FOXE3_HUMAN
ID FOXE3_HUMAN Reviewed; 319 AA.
AC Q13461; Q5SVY9; Q9NQV9;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 11-JAN-2001, sequence version 2.
DT 03-AUG-2022, entry version 179.
DE RecName: Full=Forkhead box protein E3;
DE AltName: Full=Forkhead-related protein FKHL12;
DE AltName: Full=Forkhead-related transcription factor 8;
DE Short=FREAC-8;
GN Name=FOXE3; Synonyms=FKHL12, FREAC8;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ALA-196 AND GLY-300, AND
RP INVOLVEMENT IN ASGD2.
RX PubMed=11159941; DOI=10.1093/hmg/10.3.231;
RA Semina E.V., Brownell I., Mintz-Hittner H.A., Murray J.C., Jamrich M.;
RT "Mutations in the human forkhead transcription factor FOXE3 associated with
RT anterior segment ocular dysgenesis and cataracts.";
RL Hum. Mol. Genet. 10:231-236(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ASGD2 LEU-90.
RC TISSUE=Lens epithelium;
RX PubMed=11980846;
RA Ormestad M., Blixt A., Churchill A., Martinsson T., Enerback S.,
RA Carlsson P.;
RT "Foxe3 haploinsufficiency in mice: a model for Peters' anomaly.";
RL Invest. Ophthalmol. Vis. Sci. 43:1350-1357(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 66-171.
RX PubMed=8825632; DOI=10.1006/geno.1995.1266;
RA Larsson C., Hellqvist M., Pierrou S., White I., Enerbaeck S., Carlsson P.;
RT "Chromosomal localization of six human forkhead genes, freac-1 (FKHL5), -3
RT (FKHL7), -4 (FKHL8), -5 (FKHL9), -6 (FKHL10), and -8 (FKHL12).";
RL Genomics 30:464-469(1995).
RN [5]
RP FUNCTION.
RX PubMed=22527307; DOI=10.1007/s00417-012-1944-5;
RA Wang Y., Li W., Wang Y., Huang Y.;
RT "Growth inhibition of human lens epithelial cells by short hairpin RNA in
RT transcription factor forkhead box E3 (FOXE3).";
RL Graefes Arch. Clin. Exp. Ophthalmol. 250:999-1007(2012).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, VARIANTS ASGD2 LEU-90 AND GLY-120, AND
RP CHARACTERIZATION OF VARIANTS ASGD2 LEU-90 AND GLY-120.
RX PubMed=25504734; DOI=10.1002/humu.22741;
RA Islam L., Kelberman D., Williamson L., Lewis N., Glindzicz M.B.,
RA Nischal K.K., Sowden J.C.;
RT "Functional analysis of FOXE3 mutations causing dominant and recessive
RT ocular anterior segment disease.";
RL Hum. Mutat. 36:296-300(2015).
RN [7]
RP INVOLVEMENT IN ASGD2.
RX PubMed=16826526; DOI=10.1086/505654;
RA Valleix S., Niel F., Nedelec B., Algros M.-P., Schwartz C., Delbosc B.,
RA Delpech M., Kantelip B.;
RT "Homozygous nonsense mutation in the FOXE3 gene as a cause of congenital
RT primary aphakia in humans.";
RL Am. J. Hum. Genet. 79:358-364(2006).
RN [8]
RP VARIANT ALA-49, VARIANT ASGD2 VAL-82, AND DEVELOPMENTAL STAGE.
RX PubMed=19708017; DOI=10.1002/humu.21079;
RA Iseri S.U., Osborne R.J., Farrall M., Wyatt A.W., Mirza G., Nurnberg G.,
RA Kluck C., Herbert H., Martin A., Hussain M.S., Collin J.R., Lathrop M.,
RA Nurnberg P., Ragoussis J., Ragge N.K.;
RT "Seeing clearly: the dominant and recessive nature of FOXE3 in eye
RT developmental anomalies.";
RL Hum. Mutat. 30:1378-1386(2009).
RN [9]
RP INVOLVEMENT IN AAT11, AND VARIANTS AAT11 ASP-137 AND HIS-153.
RX PubMed=26854927; DOI=10.1172/jci83778;
RA Kuang S.Q., Medina-Martinez O., Guo D.C., Gong L., Regalado E.S.,
RA Reynolds C.L., Boileau C., Jondeau G., Prakash S.K., Kwartler C.S.,
RA Zhu L.Y., Peters A.M., Duan X.Y., Bamshad M.J., Shendure J.,
RA Nickerson D.A., Santos-Cortez R.L., Dong X., Leal S.M., Majesky M.W.,
RA Swindell E.C., Jamrich M., Milewicz D.M.;
RT "FOXE3 mutations predispose to thoracic aortic aneurysms and dissections.";
RL J. Clin. Invest. 126:948-961(2016).
RN [10]
RP FUNCTION, INVOLVEMENT IN CTRCT34, VARIANTS CTRCT34 LYS-103 AND LYS-117, AND
RP CHARACTERIZATION OF VARIANTS CTRCT34 LYS-103 AND LYS-117.
RX PubMed=27218149; DOI=10.1038/ncomms10953;
RA Khan S.Y., Vasanth S., Kabir F., Gottsch J.D., Khan A.O., Chaerkady R.,
RA Lee M.C., Leitch C.C., Ma Z., Laux J., Villasmil R., Khan S.N.,
RA Riazuddin S., Akram J., Cole R.N., Talbot C.C., Pourmand N., Zaghloul N.A.,
RA Hejtmancik J.F., Riazuddin S.A.;
RT "FOXE3 contributes to Peters anomaly through transcriptional regulation of
RT an autophagy-associated protein termed DNAJB1.";
RL Nat. Commun. 7:10953-10953(2016).
CC -!- FUNCTION: Transcription factor that controls lens epithelial cell
CC growth through regulation of proliferation, apoptosis and cell cycle
CC (PubMed:22527307, PubMed:25504734). During lens development, controls
CC the ratio of the lens fiber cells to the cells of the anterior lens
CC epithelium by regulating the rate of proliferation and differentiation
CC (By similarity). Controls lens vesicle closure and subsequent
CC separation of the lens vesicle from ectoderm (By similarity). Controls
CC the expression of DNAJB1 in a pathway that is crucial for the
CC development of the anterior segment of the eye (PubMed:27218149).
CC {ECO:0000250|UniProtKB:Q9QY14, ECO:0000269|PubMed:22527307,
CC ECO:0000269|PubMed:25504734, ECO:0000269|PubMed:27218149}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:25504734}.
CC -!- DEVELOPMENTAL STAGE: Expressed in the lens during embryonic
CC development. Predominantly expressed in the anterior lens epithelium
CC but with some expression posteriorly. Not expressed in brain in
CC embryos. {ECO:0000269|PubMed:19708017}.
CC -!- DISEASE: Anterior segment dysgenesis 2 (ASGD2) [MIM:610256]: A form of
CC anterior segment dysgenesis, a group of defects affecting anterior
CC structures of the eye including cornea, iris, lens, trabecular
CC meshwork, and Schlemm canal. Anterior segment dysgeneses result from
CC abnormal migration or differentiation of the neural crest derived
CC mesenchymal cells that give rise to components of the anterior chamber
CC during eye development. Different anterior segment anomalies may exist
CC alone or in combination, including iris hypoplasia, enlarged or reduced
CC corneal diameter, corneal vascularization and opacity, posterior
CC embryotoxon, corectopia, polycoria, abnormal iridocorneal angle,
CC ectopia lentis, and anterior synechiae between the iris and posterior
CC corneal surface. Clinical conditions falling within the phenotypic
CC spectrum of anterior segment dysgeneses include aniridia, Axenfeld
CC anomaly, Reiger anomaly/syndrome, Peters anomaly, and
CC iridogoniodysgenesis. Some ASGD2 patients show congenital primary
CC aphakia, a defect caused by eye development arrest around the 4th-5th
CC week of gestation. This prevents the formation of any lens structure
CC and leads to severe secondary ocular anomalies, including a complete
CC aplasia of the anterior segment of the eye. In contrast, in secondary
CC aphakic eyes, lens induction has occurred, and the lens vesicle has
CC developed to some degree but finally has progressively resorbed
CC perinatally, leading, therefore, to less severe ocular defects. ASGD2
CC inheritance is autosomal recessive. {ECO:0000269|PubMed:11159941,
CC ECO:0000269|PubMed:11980846, ECO:0000269|PubMed:16826526,
CC ECO:0000269|PubMed:19708017, ECO:0000269|PubMed:25504734}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Cataract 34, multiple types (CTRCT34) [MIM:612968]: An
CC opacification of the crystalline lens of the eye that frequently
CC results in visual impairment or blindness. Opacities vary in
CC morphology, are often confined to a portion of the lens, and may be
CC static or progressive. In general, the more posteriorly located and
CC dense an opacity, the greater the impact on visual function.
CC {ECO:0000269|PubMed:27218149}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Aortic aneurysm, familial thoracic 11 (AAT11) [MIM:617349]: A
CC form of thoracic aortic aneurysm, a disease characterized by permanent
CC dilation of the thoracic aorta usually due to degenerative changes in
CC the aortic wall. It is primarily associated with a characteristic
CC histologic appearance known as 'medial necrosis' or 'Erdheim cystic
CC medial necrosis' in which there is degeneration and fragmentation of
CC elastic fibers, loss of smooth muscle cells, and an accumulation of
CC basophilic ground substance. {ECO:0000269|PubMed:26854927}.
CC Note=Disease susceptibility is associated with variants affecting the
CC gene represented in this entry.
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DR EMBL; AF275722; AAF82793.1; -; mRNA.
DR EMBL; AL607122; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; U42990; AAB48856.1; -; Genomic_DNA.
DR CCDS; CCDS550.1; -.
DR PIR; G02311; G02311.
DR RefSeq; NP_036318.1; NM_012186.2.
DR AlphaFoldDB; Q13461; -.
DR SMR; Q13461; -.
DR BioGRID; 108590; 9.
DR STRING; 9606.ENSP00000334472; -.
DR iPTMnet; Q13461; -.
DR PhosphoSitePlus; Q13461; -.
DR BioMuta; FOXE3; -.
DR DMDM; 12644406; -.
DR MassIVE; Q13461; -.
DR PaxDb; Q13461; -.
DR PeptideAtlas; Q13461; -.
DR PRIDE; Q13461; -.
DR ProteomicsDB; 59460; -.
DR Antibodypedia; 18909; 223 antibodies from 28 providers.
DR DNASU; 2301; -.
DR Ensembl; ENST00000335071.4; ENSP00000334472.2; ENSG00000186790.6.
DR GeneID; 2301; -.
DR KEGG; hsa:2301; -.
DR MANE-Select; ENST00000335071.4; ENSP00000334472.2; NM_012186.3; NP_036318.1.
DR UCSC; uc001crk.3; human.
DR CTD; 2301; -.
DR DisGeNET; 2301; -.
DR GeneCards; FOXE3; -.
DR GeneReviews; FOXE3; -.
DR HGNC; HGNC:3808; FOXE3.
DR HPA; ENSG00000186790; Not detected.
DR MalaCards; FOXE3; -.
DR MIM; 601094; gene.
DR MIM; 610256; phenotype.
DR MIM; 612968; phenotype.
DR MIM; 617349; phenotype.
DR neXtProt; NX_Q13461; -.
DR OpenTargets; ENSG00000186790; -.
DR Orphanet; 83461; Congenital primary aphakia.
DR Orphanet; 91387; Familial thoracic aortic aneurysm and aortic dissection.
DR Orphanet; 708; Peters anomaly.
DR PharmGKB; PA28225; -.
DR VEuPathDB; HostDB:ENSG00000186790; -.
DR eggNOG; KOG2294; Eukaryota.
DR GeneTree; ENSGT00940000163987; -.
DR HOGENOM; CLU_023357_0_1_1; -.
DR InParanoid; Q13461; -.
DR OMA; MAGRSDM; -.
DR OrthoDB; 1270467at2759; -.
DR PhylomeDB; Q13461; -.
DR TreeFam; TF316127; -.
DR PathwayCommons; Q13461; -.
DR BioGRID-ORCS; 2301; 12 hits in 1091 CRISPR screens.
DR GeneWiki; FOXE3; -.
DR GenomeRNAi; 2301; -.
DR Pharos; Q13461; Tbio.
DR PRO; PR:Q13461; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q13461; protein.
DR Bgee; ENSG00000186790; Expressed in mucosa of transverse colon and 25 other tissues.
DR ExpressionAtlas; Q13461; baseline and differential.
DR Genevisible; Q13461; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005667; C:transcription regulator complex; IDA:MGI.
DR GO; GO:0003677; F:DNA binding; 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; ISA:NTNU_SB.
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; ISS:UniProtKB.
DR GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
DR GO; GO:0048468; P:cell development; IEA:Ensembl.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0061073; P:ciliary body morphogenesis; ISS:UniProtKB.
DR GO; GO:0061303; P:cornea development in camera-type eye; ISS:UniProtKB.
DR GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0001654; P:eye development; IMP:UniProtKB.
DR GO; GO:0061072; P:iris morphogenesis; ISS:UniProtKB.
DR GO; GO:0002088; P:lens development in camera-type eye; IMP:UniProtKB.
DR GO; GO:0042789; P:mRNA transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:1902747; P:negative regulation of lens fiber cell differentiation; ISS:UniProtKB.
DR GO; GO:2001111; P:positive regulation of lens epithelial cell proliferation; IMP:UniProtKB.
DR GO; GO:0051726; P:regulation of cell cycle; IMP:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0002930; P:trabecular meshwork development; ISS:UniProtKB.
DR GO; GO:0006366; P:transcription by RNA polymerase II; IDA:MGI.
DR CDD; cd00059; FH; 1.
DR Gene3D; 1.10.10.10; -; 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 Pfam; PF00250; Forkhead; 1.
DR PRINTS; PR00053; FORKHEAD.
DR SMART; SM00339; FH; 1.
DR SUPFAM; SSF46785; SSF46785; 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 Aortic aneurysm; Cataract; Disease variant; DNA-binding; Nucleus;
KW Peters anomaly; Reference proteome; Transcription;
KW Transcription regulation.
FT CHAIN 1..319
FT /note="Forkhead box protein E3"
FT /id="PRO_0000091829"
FT DNA_BIND 71..165
FT /note="Fork-head"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089"
FT REGION 1..69
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 21..35
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VARIANT 49
FT /note="G -> A (in dbSNP:rs566961335)"
FT /evidence="ECO:0000269|PubMed:19708017"
FT /id="VAR_062582"
FT VARIANT 82
FT /note="M -> V (in ASGD2; unknown pathological significance;
FT dbSNP:rs746531116)"
FT /evidence="ECO:0000269|PubMed:19708017"
FT /id="VAR_062583"
FT VARIANT 90
FT /note="R -> L (in ASGD2; significant reduction of sequence-
FT specific DNA binding transcription factor activity;
FT dbSNP:rs371048362)"
FT /evidence="ECO:0000269|PubMed:11980846,
FT ECO:0000269|PubMed:25504734"
FT /id="VAR_062584"
FT VARIANT 103
FT /note="E -> K (in CTRCT34; decreases DNAJB1 expression;
FT dbSNP:rs1057518738)"
FT /evidence="ECO:0000269|PubMed:27218149"
FT /id="VAR_078112"
FT VARIANT 117
FT /note="N -> K (in CTRCT34; decreases DNAJB1 expression;
FT dbSNP:rs1057518737)"
FT /evidence="ECO:0000269|PubMed:27218149"
FT /id="VAR_078113"
FT VARIANT 120
FT /note="R -> G (in ASGD2; complete loss of DNA binding;
FT significant reduction of sequence-specific DNA binding
FT transcription factor activity)"
FT /evidence="ECO:0000269|PubMed:25504734"
FT /id="VAR_072783"
FT VARIANT 137
FT /note="G -> D (in AAT11; dbSNP:rs749960549)"
FT /evidence="ECO:0000269|PubMed:26854927"
FT /id="VAR_078114"
FT VARIANT 153
FT /note="D -> H (in AAT11; dbSNP:rs367943249)"
FT /evidence="ECO:0000269|PubMed:26854927"
FT /id="VAR_078115"
FT VARIANT 196
FT /note="G -> A (in dbSNP:rs281865461)"
FT /evidence="ECO:0000269|PubMed:11159941"
FT /id="VAR_026234"
FT VARIANT 300
FT /note="S -> G (in dbSNP:rs552420470)"
FT /evidence="ECO:0000269|PubMed:11159941"
FT /id="VAR_026235"
FT CONFLICT 162
FT /note="R -> P (in Ref. 4; AAB48856)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 319 AA; 33234 MW; E25A64457B7ECDF8 CRC64;
MAGRSDMDPP AAFSGFPALP AVAPSGPPPS PLAGAEPGRE PEEAAAGRGE AAPTPAPGPG
RRRRRPLQRG KPPYSYIALI AMALAHAPGR RLTLAAIYRF ITERFAFYRD SPRKWQNSIR
HNLTLNDCFV KVPREPGNPG KGNYWTLDPA AADMFDNGSF LRRRKRFKRA ELPAHAAAAP
GPPLPFPYAP YAPAPGPALL VPPPSAGPGP SPPARLFSVD SLVNLQPELA GLGAPEPPCC
AAPDAAAAAF PPCAAAASPP LYSQVPDRLV LPATRPGPGP LPAEPLLALA GPAAALGPLS
PGEAYLRQPG FASGLERYL
