although some patients show only minor external ear CC defects. Mandibular hypoplasia, micrognathia, and dental anomalies have CC also been observed. CFM2 inheritance can be autosomal dominant or CC autosomal recessive. {ECO:0000269|PubMed:36260083, CC ECO:0000269|PubMed:37041148}. Note=The disease is caused by variants CC affecting the gene represented in this entry. 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; AC012671; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BN001221; CAR63508.1; -; Genomic_DNA. DR EMBL; BN001222; CAR63509.1; -; mRNA. DR CCDS; CCDS77433.1; -. DR RefSeq; NP_001129121.1; NM_001135649.1. DR AlphaFoldDB; A8MTJ6; -. DR SMR; A8MTJ6; -. DR BioGRID; 131290; 2. DR STRING; 9606.ENSP00000478384; -. DR iPTMnet; A8MTJ6; -. DR PhosphoSitePlus; A8MTJ6; -. DR BioMuta; FOXI3; -. DR EPD; A8MTJ6; -. DR MassIVE; A8MTJ6; -. DR PaxDb; 9606-ENSP00000478384; -. DR PeptideAtlas; A8MTJ6; -. DR ProteomicsDB; 2029; -. DR Antibodypedia; 73246; 149 antibodies from 23 providers. DR DNASU; 344167; -. DR Ensembl; ENST00000428390.3; ENSP00000478384.2; ENSG00000214336.5. DR GeneID; 344167; -. DR KEGG; hsa:344167; -. DR MANE-Select; ENST00000428390.3; ENSP00000478384.2; NM_001135649.3; NP_001129121.1. DR UCSC; uc032nud.2; human. DR AGR; HGNC:35123; -. DR CTD; 344167; -. DR DisGeNET; 344167; -. DR GeneCards; FOXI3; -. DR HGNC; HGNC:35123; FOXI3. DR HPA; ENSG00000214336; Group enriched (placenta, retina). DR MalaCards; FOXI3; -. DR MIM; 612351; gene. DR MIM; 620444; phenotype. DR neXtProt; NX_A8MTJ6; -. DR OpenTargets; ENSG00000214336; -. DR PharmGKB; PA164720107; -. DR VEuPathDB; HostDB:ENSG00000214336; -. DR eggNOG; KOG2294; Eukaryota. DR GeneTree; ENSGT00940000162575; -. DR HOGENOM; CLU_046860_0_0_1; -. DR InParanoid; A8MTJ6; -. DR OMA; CGDNFGV; -. DR OrthoDB; 5385885at2759; -. DR PhylomeDB; A8MTJ6; -. DR PathwayCommons; A8MTJ6; -. DR BioGRID-ORCS; 344167; 16 hits in 269 CRISPR screens. DR GenomeRNAi; 344167; -. DR Pharos; A8MTJ6; Tbio. DR PRO; PR:A8MTJ6; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; A8MTJ6; Protein. DR Bgee; ENSG00000214336; Expressed in primordial germ cell in gonad and 8 other cell types or tissues. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:UniProtKB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central. DR GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central. DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central. DR GO; GO:0009957; P:epidermal cell fate specification; ISS:UniProtKB. DR GO; GO:0001942; P:hair follicle development; ISS:UniProtKB. DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; ISS:UniProtKB. DR GO; GO:1905040; P:otic placode development; ISS:UniProtKB. DR GO; GO:0060017; P:parathyroid gland development; ISS:UniProtKB. DR GO; GO:0060037; P:pharyngeal system development; IMP:UniProtKB. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0048538; P:thymus development; ISS:UniProtKB. DR CDD; cd20053; FH_FOXI1; 1. DR Gene3D; 1.10.10.10; Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain; 1. DR InterPro; IPR001766; Fork_head_dom. DR InterPro; IPR018122; TF_fork_head_CS_1. DR InterPro; IPR030456; TF_fork_head_CS_2. DR InterPro; IPR036388; WH-like_DNA-bd_sf. DR InterPro; IPR036390; WH_DNA-bd_sf. DR PANTHER; PTHR11829; FORKHEAD BOX PROTEIN; 1. DR PANTHER; PTHR11829:SF310; FORKHEAD BOX PROTEIN I3; 1. DR Pfam; PF00250; Forkhead; 1. DR PRINTS; PR00053; FORKHEAD. DR SMART; SM00339; FH; 1. DR SUPFAM; SSF46785; Winged helix' DNA-binding domain; 1. DR PROSITE; PS00657; FORK_HEAD_1; 1. DR PROSITE; PS00658; FORK_HEAD_2; 1. DR PROSITE; PS50039; FORK_HEAD_3; 1. PE 1: Evidence at protein level; KW Developmental protein; Disease variant; DNA-binding; Nucleus; KW Phosphoprotein; Reference proteome; Transcription; KW Transcription regulation. FT CHAIN 1..420 FT /note="Forkhead box protein I3" FT /id="PRO_0000341225" FT DNA_BIND 145..239 FT /note="Fork-head" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089" FT REGION 103..122 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 234..306 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 364..396 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 235..241 FT /note="Nuclear localization signal" FT /evidence="ECO:0000269|PubMed:37041148" FT MOTIF 406..414 FT /note="9aaTAD" FT /evidence="ECO:0000250|UniProtKB:D3Z120" FT COMPBIAS 245..262 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 290..306 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 119 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:D3Z120" FT MOD_RES 277 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:D3Z120" FT MOD_RES 285 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:D3Z120" FT MOD_RES 287 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:D3Z120" FT VARIANT 102 FT /note="F -> Y (in CFM2; uncertain significance; decreased FT transcription factor activity; does not affect localization FT to the nucleus)" FT /evidence="ECO:0000269|PubMed:37041148" FT /id="VAR_088275" FT VARIANT 119..124 FT /note="Missing (in CFM2; decreased transcription factor FT activity; does not affect localization to the nucleus)" FT /evidence="ECO:0000269|PubMed:37041148" FT /id="VAR_088276" FT VARIANT 147 FT /note="P -> T (in CFM2; decreased transcription factor FT activity; localization to the nucleus but aggregating into FT granular foci)" FT /evidence="ECO:0000269|PubMed:37041148" FT /id="VAR_088277" FT VARIANT 169 FT /note="S -> N (in CFM2; decreased transcription factor FT activity; does not affect localization to the nucleus)" FT /evidence="ECO:0000269|PubMed:37041148" FT /id="VAR_088278" FT VARIANT 199 FT /note="L -> F (in CFM2; decreased transcription factor FT activity; does not affect localization to the nucleus)" FT /evidence="ECO:0000269|PubMed:37041148" FT /id="VAR_088279" FT VARIANT 225 FT /note="C -> R (in CFM2; decreased transcription factor FT activity; localization to the nucleus but aggregating into FT granular foci)" FT /evidence="ECO:0000269|PubMed:37041148" FT /id="VAR_088280" FT VARIANT 234 FT /note="F -> L (in CFM2; decreased transcription factor FT activity; does not affect localization to the nucleus; FT dbSNP:rs955268781)" FT /evidence="ECO:0000269|PubMed:37041148" FT /id="VAR_088281" FT VARIANT 234 FT /note="F -> V (in CFM2; decreased transcription factor FT activity; localization to the nucleus but aggregating into FT granular foci)" FT /evidence="ECO:0000269|PubMed:37041148" FT /id="VAR_088282" FT VARIANT 235 FT /note="R -> C (in CFM2; decreased transcription factor FT activity; decreased localization to the nucleus; FT dbSNP:rs1316696594)" FT /evidence="ECO:0000269|PubMed:37041148" FT /id="VAR_088283" FT VARIANT 236 FT /note="R -> Q (in CFM2; decreased transcription factor FT activity; decreased localization to the nucleus; FT dbSNP:rs182321240)" FT /evidence="ECO:0000269|PubMed:37041148" FT /id="VAR_088284" FT VARIANT 236 FT /note="R -> W (in CFM2; decreased transcription factor FT activity; decreased localization to the nucleus)" FT /evidence="ECO:0000269|PubMed:36260083, FT ECO:0000269|PubMed:37041148" FT /id="VAR_088285" FT VARIANT 238 FT /note="R -> Q (in CFM2; decreased transcription factor FT activity; decreased localization to the nucleus; FT dbSNP:rs923448937)" FT /evidence="ECO:0000269|PubMed:37041148" FT /id="VAR_088286" FT VARIANT 240 FT /note="R -> C (in CFM2; decreased transcription factor FT activity; decreased localization to the nucleus; FT dbSNP:rs1451029499)" FT /evidence="ECO:0000269|PubMed:36260083, FT ECO:0000269|PubMed:37041148" FT /id="VAR_088287" FT VARIANT 240 FT /note="R -> H (in CFM2; decreased transcription factor FT activity; decreased localization to the nucleus; FT dbSNP:rs1370585001)" FT /evidence="ECO:0000269|PubMed:37041148" FT /id="VAR_088288" FT VARIANT 355 FT /note="P -> L (in CFM2; decreased transcription factor FT activity; does not affect localization to the nucleus; FT dbSNP:rs965851622)" FT /evidence="ECO:0000269|PubMed:37041148" FT /id="VAR_088289" FT VARIANT 373..376 FT /note="Missing (in CFM2; uncertain significance; decreased FT transcription factor activity; does not affect localization FT to the nucleus)" FT /evidence="ECO:0000269|PubMed:37041148" FT /id="VAR_088290" FT VARIANT 415..420 FT /note="Missing (in CFM2; decreased transcription factor FT activity; does not affect localization to the nucleus)" FT /evidence="ECO:0000269|PubMed:37041148" FT /id="VAR_088291" SQ SEQUENCE 420 AA; 43326 MW; 4531A9DA62B322E7 CRC64; MALYCGDNFG VYSQPGLPPP AATAAAPGAP PAARAPYGLA DYAAPPAAAA NPYLWLNGPG VGGPPSAAAA AAAAYLGAPP PPPPPGAAAG PFLQPPPAAG TFGCSQRPFA QPAPAAPASP AAPAGPGELG WLSMASREDL MKMVRPPYSY SALIAMAIQS APERKLTLSH IYQFVADSFP FYQRSKAGWQ NSIRHNLSLN DCFKKVPRDE DDPGKGNYWT LDPNCEKMFD NGNFRRKRKR RSEASNGSTV AAGTSKSEEG LSSGLGSGVG GKPEEESPST LLRPSHSPEP PEGTKSTASS PGGPMLTSTP CLNTFFSSLS SLSVSSSVST QRALPGSRHL GIQGAQLPSS GVFSPTSISE ASADTLQLSN STSNSTGQRS SYYSPFPAST SGGQSSPFSS PFHNFSMVNS LIYPREGSEV //