SIX3_HUMAN
ID SIX3_HUMAN Reviewed; 332 AA.
AC O95343; D6W5A5; Q53T42;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 178.
DE RecName: Full=Homeobox protein SIX3;
DE AltName: Full=Sine oculis homeobox homolog 3;
GN Name=SIX3;
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].
RX PubMed=9889003; DOI=10.1006/geno.1998.5611;
RA Granadino B., Gallardo M.E., Lopez-Rios J., Sanz R., Ramos C., Ayuso C.,
RA Bovolenta P., Rodriguez de Cordoba S.;
RT "Genomic cloning, structure, expression pattern, and chromosomal location
RT of the human SIX3 gene.";
RL Genomics 55:100-105(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=10415461; DOI=10.1076/opge.20.1.7.2298;
RA Leppert G.S., Yang J.-M., Sundin O.H.;
RT "Sequence and location of SIX3, a homeobox gene expressed in the human
RT eye.";
RL Ophthalmic Genet. 20:7-21(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Retina;
RA Clark B.J., Hanson I.M., Brown A.G., Ferrier R.K., Prosser J.,
RA van Heyningen V.;
RT "SIX3, a member of the Sine oculis/Six family of transcription factors, is
RT expressed in the developing and adult human eye.";
RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
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 [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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
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 [7]
RP INTERACTION WITH NR4A3.
RX PubMed=12543801;
RA Laflamme C., Filion C., Bridge J.A., Ladanyi M., Goldring M.B., Labelle Y.;
RT "The homeotic protein Six3 is a coactivator of the nuclear receptor NOR-1
RT and a corepressor of the fusion protein EWS/NOR-1 in human extraskeletal
RT myxoid chondrosarcomas.";
RL Cancer Res. 63:449-454(2003).
RN [8]
RP INTERACTION WITH TLE1 AND TLE5, AND MUTAGENESIS OF PHE-87; VAL-95 AND
RP LEU-99.
RX PubMed=12441302; DOI=10.1242/dev.00185;
RA Lopez-Rios J., Tessmar K., Loosli F., Wittbrodt J., Bovolenta P.;
RT "Six3 and Six6 activity is modulated by members of the groucho family.";
RL Development 130:185-195(2003).
RN [9]
RP CHARACTERIZATION OF VARIANTS HPE2 ALA-250 AND PRO-257.
RX PubMed=15523651; DOI=10.1002/humu.20102;
RA Laflamme C., Filion C., Labelle Y.;
RT "Functional characterization of SIX3 homeodomain mutations in
RT holoprosencephaly: interaction with the nuclear receptor NR4A3/NOR1.";
RL Hum. Mutat. 24:502-508(2004).
RN [10]
RP INTERACTION WITH GMNN.
RX PubMed=14973488; DOI=10.1038/nature02292;
RA Del Bene F., Tessmar-Raible K., Wittbrodt J.;
RT "Direct interaction of geminin and Six3 in eye development.";
RL Nature 427:745-749(2004).
RN [11]
RP DEVELOPMENTAL STAGE.
RX PubMed=18775421; DOI=10.1016/j.ydbio.2008.08.008;
RA Gaston-Massuet C., Andoniadou C.L., Signore M., Sajedi E., Bird S.,
RA Turner J.M., Martinez-Barbera J.P.;
RT "Genetic interaction between the homeobox transcription factors HESX1 and
RT SIX3 is required for normal pituitary development.";
RL Dev. Biol. 324:322-333(2008).
RN [12]
RP FUNCTION IN EYE DEVELOPMENT AND FOREBRAIN DORSAL/VENTRAL PATTERN FORMATION,
RP INVOLVEMENT IN HPE2, AND VARIANTS HPE2 CYS-37; ASP-93; CYS-113; LEU-114;
RP ASP-138; ILE-157; VAL-172; HIS-174; VAL-213; TRP-218; PRO-218; PRO-227;
RP CYS-244; LEU-254; LEU-258; HIS-262; SER-269 AND LEU-297.
RX PubMed=18791198; DOI=10.1093/hmg/ddn294;
RA Domene S., Roessler E., El-Jaick K.B., Snir M., Brown J.L., Velez J.I.,
RA Bale S., Lacbawan F., Muenke M., Feldman B.;
RT "Mutations in the human SIX3 gene in holoprosencephaly are loss of
RT function.";
RL Hum. Mol. Genet. 17:3919-3928(2008).
RN [13]
RP VARIANTS HPE2 VAL-226; ALA-250 AND PRO-257.
RX PubMed=10369266; DOI=10.1038/9718;
RA Wallis D.E., Roessler E., Hehr U., Nanni L., Wiltshire T.,
RA Richieri-Costa A., Gillessen-Kaesbach G., Zackai E.H., Rommens J.,
RA Muenke M.;
RT "Mutations in the homeodomain of the human SIX3 gene cause
RT holoprosencephaly.";
RL Nat. Genet. 22:196-198(1999).
RN [14]
RP VARIANTS HPE2 GLY-92; VAL-105; PRO-173; ILE-202; ARG-231 AND TRP-257.
RX PubMed=15221788; DOI=10.1002/humu.20056;
RA Dubourg C., Lazaro L., Pasquier L., Bendavid C., Blayau M., Le Duff F.,
RA Durou M.-R., Odent S., David V.;
RT "Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with
RT features of holoprosencephaly spectrum: mutation review and genotype-
RT phenotype correlations.";
RL Hum. Mutat. 24:43-51(2004).
RN [15]
RP VARIANT HPE2 ASP-69.
RX PubMed=17001667; DOI=10.1002/ajmg.a.31377;
RA Ribeiro L.A., El-Jaick K.B., Muenke M., Richieri-Costa A.;
RT "SIX3 mutations with holoprosencephaly.";
RL Am. J. Med. Genet. A 140:2577-2583(2006).
RN [16]
RP VARIANTS HPE2 VAL-79; HIS-155 DEL; GLY-257; MET-269 AND THR-269.
RX PubMed=20531442; DOI=10.1038/ejhg.2010.70;
RA Paulussen A.D., Schrander-Stumpel C.T., Tserpelis D.C., Spee M.K.,
RA Stegmann A.P., Mancini G.M., Brooks A.S., Collee M., Maat-Kievit A.,
RA Simon M.E., van Bever Y., Stolte-Dijkstra I., Kerstjens-Frederikse W.S.,
RA Herkert J.C., van Essen A.J., Lichtenbelt K.D., van Haeringen A.,
RA Kwee M.L., Lachmeijer A.M., Tan-Sindhunata G.M., van Maarle M.C.,
RA Arens Y.H., Smeets E.E., de Die-Smulders C.E., Engelen J.J., Smeets H.J.,
RA Herbergs J.;
RT "The unfolding clinical spectrum of holoprosencephaly due to mutations in
RT SHH, ZIC2, SIX3 and TGIF genes.";
RL Eur. J. Hum. Genet. 18:999-1005(2010).
RN [17]
RP INVOLVEMENT IN SCHZC, AND VARIANTS SCHZC CYS-37 AND SER-167.
RX PubMed=20157829; DOI=10.1007/s00439-010-0797-4;
RA Hehr U., Pineda-Alvarez D.E., Uyanik G., Hu P., Zhou N., Hehr A.,
RA Schell-Apacik C., Altus C., Daumer-Haas C., Meiner A., Steuernagel P.,
RA Roessler E., Winkler J., Muenke M.;
RT "Heterozygous mutations in SIX3 and SHH are associated with schizencephaly
RT and further expand the clinical spectrum of holoprosencephaly.";
RL Hum. Genet. 127:555-561(2010).
CC -!- FUNCTION: Transcriptional regulator which can act as both a
CC transcriptional repressor and activator by binding a ATTA homeodomain
CC core recognition sequence on these target genes. During forebrain
CC development represses WNT1 expression allowing zona limitans
CC intrathalamica formation and thereby ensuring proper anterio-posterior
CC patterning of the diencephalon and formation of the rostral
CC diencephalon. Acts as a direct upstream activator of SHH expression in
CC the rostral diencephalon ventral midline and that in turn SHH maintains
CC its expression. In addition, Six3 activity is required for the
CC formation of the telencephalon. During postnatal stages of brain
CC development is necessary for ependymal cell maturation by promoting the
CC maturation of radial glia into ependymal cells through regulation of
CC neuroblast proliferation and migration. Acts on the proliferation and
CC differentiation of neural progenitor cells through activating
CC transcription of CCND1 AND CCND2. During early lens formation plays a
CC role in lens induction and specification by activating directly PAX6 in
CC the presumptive lens ectoderm. In turn PAX6 activates SIX3 resulting in
CC activation of PDGFRA and CCND1 promoting cell proliferation. Also is
CC required for the neuroretina development by directly suppressing WNT8B
CC expression in the anterior neural plate territory. Its action during
CC retina development and lens morphogenesis is TLE5 and TLE4-dependent
CC manner. Furthermore, during eye development regulates several genes
CC expression. Before and during early lens development represses the
CC CRYGF promoter by binding a SIX repressor element. Directly activates
CC RHO transcription, or cooperates with CRX or NRL. Six3 functions also
CC in the formation of the proximodistal axis of the optic cup, and
CC promotes the formation of optic vesicles-like structures. During
CC pituitary development, acts in parallel or alternatively with HESX1 to
CC control cell proliferation through Wnt/beta-catenin pathway (By
CC similarity). Plays a role in eye development by suppressing WNT1
CC expression and in dorsal-ventral patterning by repressing BMP signaling
CC pathway. {ECO:0000250|UniProtKB:Q62233, ECO:0000269|PubMed:18791198}.
CC -!- SUBUNIT: Interacts with EYA4; translocates EYA4 from the cytoplasm to
CC the nucleus and promotes activation of their target genes (By
CC similarity). Interacts with MTA1 and HDAC2; represses its own
CC transcription (By similarity). Interacts with MTA1; facilitates the
CC binding of SIX3 to the core DNA motif of SIX3 promoter (By similarity).
CC Interacts with EYA1; promotes EYA1 translocation to the nucleus (By
CC similarity). Interacts with TLE1 and TLE5 (via Q domain); can act in
CC combination with either TLE1 and/or TLE5 leading to transcriptional
CC repression or activation, respectively. Interacts (via homeobox) with
CC NR4A3; differentially regulates the transcriptional activities NR4A3.
CC Interacts with GMNN. Interacts with TLE4.
CC {ECO:0000250|UniProtKB:Q62233, ECO:0000269|PubMed:12441302,
CC ECO:0000269|PubMed:12543801, ECO:0000269|PubMed:14973488}.
CC -!- INTERACTION:
CC O95343; Q92570: NR4A3; NbExp=3; IntAct=EBI-13644574, EBI-13644623;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q62233,
CC ECO:0000255|PROSITE-ProRule:PRU00108}.
CC -!- DEVELOPMENTAL STAGE: Expression is detected in Rathke's pouch and
CC overlying ventral diencephalon at carnegie stage 17 and in the anterior
CC and posterior lobes of the pituitary at carnegie stage 20. At fetal
CC stage, expression is observed in the anterior pituitary, and the
CC ventricular zones of the hypothalamus and telencephalic vesicles.
CC {ECO:0000269|PubMed:18775421}.
CC -!- DISEASE: Holoprosencephaly 2 (HPE2) [MIM:157170]: A structural anomaly
CC of the brain, in which the developing forebrain fails to correctly
CC separate into right and left hemispheres. Holoprosencephaly is
CC genetically heterogeneous and associated with several distinct facies
CC and phenotypic variability. {ECO:0000269|PubMed:10369266,
CC ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:15523651,
CC ECO:0000269|PubMed:17001667, ECO:0000269|PubMed:18791198,
CC ECO:0000269|PubMed:20531442}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Schizencephaly (SCHZC) [MIM:269160]: Extremely rare human
CC congenital disorder characterized by a full-thickness cleft within the
CC cerebral hemispheres. These clefts are lined with gray matter and most
CC commonly involve the parasylvian regions. Large portions of the
CC cerebral hemispheres may be absent and replaced by cerebro-spinal
CC fluid. {ECO:0000269|PubMed:20157829}. Note=The disease is caused by
CC variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the SIX/Sine oculis homeobox family.
CC {ECO:0000305}.
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DR EMBL; AF092047; AAD11939.1; -; Genomic_DNA.
DR EMBL; AF049339; AAD15753.1; -; Genomic_DNA.
DR EMBL; AF083891; AAD51091.1; -; Genomic_DNA.
DR EMBL; AJ012611; CAB42539.1; -; mRNA.
DR EMBL; AC012354; AAX93283.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00267.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00268.1; -; Genomic_DNA.
DR CCDS; CCDS1821.1; -.
DR RefSeq; NP_005404.1; NM_005413.3.
DR AlphaFoldDB; O95343; -.
DR BMRB; O95343; -.
DR SMR; O95343; -.
DR BioGRID; 112387; 32.
DR IntAct; O95343; 2.
DR STRING; 9606.ENSP00000260653; -.
DR iPTMnet; O95343; -.
DR PhosphoSitePlus; O95343; -.
DR BioMuta; SIX3; -.
DR EPD; O95343; -.
DR MassIVE; O95343; -.
DR MaxQB; O95343; -.
DR PaxDb; O95343; -.
DR PeptideAtlas; O95343; -.
DR PRIDE; O95343; -.
DR ProteomicsDB; 50811; -.
DR Antibodypedia; 29931; 272 antibodies from 29 providers.
DR DNASU; 6496; -.
DR Ensembl; ENST00000260653.5; ENSP00000260653.3; ENSG00000138083.5.
DR GeneID; 6496; -.
DR KEGG; hsa:6496; -.
DR MANE-Select; ENST00000260653.5; ENSP00000260653.3; NM_005413.4; NP_005404.1.
DR UCSC; uc002run.2; human.
DR CTD; 6496; -.
DR DisGeNET; 6496; -.
DR GeneCards; SIX3; -.
DR GeneReviews; SIX3; -.
DR HGNC; HGNC:10889; SIX3.
DR HPA; ENSG00000138083; Group enriched (brain, choroid plexus, parathyroid gland, pituitary gland, retina).
DR MalaCards; SIX3; -.
DR MIM; 157170; phenotype.
DR MIM; 269160; phenotype.
DR MIM; 603714; gene.
DR neXtProt; NX_O95343; -.
DR OpenTargets; ENSG00000138083; -.
DR Orphanet; 485275; Acquired schizencephaly.
DR Orphanet; 93925; Alobar holoprosencephaly.
DR Orphanet; 93924; Lobar holoprosencephaly.
DR Orphanet; 280200; Microform holoprosencephaly.
DR Orphanet; 93926; Midline interhemispheric variant of holoprosencephaly.
DR Orphanet; 220386; Semilobar holoprosencephaly.
DR Orphanet; 280195; Septopreoptic holoprosencephaly.
DR PharmGKB; PA35789; -.
DR VEuPathDB; HostDB:ENSG00000138083; -.
DR eggNOG; KOG0775; Eukaryota.
DR GeneTree; ENSGT00940000160346; -.
DR HOGENOM; CLU_046914_0_0_1; -.
DR InParanoid; O95343; -.
DR OMA; PGCPTHN; -.
DR OrthoDB; 1197104at2759; -.
DR PhylomeDB; O95343; -.
DR TreeFam; TF315545; -.
DR PathwayCommons; O95343; -.
DR SignaLink; O95343; -.
DR SIGNOR; O95343; -.
DR BioGRID-ORCS; 6496; 7 hits in 1089 CRISPR screens.
DR ChiTaRS; SIX3; human.
DR GeneWiki; SIX3; -.
DR GenomeRNAi; 6496; -.
DR Pharos; O95343; Tbio.
DR PRO; PR:O95343; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; O95343; protein.
DR Bgee; ENSG00000138083; Expressed in pigmented layer of retina and 78 other tissues.
DR Genevisible; O95343; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0005667; C:transcription regulator complex; IBA:GO_Central.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISS: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; IDA:MGI.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0001222; F:transcription corepressor binding; IPI:UniProtKB.
DR GO; GO:1902742; P:apoptotic process involved in development; ISS:UniProtKB.
DR GO; GO:0007420; P:brain development; IBA:GO_Central.
DR GO; GO:0021846; P:cell proliferation in forebrain; ISS:UniProtKB.
DR GO; GO:0002070; P:epithelial cell maturation; ISS:UniProtKB.
DR GO; GO:0001654; P:eye development; IDA:UniProtKB.
DR GO; GO:0021798; P:forebrain dorsal/ventral pattern formation; IDA:UniProtKB.
DR GO; GO:0002088; P:lens development in camera-type eye; ISS:UniProtKB.
DR GO; GO:1990086; P:lens fiber cell apoptotic process; ISS:UniProtKB.
DR GO; GO:0070306; P:lens fiber cell differentiation; ISS:UniProtKB.
DR GO; GO:0045665; P:negative regulation of neuron differentiation; ISS:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0014016; P:neuroblast differentiation; ISS:UniProtKB.
DR GO; GO:0097402; P:neuroblast migration; ISS:UniProtKB.
DR GO; GO:0003404; P:optic vesicle morphogenesis; ISS:UniProtKB.
DR GO; GO:0021983; P:pituitary gland development; ISS:UniProtKB.
DR GO; GO:0009946; P:proximal/distal axis specification; ISS:UniProtKB.
DR GO; GO:1901987; P:regulation of cell cycle phase transition; ISS:UniProtKB.
DR GO; GO:0042127; P:regulation of cell population proliferation; ISS:UniProtKB.
DR GO; GO:2000177; P:regulation of neural precursor cell proliferation; ISS:UniProtKB.
DR GO; GO:0061074; P:regulation of neural retina development; ISS:UniProtKB.
DR GO; GO:1902692; P:regulation of neuroblast proliferation; ISS:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0021537; P:telencephalon development; ISS:UniProtKB.
DR GO; GO:0021978; P:telencephalon regionalization; ISS:UniProtKB.
DR GO; GO:0007601; P:visual perception; TAS:ProtInc.
DR CDD; cd00086; homeodomain; 1.
DR InterPro; IPR009057; Homeobox-like_sf.
DR InterPro; IPR001356; Homeobox_dom.
DR InterPro; IPR031701; SIX1_SD.
DR InterPro; IPR032949; SIX3/SIX6.
DR PANTHER; PTHR10390:SF31; PTHR10390:SF31; 1.
DR Pfam; PF00046; Homeodomain; 1.
DR Pfam; PF16878; SIX1_SD; 1.
DR SMART; SM00389; HOX; 1.
DR SUPFAM; SSF46689; SSF46689; 1.
DR PROSITE; PS50071; HOMEOBOX_2; 1.
PE 1: Evidence at protein level;
KW Developmental protein; Disease variant; DNA-binding; Holoprosencephaly;
KW Homeobox; Nucleus; Reference proteome; Repressor; Transcription;
KW Transcription regulation.
FT CHAIN 1..332
FT /note="Homeobox protein SIX3"
FT /id="PRO_0000049299"
FT DNA_BIND 206..265
FT /note="Homeobox"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108"
FT REGION 72..119
FT /note="Interaction with TLE5"
FT /evidence="ECO:0000250|UniProtKB:Q62233"
FT REGION 232..251
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 232..234
FT /note="Bind to RHO promoter"
FT /evidence="ECO:0000250|UniProtKB:Q62233"
FT REGION 258..332
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 292..332
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VARIANT 37
FT /note="G -> C (in SCHZC AND HPE2; dbSNP:rs199823175)"
FT /evidence="ECO:0000269|PubMed:18791198,
FT ECO:0000269|PubMed:20157829"
FT /id="VAR_071335"
FT VARIANT 69
FT /note="G -> D (in HPE2; dbSNP:rs121917881)"
FT /evidence="ECO:0000269|PubMed:17001667"
FT /id="VAR_038418"
FT VARIANT 79
FT /note="M -> V (in HPE2)"
FT /evidence="ECO:0000269|PubMed:20531442"
FT /id="VAR_071336"
FT VARIANT 92
FT /note="V -> G (in HPE2)"
FT /evidence="ECO:0000269|PubMed:15221788"
FT /id="VAR_023797"
FT VARIANT 93
FT /note="A -> D (in HPE2)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071337"
FT VARIANT 105
FT /note="I -> V (in HPE2)"
FT /evidence="ECO:0000269|PubMed:15221788"
FT /id="VAR_023798"
FT VARIANT 113
FT /note="W -> C (in HPE2; dbSNP:rs137853021)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071338"
FT VARIANT 114
FT /note="S -> L (in HPE2)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071339"
FT VARIANT 138
FT /note="V -> D (in HPE2)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071340"
FT VARIANT 155
FT /note="Missing (in HPE2)"
FT /evidence="ECO:0000269|PubMed:20531442"
FT /id="VAR_071341"
FT VARIANT 157
FT /note="F -> I (in HPE2)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071342"
FT VARIANT 167
FT /note="A -> S (in SCHZC; dbSNP:rs387906868)"
FT /evidence="ECO:0000269|PubMed:20157829"
FT /id="VAR_071343"
FT VARIANT 172
FT /note="A -> V (in HPE2)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071344"
FT VARIANT 173
FT /note="H -> P (in HPE2)"
FT /evidence="ECO:0000269|PubMed:15221788"
FT /id="VAR_023799"
FT VARIANT 174
FT /note="Y -> H (in HPE2)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071345"
FT VARIANT 202
FT /note="T -> I (in HPE2)"
FT /evidence="ECO:0000269|PubMed:15221788"
FT /id="VAR_023800"
FT VARIANT 213
FT /note="F -> V (in HPE2)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071346"
FT VARIANT 218
FT /note="R -> P (in HPE2)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071347"
FT VARIANT 218
FT /note="R -> W (in HPE2)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071348"
FT VARIANT 226
FT /note="L -> V (in HPE2; dbSNP:rs121917878)"
FT /evidence="ECO:0000269|PubMed:10369266"
FT /id="VAR_003771"
FT VARIANT 227
FT /note="Q -> P (in HPE2)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071349"
FT VARIANT 231
FT /note="P -> R (in HPE2)"
FT /evidence="ECO:0000269|PubMed:15221788"
FT /id="VAR_023801"
FT VARIANT 244
FT /note="G -> C (in HPE2; dbSNP:rs989286015)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071350"
FT VARIANT 250
FT /note="V -> A (in HPE2; Significantly decreased its ability
FT to activate NR4A3; dbSNP:rs121917880)"
FT /evidence="ECO:0000269|PubMed:10369266,
FT ECO:0000269|PubMed:15523651"
FT /id="VAR_003772"
FT VARIANT 254
FT /note="F -> L (in HPE2)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071351"
FT VARIANT 257
FT /note="R -> G (in HPE2)"
FT /evidence="ECO:0000269|PubMed:20531442"
FT /id="VAR_071352"
FT VARIANT 257
FT /note="R -> P (in HPE2; Significantly decreased interaction
FT with NR4A3; Significantly decreased its ability to activate
FT NR4A3; dbSNP:rs121917879)"
FT /evidence="ECO:0000269|PubMed:10369266,
FT ECO:0000269|PubMed:15523651"
FT /id="VAR_003773"
FT VARIANT 257
FT /note="R -> W (in HPE2)"
FT /evidence="ECO:0000269|PubMed:15221788"
FT /id="VAR_023802"
FT VARIANT 258
FT /note="R -> L (in HPE2)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071353"
FT VARIANT 262
FT /note="R -> H (in HPE2)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071354"
FT VARIANT 269
FT /note="R -> M (in HPE2)"
FT /evidence="ECO:0000269|PubMed:20531442"
FT /id="VAR_071355"
FT VARIANT 269
FT /note="R -> S (in HPE2)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071356"
FT VARIANT 269
FT /note="R -> T (in HPE2)"
FT /evidence="ECO:0000269|PubMed:20531442"
FT /id="VAR_071357"
FT VARIANT 297
FT /note="P -> L (in HPE2; dbSNP:rs780942050)"
FT /evidence="ECO:0000269|PubMed:18791198"
FT /id="VAR_071358"
FT MUTAGEN 87
FT /note="F->E: Decreased interaction with TLE5 and loss
FT ineteraction with TLE1."
FT /evidence="ECO:0000269|PubMed:12441302"
FT MUTAGEN 95
FT /note="V->P: Loss of interaction with TLE1 and TLE5; when
FT associated with P-99."
FT /evidence="ECO:0000269|PubMed:12441302"
FT MUTAGEN 99
FT /note="L->P: Loss of interaction with TLE1 and TLE5; when
FT associated with P-95."
FT /evidence="ECO:0000269|PubMed:12441302"
SQ SEQUENCE 332 AA; 35487 MW; 21EA07F6A2DD978F CRC64;
MVFRSPLDLY SSHFLLPNFA DSHHRSILLA SSGGGNGAGG GGGAGGGSGG GNGAGGGGAG
GAGGGGGGGS RAPPEELSMF QLPTLNFSPE QVASVCETLE ETGDIERLGR FLWSLPVAPG
ACEAINKHES ILRARAVVAF HTGNFRDLYH ILENHKFTKE SHGKLQAMWL EAHYQEAEKL
RGRPLGPVDK YRVRKKFPLP RTIWDGEQKT HCFKERTRSL LREWYLQDPY PNPSKKRELA
QATGLTPTQV GNWFKNRRQR DRAAAAKNRL QHQAIGPSGM RSLAEPGCPT HGSAESPSTA
ASPTTSVSSL TERADTGTSI LSVTSSDSEC DV
