HESX1_HUMAN
ID HESX1_HUMAN Reviewed; 185 AA.
AC Q9UBX0; Q52LC5; Q99667;
DT 11-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 184.
DE RecName: Full=Homeobox expressed in ES cells 1;
DE AltName: Full=Homeobox protein ANF;
DE Short=hAnf;
GN Name=HESX1; Synonyms=HANF;
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], VARIANT SOD CYS-160, AND VARIANT
RP SER-125.
RC TISSUE=Fibrosarcoma;
RX PubMed=9620767; DOI=10.1038/477;
RA Dattani M.T., Martinez-Barbera J.-P., Thomas P.Q., Brickman J.M., Gupta R.,
RA Maartensson I.-L., Toresson H., Fox M., Wales J.K.H., Hindmarsh P.C.,
RA Krauss S., Beddington R.S.P., Robinson I.C.A.F.;
RT "Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic
RT dysplasia in human and mouse.";
RL Nat. Genet. 19:125-133(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Teratocarcinoma;
RX PubMed=9373136; DOI=10.1016/s0378-1119(97)00326-0;
RA Kazanskaya O.V., Severtzova E.A., Barth K.A., Ermakova G.V., Lukyanov S.A.,
RA Benyumov A.O., Pannese M., Boncinelli E., Wilson S.W., Zaraisky A.G.;
RT "Anf: a novel class of vertebrate homeobox genes expressed at the anterior
RT end of the main embryonic axis.";
RL Gene 200:25-34(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP INTERACTION WITH TLE1.
RX PubMed=11731482; DOI=10.1101/gad.932601;
RA Dasen J.S., Martinez-Barbera J.-P., Herman T.S., O'Connell S., Olson L.,
RA Ju B., Tollkuhn J., Baek S.H., Rose D.W., Rosenfeld M.G.;
RT "Temporal regulation of a paired-like homeodomain repressor/TLE corepressor
RT complex and a related activator is required for pituitary organogenesis.";
RL Genes Dev. 15:3193-3207(2001).
RN [5]
RP STRUCTURE BY NMR OF 108-174, AND DNA-BINDING.
RX PubMed=19561080; DOI=10.1074/jbc.m109.012054;
RA Torrado M., Revuelta J., Gonzalez C., Corzana F., Bastida A., Asensio J.L.;
RT "Role of conserved salt bridges in homeodomain stability and DNA binding.";
RL J. Biol. Chem. 284:23765-23779(2009).
RN [6]
RP VARIANT SOD LEU-170, VARIANT GHDPA ALA-181, AND VARIANT CPHD5 HIS-6.
RX PubMed=11136712; DOI=10.1093/hmg/10.1.39;
RA Thomas P.Q., Dattani M.T., Brickman J.M., McNay D., Warne G., Zacharin M.,
RA Cameron F., Hurst J., Woods K., Dunger D., Stanhope R., Forrest S.,
RA Robinson I.C., Beddington R.S.;
RT "Heterozygous HESX1 mutations associated with isolated congenital pituitary
RT hypoplasia and septo-optic dysplasia.";
RL Hum. Mol. Genet. 10:39-45(2001).
RN [7]
RP VARIANT CPHD5 THR-26, AND CHARACTERIZATION OF VARIANT CPHD5 THR-26.
RX PubMed=14561704; DOI=10.1172/jci200318589;
RA Carvalho L.R., Woods K.S., Mendonca B.B., Marcal N., Zamparini A.L.,
RA Stifani S., Brickman J.M., Arnhold I.J., Dattani M.T.;
RT "A homozygous mutation in HESX1 is associated with evolving hypopituitarism
RT due to impaired repressor-corepressor interaction.";
RL J. Clin. Invest. 112:1192-1201(2003).
RN [8]
RP VARIANT GHDPA LYS-149, AND CHARACTERIZATION OF VARIANT GHDPA LYS-149.
RX PubMed=17148560; DOI=10.1210/jc.2006-1609;
RA McNay D.E.G., Turton J.P., Kelberman D., Woods K.S., Brauner R.,
RA Papadimitriou A., Keller E., Keller A., Haufs N., Krude H., Shalet S.M.,
RA Dattani M.T.;
RT "HESX1 mutations are an uncommon cause of septooptic dysplasia and
RT hypopituitarism.";
RL J. Clin. Endocrinol. Metab. 92:691-697(2007).
RN [9]
RP VARIANT CPHD5 GLN-109, CHARACTERIZATION OF VARIANT CPHD5 GLN-109, FUNCTION,
RP DNA-BINDING, AND SUBCELLULAR LOCATION.
RX PubMed=26781211; DOI=10.1507/endocrj.ej15-0409;
RA Takagi M., Takahashi M., Ohtsu Y., Sato T., Narumi S., Arakawa H.,
RA Hasegawa T.;
RT "A novel mutation in HESX1 causes combined pituitary hormone deficiency
RT without septo optic dysplasia phenotypes.";
RL Endocr. J. 63:405-410(2016).
CC -!- FUNCTION: Required for the normal development of the forebrain, eyes
CC and other anterior structures such as the olfactory placodes and
CC pituitary gland. Possible transcriptional repressor. Binds to the
CC palindromic PIII sequence, 5'-AGCTTGAGTCTAATTGAATTAACTGTAC-3'. HESX1
CC and PROP1 bind as heterodimers on this palindromic site, and, in vitro,
CC HESX1 can antagonize PROP1 activation. {ECO:0000250|UniProtKB:Q61658,
CC ECO:0000269|PubMed:26781211}.
CC -!- SUBUNIT: Can form heterodimers with PROP1 in binding to DNA (By
CC similarity). Interacts with TLE1. {ECO:0000250,
CC ECO:0000269|PubMed:11731482}.
CC -!- INTERACTION:
CC Q9UBX0; Q9NX04: C1orf109; NbExp=3; IntAct=EBI-8470369, EBI-8643161;
CC Q9UBX0; Q7Z7H3: CATIP; NbExp=3; IntAct=EBI-8470369, EBI-10258233;
CC Q9UBX0; Q96NT3-2: GUCD1; NbExp=3; IntAct=EBI-8470369, EBI-11978177;
CC Q9UBX0; P31273: HOXC8; NbExp=3; IntAct=EBI-8470369, EBI-1752118;
CC Q9UBX0; O60341: KDM1A; NbExp=2; IntAct=EBI-8470369, EBI-710124;
CC Q9UBX0; Q96LA8: PRMT6; NbExp=2; IntAct=EBI-8470369, EBI-912440;
CC Q9UBX0; Q9BZL1: UBL5; NbExp=3; IntAct=EBI-8470369, EBI-607755;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:26781211}.
CC -!- DEVELOPMENTAL STAGE: Strongly expressed in Rathke pouch in seven-week-
CC old embryo.
CC -!- DISEASE: Septooptic dysplasia (SOD) [MIM:182230]: A clinically
CC heterogeneous disorder defined by any combination of optic nerve
CC hypoplasia, pituitary gland hypoplasia with panhypopopituitarism, and
CC midline abnormalities of the brain, including absence of the corpus
CC callosum and septum pellucidum. {ECO:0000269|PubMed:11136712,
CC ECO:0000269|PubMed:9620767}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Growth hormone deficiency with pituitary anomalies (GHDPA)
CC [MIM:182230]: A disease characterized by low or absent growth hormone
CC levels, in the presence of a hypoplastic anterior pituitary lobe and
CC ectopic or absent posterior pituitary lobe.
CC {ECO:0000269|PubMed:11136712, ECO:0000269|PubMed:17148560}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Pituitary hormone deficiency, combined, 5 (CPHD5)
CC [MIM:182230]: Combined pituitary hormone deficiency is defined as the
CC impaired production of growth hormone and one or more of the other five
CC anterior pituitary hormones. CPHD5 is characterized by complete or
CC partial deficiencies of growth hormone, thyroid-stimulating hormone,
CC luteinizing hormone, follicle stimulating hormone and
CC adrenocorticotropic hormone. {ECO:0000269|PubMed:11136712,
CC ECO:0000269|PubMed:14561704, ECO:0000269|PubMed:26781211}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the ANF homeobox family. {ECO:0000305}.
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DR EMBL; AF059734; AAC24523.1; -; Genomic_DNA.
DR EMBL; U82811; AAB88275.1; -; mRNA.
DR EMBL; U65437; AAB39561.1; -; Genomic_DNA.
DR EMBL; BC069515; AAH69515.1; -; mRNA.
DR EMBL; BC093979; AAH93979.1; -; mRNA.
DR EMBL; BC112089; AAI12090.1; -; mRNA.
DR CCDS; CCDS2881.1; -.
DR RefSeq; NP_003856.1; NM_003865.2.
DR RefSeq; XP_005265583.1; XM_005265526.4.
DR RefSeq; XP_006713442.1; XM_006713379.3.
DR RefSeq; XP_011532506.1; XM_011534204.2.
DR RefSeq; XP_011532507.1; XM_011534205.2.
DR RefSeq; XP_016862910.1; XM_017007421.1.
DR PDB; 2K40; NMR; -; A=108-174.
DR PDBsum; 2K40; -.
DR AlphaFoldDB; Q9UBX0; -.
DR SMR; Q9UBX0; -.
DR BioGRID; 114347; 13.
DR CORUM; Q9UBX0; -.
DR IntAct; Q9UBX0; 10.
DR MINT; Q9UBX0; -.
DR STRING; 9606.ENSP00000295934; -.
DR iPTMnet; Q9UBX0; -.
DR PhosphoSitePlus; Q9UBX0; -.
DR BioMuta; HESX1; -.
DR DMDM; 12230168; -.
DR MassIVE; Q9UBX0; -.
DR PaxDb; Q9UBX0; -.
DR PeptideAtlas; Q9UBX0; -.
DR PRIDE; Q9UBX0; -.
DR Antibodypedia; 14999; 103 antibodies from 21 providers.
DR DNASU; 8820; -.
DR Ensembl; ENST00000295934.8; ENSP00000295934.3; ENSG00000163666.10.
DR Ensembl; ENST00000647958.1; ENSP00000498190.1; ENSG00000163666.10.
DR GeneID; 8820; -.
DR KEGG; hsa:8820; -.
DR MANE-Select; ENST00000295934.8; ENSP00000295934.3; NM_003865.3; NP_003856.1.
DR UCSC; uc003din.5; human.
DR CTD; 8820; -.
DR DisGeNET; 8820; -.
DR GeneCards; HESX1; -.
DR HGNC; HGNC:4877; HESX1.
DR HPA; ENSG00000163666; Low tissue specificity.
DR MalaCards; HESX1; -.
DR MIM; 182230; phenotype.
DR MIM; 262600; phenotype.
DR MIM; 601802; gene.
DR neXtProt; NX_Q9UBX0; -.
DR OpenTargets; ENSG00000163666; -.
DR Orphanet; 95494; Combined pituitary hormone deficiencies, genetic forms.
DR Orphanet; 226307; Hypothyroidism due to deficient transcription factors involved in pituitary development or function.
DR Orphanet; 478; Kallmann syndrome.
DR Orphanet; 95496; Pituitary stalk interruption syndrome.
DR Orphanet; 3157; Septo-optic dysplasia spectrum.
DR PharmGKB; PA29255; -.
DR VEuPathDB; HostDB:ENSG00000163666; -.
DR eggNOG; KOG0490; Eukaryota.
DR GeneTree; ENSGT00940000156780; -.
DR HOGENOM; CLU_125528_0_0_1; -.
DR InParanoid; Q9UBX0; -.
DR OMA; MDACTNL; -.
DR OrthoDB; 1270742at2759; -.
DR PhylomeDB; Q9UBX0; -.
DR TreeFam; TF335506; -.
DR PathwayCommons; Q9UBX0; -.
DR SignaLink; Q9UBX0; -.
DR BioGRID-ORCS; 8820; 16 hits in 1085 CRISPR screens.
DR ChiTaRS; HESX1; human.
DR EvolutionaryTrace; Q9UBX0; -.
DR GeneWiki; HESX1; -.
DR GenomeRNAi; 8820; -.
DR Pharos; Q9UBX0; Tbio.
DR PRO; PR:Q9UBX0; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q9UBX0; protein.
DR Bgee; ENSG00000163666; Expressed in buccal mucosa cell and 95 other tissues.
DR ExpressionAtlas; Q9UBX0; baseline and differential.
DR Genevisible; Q9UBX0; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0003682; F:chromatin binding; IEA:Ensembl.
DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:NTNU_SB.
DR GO; GO:0008022; F:protein C-terminus binding; IEA:Ensembl.
DR GO; GO:0042803; F:protein homodimerization activity; IEA:Ensembl.
DR GO; GO:0047485; F:protein N-terminus binding; IEA:Ensembl.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0007420; P:brain development; TAS:ProtInc.
DR GO; GO:0043010; P:camera-type eye development; IEA:Ensembl.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; IEA:Ensembl.
DR GO; GO:0071276; P:cellular response to cadmium ion; IEA:Ensembl.
DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IEA:Ensembl.
DR GO; GO:0048853; P:forebrain morphogenesis; IEA:Ensembl.
DR GO; GO:0010467; P:gene expression; IEA:Ensembl.
DR GO; GO:0008406; P:gonad development; IEA:Ensembl.
DR GO; GO:0048861; P:leukemia inhibitory factor signaling pathway; IEA:Ensembl.
DR GO; GO:0035264; P:multicellular organism growth; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:NTNU_SB.
DR GO; GO:0043584; P:nose development; IEA:Ensembl.
DR GO; GO:0030916; P:otic vesicle formation; IEA:Ensembl.
DR GO; GO:0021983; P:pituitary gland development; IMP:UniProtKB.
DR GO; GO:0045995; P:regulation of embryonic development; IEA:Ensembl.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0048863; P:stem cell differentiation; IEA:Ensembl.
DR GO; GO:0019827; P:stem cell population maintenance; IEA:Ensembl.
DR GO; GO:0030878; P:thyroid gland development; IEA:Ensembl.
DR CDD; cd00086; homeodomain; 1.
DR InterPro; IPR043402; Hesx1.
DR InterPro; IPR009057; Homeobox-like_sf.
DR InterPro; IPR017970; Homeobox_CS.
DR InterPro; IPR001356; Homeobox_dom.
DR PANTHER; PTHR46966; PTHR46966; 1.
DR Pfam; PF00046; Homeodomain; 1.
DR SMART; SM00389; HOX; 1.
DR SUPFAM; SSF46689; SSF46689; 1.
DR PROSITE; PS00027; HOMEOBOX_1; 1.
DR PROSITE; PS50071; HOMEOBOX_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Developmental protein; Disease variant; DNA-binding;
KW Dwarfism; Homeobox; Nucleus; Reference proteome; Transcription;
KW Transcription regulation.
FT CHAIN 1..185
FT /note="Homeobox expressed in ES cells 1"
FT /id="PRO_0000048922"
FT DNA_BIND 108..167
FT /note="Homeobox"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108"
FT VARIANT 6
FT /note="Q -> H (in CPHD5; dbSNP:rs121909173)"
FT /evidence="ECO:0000269|PubMed:11136712"
FT /id="VAR_063230"
FT VARIANT 26
FT /note="I -> T (in CPHD5; the mutated protein is associated
FT with impaired transcriptional repression but not DNA
FT binding; dbSNP:rs28936416)"
FT /evidence="ECO:0000269|PubMed:14561704"
FT /id="VAR_063231"
FT VARIANT 109
FT /note="R -> Q (in CPHD5; unknown pathological significance;
FT loss of DNA binding ability; unable to repress PROP1-
FT mediated activation; no effect on nuclear location; no
FT effect on protein abundance; dbSNP:rs768165720)"
FT /evidence="ECO:0000269|PubMed:26781211"
FT /id="VAR_078488"
FT VARIANT 125
FT /note="N -> S (in dbSNP:rs9878928)"
FT /evidence="ECO:0000269|PubMed:9620767"
FT /id="VAR_010400"
FT VARIANT 149
FT /note="E -> K (in GHDPA; unable to repress PROP1-mediated
FT activation; dbSNP:rs104893742)"
FT /evidence="ECO:0000269|PubMed:17148560"
FT /id="VAR_063232"
FT VARIANT 160
FT /note="R -> C (in SOD; loss of DNA-binding;
FT dbSNP:rs28936702)"
FT /evidence="ECO:0000269|PubMed:9620767"
FT /id="VAR_010225"
FT VARIANT 170
FT /note="S -> L (in SOD; mild; dbSNP:rs28936703)"
FT /evidence="ECO:0000269|PubMed:11136712"
FT /id="VAR_063233"
FT VARIANT 181
FT /note="T -> A (in GHDPA; dbSNP:rs28936704)"
FT /evidence="ECO:0000269|PubMed:11136712"
FT /id="VAR_063234"
FT HELIX 117..127
FT /evidence="ECO:0007829|PDB:2K40"
FT HELIX 135..145
FT /evidence="ECO:0007829|PDB:2K40"
FT HELIX 149..164
FT /evidence="ECO:0007829|PDB:2K40"
SQ SEQUENCE 185 AA; 21409 MW; 1F23D319EB4FDBF0 CRC64;
MSPSLQEGAQ LGENKPSTCS FSIERILGLD QKKDCVPLMK PHRPWADTCS SSGKDGNLCL
HVPNPPSGIS FPSVVDHPMP EERASKYENY FSASERLSLK RELSWYRGRR PRTAFTQNQI
EVLENVFRVN CYPGIDIRED LAQKLNLEED RIQIWFQNRR AKLKRSHRES QFLMAKKNFN
TNLLE
