ID SIX5_HUMAN Reviewed; 739 AA. AC Q8N196; DT 13-APR-2004, integrated into UniProtKB/Swiss-Prot. DT 26-JUN-2007, sequence version 3. DT 27-MAR-2024, entry version 175. DE RecName: Full=Homeobox protein SIX5; DE AltName: Full=DM locus-associated homeodomain protein; DE AltName: Full=Sine oculis homeobox homolog 5; GN Name=SIX5; Synonyms=DMAHP; 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=8595416; DOI=10.1093/hmg/4.10.1919; RA Boucher C.A., King S.K., Carey N., Krahe R., Winchester C.L., Rahman S., RA Creavin T., Meghji P., Bailey M.E., Chartier F.L., Brown S.D., RA Sicilliano M.J., Johnson K.J.; RT "A novel homeodomain-encoding gene is associated with a large CpG island RT interrupted by the myotonic dystrophy unstable (CTG)n repeat."; RL Hum. Mol. Genet. 4:1919-1925(1995). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A., RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Eye; 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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 185-739. RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP TISSUE SPECIFICITY. RX PubMed=9949207; DOI=10.1093/hmg/8.3.481; RA Winchester C.L., Ferrier R.K., Sermoni A., Clark B.J., Johnson K.J.; RT "Characterization of the expression of DMPK and SIX5 in the human eye and RT implications for pathogenesis in myotonic dystrophy."; RL Hum. Mol. Genet. 8:481-492(1999). RN [6] RP DNA-BINDING. RX PubMed=10756185; DOI=10.1093/nar/28.9.1871; RA Harris S.E., Winchester C.L., Johnson K.J.; RT "Functional analysis of the homeodomain protein SIX5."; RL Nucleic Acids Res. 28:1871-1878(2000). RN [7] RP SUBCELLULAR LOCATION, AND DEVELOPMENTAL STAGE. RX PubMed=12500905; DOI=10.1023/a:1020990825644; RA Fougerousse F., Durand M., Lopez S., Suel L., Demignon J., Thornton C., RA Ozaki H., Kawakami K., Barbet P., Beckmann J.S., Maire P.; RT "Six and Eya expression during human somitogenesis and MyoD gene family RT activation."; RL J. Muscle Res. Cell Motil. 23:255-264(2002). RN [8] RP VARIANTS BOR2 THR-158; THR-296; ARG-365 AND MET-552, AND CHARACTERIZATION RP OF VARIANTS BOR2 THR-158 AND MET-552. RX PubMed=17357085; DOI=10.1086/513322; RA Hoskins B.E., Cramer C.H., Silvius D., Zou D., Raymond R.M., Orten D.J., RA Kimberling W.J., Smith R.J.H., Weil D., Petit C., Otto E.A., Xu P.-X., RA Hildebrandt F.; RT "Transcription factor SIX5 is mutated in patients with branchio-oto-renal RT syndrome."; RL Am. J. Hum. Genet. 80:800-804(2007). CC -!- FUNCTION: Transcription factor that is thought to be involved in CC regulation of organogenesis. May be involved in determination and CC maintenance of retina formation. Binds a 5'-GGTGTCAG-3' motif present CC in the ARE regulatory element of ATP1A1. Binds a 5'-TCA[AG][AG]TTNC-3' CC motif present in the MEF3 element in the myogenin promoter, and in the CC IGFBP5 promoter (By similarity). Thought to be regulated by association CC with Dach and Eya proteins, and seems to be coactivated by EYA1, EYA2 CC and EYA3 (By similarity). {ECO:0000250}. CC -!- SUBUNIT: Probably binds DNA dimer. Interacts with EYA3, and probably CC EYA1 and EYA2 (By similarity). {ECO:0000250}. CC -!- INTERACTION: CC Q8N196; P54253: ATXN1; NbExp=4; IntAct=EBI-946167, EBI-930964; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:12500905}. Nucleus CC {ECO:0000255|PROSITE-ProRule:PRU00108, ECO:0000269|PubMed:12500905}. CC -!- TISSUE SPECIFICITY: Expressed in adult but not in fetal eyes. Found in CC corneal epithelium and endothelium, lens epithelium, ciliary body CC epithelia, cellular layers of the retina and the sclera. CC {ECO:0000269|PubMed:9949207}. CC -!- DEVELOPMENTAL STAGE: At the begin of fourth week of development CC detected in cytoplasm of somite cells, and at the end of fourth week is CC accumulated in the nucleus. Between the sixth and eighth week of CC development detected in the nucleus of limb bud cells. CC {ECO:0000269|PubMed:12500905}. CC -!- DISEASE: Branchiootorenal syndrome 2 (BOR2) [MIM:610896]: A syndrome CC characterized by branchial cleft fistulas or cysts, sensorineural CC and/or conductive hearing loss, pre-auricular pits, structural defects CC of the outer, middle or inner ear, and renal malformations. CC {ECO:0000269|PubMed:17357085}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the SIX/Sine oculis homeobox family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH33204.1; Type=Miscellaneous discrepancy; Note=Aberrant splicing.; Evidence={ECO:0000305}; CC Sequence=AK074826; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305}; 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; X84813; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC074212; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC033204; AAH33204.1; ALT_SEQ; mRNA. DR EMBL; BU859227; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AK074826; -; NOT_ANNOTATED_CDS; mRNA. DR CCDS; CCDS12673.1; -. DR RefSeq; NP_787071.2; NM_175875.4. DR AlphaFoldDB; Q8N196; -. DR SMR; Q8N196; -. DR BioGRID; 127096; 75. DR IntAct; Q8N196; 12. DR MINT; Q8N196; -. DR STRING; 9606.ENSP00000316842; -. DR GlyGen; Q8N196; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q8N196; -. DR PhosphoSitePlus; Q8N196; -. DR BioMuta; SIX5; -. DR DMDM; 150421671; -. DR EPD; Q8N196; -. DR jPOST; Q8N196; -. DR MassIVE; Q8N196; -. DR MaxQB; Q8N196; -. DR PaxDb; 9606-ENSP00000316842; -. DR PeptideAtlas; Q8N196; -. DR ProteomicsDB; 71575; -. DR Pumba; Q8N196; -. DR Antibodypedia; 31386; 211 antibodies from 28 providers. DR DNASU; 147912; -. DR Ensembl; ENST00000317578.7; ENSP00000316842.4; ENSG00000177045.11. DR GeneID; 147912; -. DR KEGG; hsa:147912; -. DR MANE-Select; ENST00000317578.7; ENSP00000316842.4; NM_175875.5; NP_787071.3. DR UCSC; uc002pdb.4; human. DR AGR; HGNC:10891; -. DR CTD; 147912; -. DR DisGeNET; 147912; -. DR GeneCards; SIX5; -. DR GeneReviews; SIX5; -. DR HGNC; HGNC:10891; SIX5. DR HPA; ENSG00000177045; Low tissue specificity. DR MalaCards; SIX5; -. DR MIM; 600963; gene. DR MIM; 610896; phenotype. DR neXtProt; NX_Q8N196; -. DR OpenTargets; ENSG00000177045; -. DR Orphanet; 107; BOR syndrome. DR PharmGKB; PA35791; -. DR VEuPathDB; HostDB:ENSG00000177045; -. DR eggNOG; KOG0775; Eukaryota. DR GeneTree; ENSGT00940000162237; -. DR HOGENOM; CLU_022250_0_0_1; -. DR InParanoid; Q8N196; -. DR OMA; AAMPIWP; -. DR OrthoDB; 5265771at2759; -. DR PhylomeDB; Q8N196; -. DR TreeFam; TF315545; -. DR PathwayCommons; Q8N196; -. DR SignaLink; Q8N196; -. DR BioGRID-ORCS; 147912; 18 hits in 1173 CRISPR screens. DR GeneWiki; SIX5; -. DR GenomeRNAi; 147912; -. DR Pharos; Q8N196; Tbio. DR PRO; PR:Q8N196; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; Q8N196; Protein. DR Bgee; ENSG00000177045; Expressed in cardiac muscle of right atrium and 146 other cell types or tissues. DR ExpressionAtlas; Q8N196; baseline and differential. DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. 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; IEA:Ensembl. 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:0002088; P:lens development in camera-type eye; IEA:Ensembl. DR GO; GO:0160024; P:Leydig cell proliferation; IEA:Ensembl. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IEA:Ensembl. DR GO; GO:1902723; P:negative regulation of skeletal muscle satellite cell proliferation; IEA:Ensembl. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0007286; P:spermatid development; IEA:Ensembl. DR CDD; cd00086; homeodomain; 1. DR Gene3D; 1.10.10.60; Homeodomain-like; 1. DR InterPro; IPR009057; Homeobox-like_sf. DR InterPro; IPR017970; Homeobox_CS. DR InterPro; IPR001356; Homeobox_dom. DR InterPro; IPR031701; SIX1_SD. DR PANTHER; PTHR10390; HOMEOBOX PROTEIN SIX; 1. DR PANTHER; PTHR10390:SF40; HOMEOBOX PROTEIN SIX5; 1. DR Pfam; PF00046; Homeodomain; 1. DR Pfam; PF16878; SIX1_SD; 1. DR SMART; SM00389; HOX; 1. DR SUPFAM; SSF46689; Homeodomain-like; 1. DR PROSITE; PS00027; HOMEOBOX_1; 1. DR PROSITE; PS50071; HOMEOBOX_2; 1. DR Genevisible; Q8N196; HS. PE 1: Evidence at protein level; KW Activator; Cytoplasm; Deafness; Developmental protein; Disease variant; KW DNA-binding; Homeobox; Nucleus; Reference proteome; Transcription; KW Transcription regulation. FT CHAIN 1..739 FT /note="Homeobox protein SIX5" FT /id="PRO_0000049305" FT DNA_BIND 201..260 FT /note="Homeobox" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108" FT REGION 1..84 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 251..294 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 361..381 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 617..650 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 272..286 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 621..639 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VARIANT 158 FT /note="A -> T (in BOR2; affects Eya1 binding and the FT ability to activate gene transcription; dbSNP:rs80356461)" FT /evidence="ECO:0000269|PubMed:17357085" FT /id="VAR_032941" FT VARIANT 296 FT /note="A -> T (in BOR2; dbSNP:rs80356462)" FT /evidence="ECO:0000269|PubMed:17357085" FT /id="VAR_032942" FT VARIANT 365 FT /note="G -> R (in BOR2; dbSNP:rs80356463)" FT /evidence="ECO:0000269|PubMed:17357085" FT /id="VAR_032943" FT VARIANT 552 FT /note="T -> M (in BOR2; affects Eya1 binding and the FT ability to activate gene transcription; dbSNP:rs80356464)" FT /evidence="ECO:0000269|PubMed:17357085" FT /id="VAR_032944" FT VARIANT 556 FT /note="L -> V (in dbSNP:rs2014377)" FT /id="VAR_032945" FT VARIANT 635 FT /note="P -> S (in dbSNP:rs2014576)" FT /id="VAR_032946" FT VARIANT 693 FT /note="V -> M (in dbSNP:rs2341097)" FT /id="VAR_032947" SQ SEQUENCE 739 AA; 74562 MW; D8A2E8DBBBA263A2 CRC64; MATLPAEPSA GPAAGGEAVA AAAATEEEEE EARQLLQTLQ AAEGEAAAAA GAGAGAAAAG AEGPGSPGVP GSPPEAASEP PTGLRFSPEQ VACVCEALLQ AGHAGRLSRF LGALPPAERL RGSDPVLRAR ALVAFQRGEY AELYRLLESR PFPAAHHAFL QDLYLRARYH EAERARGRAL GAVDKYRLRK KFPLPKTIWD GEETVYCFKE RSRAALKACY RGNRYPTPDE KRRLATLTGL SLTQVSNWFK NRRQRDRTGA GGGAPCKSES DGNPTTEDES SRSPEDLERG AAPVSAEAAA QGSIFLAGTG PPAPCPASSS ILVNGSFLAA SGSPAVLLNG GPVIINGLAL GEASSLGPLL LTGGGGAPPP QPSPQGASET KTSLVLDPQT GEVRLEEAQS EAPETKGAQV AAPGPALGEE VLGPLAQVVP GPPTAATFPL PPGPVPAVAA PQVVPLSPPP GYPTGLSPTS PLLNLPQVVP TSQVVTLPQA VGPLQLLAAG PGSPVKVAAA AGPANVHLIN SGVGVTALQL PSATAPGNFL LANPVSGSPI VTGVALQQGK IILTATFPTS MLVSQVLPPA PGLALPLKPE TAISVPEGGL PVAPSPALPE AHALGTLSAQ QPPPAAATTS STSLPFSPDS PGLLPNFPAP PPEGLMLSPA AVPVWSAGLE LSAGTEGLLE AEKGLGTQAP HTVLRLPDPD PEGLLLGATA GGEVDEGLEA EAKVLTQLQS VPVEEPLEL //