ID FOXE1_HUMAN Reviewed; 373 AA. AC O00358; O75765; Q5T109; Q99526; DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot. DT 23-SEP-2008, sequence version 3. DT 24-JAN-2024, entry version 197. DE RecName: Full=Forkhead box protein E1; DE AltName: Full=Forkhead box protein E2; DE AltName: Full=Forkhead-related protein FKHL15; DE AltName: Full=HFKH4; DE AltName: Full=HNF-3/fork head-like protein 5; DE Short=HFKL5; DE AltName: Full=Thyroid transcription factor 2; DE Short=TTF-2; GN Name=FOXE1; Synonyms=FKHL15, FOXE2, TITF2, TTF2; 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 PRELIMINARY NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Fetal brain; RX PubMed=9052737; DOI=10.1089/dna.1997.16.165; RA Wiese S., Emmerich D., Schroeder B., Murphy D.B., Grzeschik K.H., RA Van Kessel A.G., Thies U.; RT "The novel human HNF-3/fork head-like 5 gene: chromosomal localization and RT expression pattern."; RL DNA Cell Biol. 16:165-171(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND POLYMORPHISM OF POLY-ALA REGION. RC TISSUE=Keratinocyte; RX PubMed=9169137; DOI=10.1006/geno.1997.4692; RA Chadwick B.P., Obermayr F., Frischauf A.-M.; RT "FKHL15, a new human member of the forkhead gene family located on RT chromosome 9q22."; RL Genomics 41:390-396(1997). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND POLYMORPHISM. RX PubMed=10403172; DOI=10.1016/s0300-9084(99)80092-3; RA Macchia P.E., Mattei M.-G., Lapi P., Fenzi G., Di Lauro R.; RT "Cloning, chromosomal localization and identification of polymorphisms in RT the human thyroid transcription factor 2 gene (TITF2)."; RL Biochimie 81:433-440(1999). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164053; DOI=10.1038/nature02465; RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., RA Dunham I.; RT "DNA sequence and analysis of human chromosome 9."; RL Nature 429:369-374(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP FUNCTION, INVOLVEMENT IN BAMLAZ, VARIANT BAMLAZ VAL-65, AND RP CHARACTERIZATION OF VARIANT BAMLAZ VAL-65. RX PubMed=9697705; DOI=10.1038/1294; RA Clifton-Bligh R.J., Wentworth J.M., Heinz P., Crisp M.S., John R., RA Lazarus J.H., Ludgate M., Chatterjee V.K.; RT "Mutation of the gene encoding human TTF-2 associated with thyroid RT agenesis, cleft palate and choanal atresia."; RL Nat. Genet. 19:399-401(1998). RN [7] RP FUNCTION, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS BAMLAZ ASN-57 RP AND VAL-65, AND CHARACTERIZATION OF VARIANTS CONGENITAL HYPOTHYROIDISM RP CYS-102 AND SER-137. RX PubMed=21177256; DOI=10.1093/hmg/ddq547; RA Venza I., Visalli M., Parrillo L., De Felice M., Teti D., Venza M.; RT "MSX1 and TGF-beta3 are novel target genes functionally regulated by RT FOXE1."; RL Hum. Mol. Genet. 20:1016-1025(2011). RN [8] RP FUNCTION, INVOLVEMENT IN NMTC4, VARIANT NMTC4 GLY-248, AND CHARACTERIZATION RP OF VARIANT NMTC4 GLY-248. RX PubMed=25381600; DOI=10.1007/s12020-014-0470-0; RA Pereira J.S., da Silva J.G., Tomaz R.A., Pinto A.E., Bugalho M.J., RA Leite V., Cavaco B.M.; RT "Identification of a novel germline FOXE1 variant in patients with familial RT non-medullary thyroid carcinoma (FNMTC)."; RL Endocrine 49:204-214(2015). RN [9] RP VARIANT BAMLAZ ASN-57, CHARACTERIZATION OF VARIANT BAMLAZ ASN-57 AND RP VAL-65, AND FUNCTION. RX PubMed=12165566; DOI=10.1093/hmg/11.17.2051; RA Castanet M., Park S.M., Smith A., Bost M., Leger J., Lyonnet S., Pelet A., RA Czernichow P., Chatterjee K., Polak M.; RT "A novel loss-of-function mutation in TTF-2 is associated with congenital RT hypothyroidism, thyroid agenesis and cleft palate."; RL Hum. Mol. Genet. 11:2051-2059(2002). RN [10] RP VARIANT CONGENITAL HYPOTHYROIDISM CYS-102, CHARACTERIZATION OF VARIANT RP CONGENITAL HYPOTHYROIDISM CYS-102, AND FUNCTION. RX PubMed=16882747; DOI=10.1210/jc.2006-0405; RA Baris I., Arisoy A.E., Smith A., Agostini M., Mitchell C.S., Park S.M., RA Halefoglu A.M., Zengin E., Chatterjee V.K., Battaloglu E.; RT "A novel missense mutation in human TTF-2 (FKHL15) gene associated with RT congenital hypothyroidism but not athyreosis."; RL J. Clin. Endocrinol. Metab. 91:4183-4187(2006). RN [11] RP VARIANT CONGENITAL HYPOTHYROIDISM ASP-132, CHARACTERIZATION OF VARIANT RP CONGENITAL HYPOTHYROIDISM ASP-132, AND FUNCTION. RX PubMed=20094846; DOI=10.1007/s10528-009-9306-7; RA Kang I.N., Musa M., Harun F., Junit S.M.; RT "Characterization of mutations in the FOXE1 gene in a cohort of unrelated RT Malaysian patients with congenital hypothyroidism and thyroid dysgenesis."; RL Biochem. Genet. 48:141-151(2010). RN [12] RP VARIANT CONGENITAL HYPOTHYROIDISM SER-137, CHARACTERIZATION OF VARIANT RP CONGENITAL HYPOTHYROIDISM SER-137, AND FUNCTION. RX PubMed=20484477; DOI=10.1210/jc.2010-0275; RA Castanet M., Mallya U., Agostini M., Schoenmakers E., Mitchell C., RA Demuth S., Raymond F.L., Schwabe J., Gurnell M., Chatterjee V.K.; RT "Maternal isodisomy for chromosome 9 causing homozygosity for a novel FOXE1 RT mutation in syndromic congenital hypothyroidism."; RL J. Clin. Endocrinol. Metab. 95:4031-4036(2010). RN [13] RP VARIANT BAMLAZ SER-73, CHARACTERIZATION OF VARIANT BAMLAZ SER-73, AND RP FUNCTION. RX PubMed=24219130; DOI=10.1089/thy.2013.0417; RA Carre A., Hamza R.T., Kariyawasam D., Guillot L., Teissier R., Tron E., RA Castanet M., Dupuy C., El Kholy M., Polak M.; RT "A novel FOXE1 mutation (R73S) in Bamforth-Lazarus syndrome causing RT increased thyroidal gene expression."; RL Thyroid 24:649-654(2014). CC -!- FUNCTION: Transcription factor that binds consensus sites on a variety CC of gene promoters and activate their transcription. Involved in proper CC palate formation, most probably through the expression of MSX1 and CC TGFB3 genes which are direct targets of this transcription factor. Also CC implicated in thyroid gland morphogenesis. May indirectly play a role CC in cell growth and migration through the regulation of WNT5A CC expression. {ECO:0000269|PubMed:12165566, ECO:0000269|PubMed:16882747, CC ECO:0000269|PubMed:20094846, ECO:0000269|PubMed:20484477, CC ECO:0000269|PubMed:21177256, ECO:0000269|PubMed:24219130, CC ECO:0000269|PubMed:25381600, ECO:0000269|PubMed:9697705}. CC -!- INTERACTION: CC O00358; P19419: ELK1; NbExp=8; IntAct=EBI-11317834, EBI-726632; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:21177256}. CC -!- TISSUE SPECIFICITY: Detected in adult brain, placenta, lung, liver, CC skeletal muscle, kidney, pancreas, heart, colon, small intestine testis CC and thymus. Expression was strongest in heart and pancreas. CC -!- PTM: Phosphorylated. {ECO:0000250}. CC -!- POLYMORPHISM: An alanine stretch that varies from 12 to 19 residues is CC present. This polymorphisms can be used as a marker to study the role CC of FOXE1 in other cases of thyroid dysgenesis, especially in familial CC cases. CC -!- DISEASE: Bamforth-Lazarus syndrome (BAMLAZ) [MIM:241850]: An autosomal CC recessive disease characterized by congenital hypothyroidism due to CC thyroid agenesis or thyroid hypoplasia, cleft palate, spiky hair, with CC or without choanal atresia, and bifid epiglottis. CC {ECO:0000269|PubMed:12165566, ECO:0000269|PubMed:21177256, CC ECO:0000269|PubMed:24219130, ECO:0000269|PubMed:9697705}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Thyroid cancer, non-medullary, 4 (NMTC4) [MIM:616534]: A form CC of non-medullary thyroid cancer (NMTC), a cancer characterized by CC tumors originating from the thyroid follicular cells. NMTCs represent CC approximately 95% of all cases of thyroid cancer and are classified CC into papillary, follicular, Hurthle cell, and anaplastic neoplasms. CC {ECO:0000269|PubMed:25381600}. Note=Disease susceptibility is CC associated with variants affecting the gene represented in this entry. CC -!- SEQUENCE CAUTION: CC Sequence=CAA64246.1; Type=Miscellaneous discrepancy; Note=Several conflicts.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/47197/FOXE1"; 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; X94553; CAA64246.1; ALT_SEQ; mRNA. DR EMBL; U89995; AAC51294.1; -; mRNA. DR EMBL; Y13386; CAA73816.1; -; Genomic_DNA. DR EMBL; AL499604; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471105; EAW58856.1; -; Genomic_DNA. DR CCDS; CCDS35078.1; -. DR RefSeq; NP_004464.2; NM_004473.3. DR AlphaFoldDB; O00358; -. DR SMR; O00358; -. DR BioGRID; 108593; 105. DR IntAct; O00358; 76. DR MINT; O00358; -. DR STRING; 9606.ENSP00000364265; -. DR iPTMnet; O00358; -. DR PhosphoSitePlus; O00358; -. DR BioMuta; FOXE1; -. DR jPOST; O00358; -. DR MassIVE; O00358; -. DR PaxDb; 9606-ENSP00000364265; -. DR PeptideAtlas; O00358; -. DR ProteomicsDB; 47861; -. DR Pumba; O00358; -. DR Antibodypedia; 28896; 300 antibodies from 34 providers. DR DNASU; 2304; -. DR Ensembl; ENST00000375123.5; ENSP00000364265.3; ENSG00000178919.9. DR GeneID; 2304; -. DR KEGG; hsa:2304; -. DR MANE-Select; ENST00000375123.5; ENSP00000364265.3; NM_004473.4; NP_004464.2. DR UCSC; uc004axu.4; human. DR AGR; HGNC:3806; -. DR CTD; 2304; -. DR DisGeNET; 2304; -. DR GeneCards; FOXE1; -. DR HGNC; HGNC:3806; FOXE1. DR HPA; ENSG00000178919; Tissue enriched (thyroid). DR MalaCards; FOXE1; -. DR MIM; 241850; phenotype. DR MIM; 602617; gene. DR MIM; 616534; phenotype. DR neXtProt; NX_O00358; -. DR OpenTargets; ENSG00000178919; -. DR Orphanet; 95713; Athyreosis. DR Orphanet; 1226; Bamforth-Lazarus syndrome. DR Orphanet; 146; Differentiated thyroid carcinoma. DR Orphanet; 319487; Familial papillary or follicular thyroid carcinoma. DR PharmGKB; PA28223; -. DR VEuPathDB; HostDB:ENSG00000178919; -. DR eggNOG; KOG2294; Eukaryota. DR GeneTree; ENSGT00940000162270; -. DR HOGENOM; CLU_023357_0_1_1; -. DR InParanoid; O00358; -. DR OMA; HETPVFS; -. DR OrthoDB; 5385885at2759; -. DR PhylomeDB; O00358; -. DR TreeFam; TF316127; -. DR PathwayCommons; O00358; -. DR SignaLink; O00358; -. DR SIGNOR; O00358; -. DR BioGRID-ORCS; 2304; 21 hits in 1173 CRISPR screens. DR ChiTaRS; FOXE1; human. DR GeneWiki; FOXE1; -. DR GenomeRNAi; 2304; -. DR Pharos; O00358; Tbio. DR PRO; PR:O00358; -. DR Proteomes; UP000005640; Chromosome 9. DR RNAct; O00358; Protein. DR Bgee; ENSG00000178919; Expressed in right lobe of thyroid gland and 74 other cell types or tissues. DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0003700; F:DNA-binding transcription factor activity; 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:0043565; F:sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL. DR GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central. DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central. DR GO; GO:0016477; P:cell migration; ISS:UniProtKB. DR GO; GO:0160093; P:chordate pharynx development; IEP:UniProtKB. DR GO; GO:1904888; P:cranial skeletal system development; IEA:Ensembl. DR GO; GO:0048562; P:embryonic organ morphogenesis; ISS:UniProtKB. DR GO; GO:0031069; P:hair follicle morphogenesis; ISS:UniProtKB. DR GO; GO:0060022; P:hard palate development; IMP:UniProtKB. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; ISS:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0060023; P:soft palate development; IMP:UniProtKB. DR GO; GO:0048538; P:thymus development; IEP:UniProtKB. DR GO; GO:0030878; P:thyroid gland development; IMP:UniProtKB. DR GO; GO:0006590; P:thyroid hormone generation; ISS:UniProtKB. DR CDD; cd20019; FH_FOXE; 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:SF368; FORKHEAD BOX PROTEIN E1; 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. DR Genevisible; O00358; HS. PE 1: Evidence at protein level; KW Congenital hypothyroidism; Disease variant; DNA-binding; Nucleus; KW Phosphoprotein; Reference proteome; Transcription; KW Transcription regulation. FT CHAIN 1..373 FT /note="Forkhead box protein E1" FT /id="PRO_0000091826" FT DNA_BIND 53..147 FT /note="Fork-head" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089" FT REGION 19..51 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VARIANT 57 FT /note="S -> N (in BAMLAZ; without choanal atresia; no FT effect on protein abundance; no effect on localization to FT the nucleus; decreased sequence-specific DNA binding; FT decreased transcriptional activity; dbSNP:rs28937575)" FT /evidence="ECO:0000269|PubMed:12165566, FT ECO:0000269|PubMed:21177256" FT /id="VAR_016882" FT VARIANT 65 FT /note="A -> V (in BAMLAZ; loss of sequence-specific DNA FT binding; loss of transcriptional activity; FT dbSNP:rs104894110)" FT /evidence="ECO:0000269|PubMed:12165566, FT ECO:0000269|PubMed:21177256, ECO:0000269|PubMed:9697705" FT /id="VAR_008857" FT VARIANT 73 FT /note="R -> S (in BAMLAZ; no effect on protein abundance; FT no effect on sequence-specific DNA binding; enhances FT transcriptional activity toward TG and TPO genes)" FT /evidence="ECO:0000269|PubMed:24219130" FT /id="VAR_075978" FT VARIANT 102 FT /note="R -> C (in congenital hypothyroidism; with absence FT of thyroid agenesis; loss of sequence-specific DNA binding; FT loss of transcriptional activity; dbSNP:rs104894111)" FT /evidence="ECO:0000269|PubMed:16882747, FT ECO:0000269|PubMed:21177256" FT /id="VAR_027508" FT VARIANT 132 FT /note="N -> D (in congenital hypothyroidism; slightly FT decreased sequence-specific DNA binding to the TPO FT promoter; 0.5 fold decreased transcriptional activity; FT dbSNP:rs762041111)" FT /evidence="ECO:0000269|PubMed:20094846" FT /id="VAR_075979" FT VARIANT 137 FT /note="F -> S (in congenital hypothyroidism; loss of FT sequence-specific DNA binding; loss of transcriptional FT activity)" FT /evidence="ECO:0000269|PubMed:20484477, FT ECO:0000269|PubMed:21177256" FT /id="VAR_075980" FT VARIANT 179 FT /note="A -> AAA" FT /id="VAR_037643" FT VARIANT 248 FT /note="A -> G (in NMTC4; increased cell growth; increased FT cell migration; dbSNP:rs538912281)" FT /evidence="ECO:0000269|PubMed:25381600" FT /id="VAR_075981" SQ SEQUENCE 373 AA; 38076 MW; D201EAF05572FCF0 CRC64; MTAESGPPPP QPEVLATVKE ERGETAAGAG VPGEATGRGA GGRRRKRPLQ RGKPPYSYIA LIAMAIAHAP ERRLTLGGIY KFITERFPFY RDNPKKWQNS IRHNLTLNDC FLKIPREAGR PGKGNYWALD PNAEDMFESG SFLRRRKRFK RSDLSTYPAY MHDAAAAAAA AAAAAAAAAI FPGAVPAARP PYPGAVYAGY APPSLAAPPP VYYPAASPGP CRVFGLVPER PLSPELGPAP SGPGGSCAFA SAGAPATTTG YQPAGCTGAR PANPSAYAAA YAGPDGAYPQ GAGSAIFAAA GRLAGPASPP AGGSSGGVET TVDFYGRTSP GQFGALGACY NPGGQLGGAS AGAYHARHAA AYPGGIDRFV SAM //