SIX5_HUMAN
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 03-AUG-2022, entry version 166.
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};
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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; 74.
DR IntAct; Q8N196; 13.
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; Q8N196; -.
DR PeptideAtlas; Q8N196; -.
DR PRIDE; Q8N196; -.
DR ProteomicsDB; 71575; -.
DR Antibodypedia; 31386; 185 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 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; 1061244at2759; -.
DR PhylomeDB; Q8N196; -.
DR TreeFam; TF315545; -.
DR PathwayCommons; Q8N196; -.
DR SignaLink; Q8N196; -.
DR BioGRID-ORCS; 147912; 18 hits in 1097 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 145 other tissues.
DR ExpressionAtlas; Q8N196; baseline and differential.
DR Genevisible; Q8N196; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
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:1902723; P:negative regulation of skeletal muscle satellite cell proliferation; IEA:Ensembl.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; 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 InterPro; IPR009057; Homeobox-like_sf.
DR InterPro; IPR017970; Homeobox_CS.
DR InterPro; IPR001356; Homeobox_dom.
DR InterPro; IPR031701; SIX1_SD.
DR Pfam; PF00046; Homeodomain; 1.
DR Pfam; PF16878; SIX1_SD; 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 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
