Reviewed, UniProtKB/Swiss-Prot Q8N196 (SIX5_HUMAN)

Names and origin

Protein names

Recommended name:
    Homeobox protein SIX5
Alternative name(s):
    DM locus-associated homeodomain protein

Gene names

Name:	SIX5
Synonyms:	DMAHP

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	739 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Transcription factor that is thought to be involved in regulation of organogenesis. May be involved in determination and maintenance of retina formation. Binds a 5'-GGTGTCAG-3' motif present in the ARE regulatory element of ATP1A1. Binds a 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 element in the myogenin promoter, and in the IGFBP5 promoter By similarity. Thought to be regulated by association with Dach and Eya proteins, and seems to be coactivated by EYA1, EYA2 and EYA3 By similarity.
Subunit structure	Probably binds DNA dimer. Interacts with EYA3, and probably EYA1 and EYA2 By similarity.
Subcellular location	Cytoplasm. Nucleus. Ref.9
Tissue specificity	Expressed in adult but not in fetal eyes. Found in corneal epithelium and endothelium, lens epithelium, ciliary body epithelia, cellular layers of the retina and the sclera. Ref.7
Developmental stage	At the begin of fourth week of development detected in cytoplasm of somite cells, and at the end of fourth week is accumulated in the nucleus. Between the sixth and eighth week of development detected in the nucleus of limb bud cells. Ref.9
Involvement in disease	Defects in SIX5 are the cause of branchiootorenal syndrome type 2 (BOR2) [MIM:610896]. BOR is an autosomal dominant disorder manifested by various combinations of preauricular pits, branchial fistulae or cysts, lacrimal duct stenosis, hearing loss, structural defects of the outer, middle, or inner ear, and renal dysplasia. Associated defects include asthenic habitus, long narrow facies, constricted palate, deep overbite, and myopia. Hearing loss may be due to mondini type cochlear defect and stapes fixation. Penetrance of BOR syndrome is high, although expressivity can be extremely variable. Ref.10
Sequence similarities	Belongs to the SIX/Sine oculis homeobox family. Contains 1 homeobox DNA-binding domain.
Caution	The region from 1 to 184 was deduced from the genomic sequence and ESTs.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Deafness Disease mutation
Domain	Homeobox
Ligand	DNA-binding
Molecular function	Activator Developmental protein
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW sensory perception of sound Inferred from electronic annotation. Source: UniProtKB-KW transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	protein binding Inferred from physical interaction. Source: IntAct transcription factor activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ATXN1	P54253	1	EBI-946167,EBI-930964

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q8N196-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q8N196-2)

The sequence of this isoform differs from the canonical sequence as follows:
     4-584: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 739	739	Homeobox protein SIX5		PRO_0000049305
Regions
	DNA binding	201 – 260	60	Homeobox Ref.8
Natural variations
	Alternative sequence	4 – 584	581	Missing in isoform 2.		VSP_010072
	Natural variant	158	1	A → T in BOR2; affects Eya1 binding and the ability to activate gene transcription. Ref.10		VAR_032941
	Natural variant	296	1	A → T in BOR2. Ref.10		VAR_032942
	Natural variant	365	1	G → R in BOR2. Ref.10		VAR_032943
	Natural variant	552	1	T → M in BOR2; affects Eya1 binding and the ability to activate gene transcription. Ref.10		VAR_032944
	Natural variant	556	1	L → V: dbSNP rs2014377.		VAR_032945
	Natural variant	635	1	P → S: dbSNP rs2014576.		VAR_032946
	Natural variant	693	1	V → M: dbSNP rs2341097.		VAR_032947
Experimental info
	Sequence conflict	691	1	H → HT Ref.1
	Sequence conflict	721	1	Missing Ref.6

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified June 26, 2007. Version 3. Checksum: D8A2E8DBBBA263A2	FASTA	739	74,562
	10 20 30 40 50 60 MATLPAEPSA GPAAGGEAVA AAAATEEEEE EARQLLQTLQ AAEGEAAAAA GAGAGAAAAG 70 80 90 100 110 120 AEGPGSPGVP GSPPEAASEP PTGLRFSPEQ VACVCEALLQ AGHAGRLSRF LGALPPAERL 130 140 150 160 170 180 RGSDPVLRAR ALVAFQRGEY AELYRLLESR PFPAAHHAFL QDLYLRARYH EAERARGRAL 190 200 210 220 230 240 GAVDKYRLRK KFPLPKTIWD GEETVYCFKE RSRAALKACY RGNRYPTPDE KRRLATLTGL 250 260 270 280 290 300 SLTQVSNWFK NRRQRDRTGA GGGAPCKSES DGNPTTEDES SRSPEDLERG AAPVSAEAAA 310 320 330 340 350 360 QGSIFLAGTG PPAPCPASSS ILVNGSFLAA SGSPAVLLNG GPVIINGLAL GEASSLGPLL 370 380 390 400 410 420 LTGGGGAPPP QPSPQGASET KTSLVLDPQT GEVRLEEAQS EAPETKGAQV AAPGPALGEE 430 440 450 460 470 480 VLGPLAQVVP GPPTAATFPL PPGPVPAVAA PQVVPLSPPP GYPTGLSPTS PLLNLPQVVP 490 500 510 520 530 540 TSQVVTLPQA VGPLQLLAAG PGSPVKVAAA AGPANVHLIN SGVGVTALQL PSATAPGNFL 550 560 570 580 590 600 LANPVSGSPI VTGVALQQGK IILTATFPTS MLVSQVLPPA PGLALPLKPE TAISVPEGGL 610 620 630 640 650 660 PVAPSPALPE AHALGTLSAQ QPPPAAATTS STSLPFSPDS PGLLPNFPAP PPEGLMLSPA 670 680 690 700 710 720 AVPVWSAGLE LSAGTEGLLE AEKGLGTQAP HTVLRLPDPD PEGLLLGATA GGEVDEGLEA 730 EAKVLTQLQS VPVEEPLEL
	Isoform 2. Checksum: 78E1E7E04E8075BF	FASTA	158	15,835
	10 20 30 40 50 60 MATLPLKPET AISVPEGGLP VAPSPALPEA HALGTLSAQQ PPPAAATTSS TSLPFSPDSP 70 80 90 100 110 120 GLLPNFPAPP PEGLMLSPAA VPVWSAGLEL SAGTEGLLEA EKGLGTQAPH TVLRLPDPDP 130 140 150 EGLLLGATAG GEVDEGLEAE AKVLTQLQSV PVEEPLEL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat." Boucher C.A., King S.K., Carey N., Krahe R., Winchester C.L., Rahman S., Creavin T., Meghji P., Bailey M.E., Chartier F.L., Brown S.D., Sicilliano M.J., Johnson K.J. Hum. Mol. Genet. 4:1919-1925(1995) [PubMed: 8595416] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"The DNA sequence and biology of human chromosome 19." Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., Carrano A.V. , Caoile C., Chan Y.M., Christensen M., Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., Rubin E.M., Lucas S.M. Nature 428:529-535(2004) [PubMed: 15057824] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Eye.
[4]	Roechert B. Unpublished observations (JAN-2004) Cited for: RECONSTRUCTION FROM GENOMIC SEQUENCE AND ESTS, CONCEPTUAL TRANSLATION OF 5-184 (ISOFORM 1).
[5]	The MGC Project Team Submitted (OCT-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE OF 74-290 (ISOFORM 1).
[6]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 185-739 (ISOFORM 1).
[7]	"Characterization of the expression of DMPK and SIX5 in the human eye and implications for pathogenesis in myotonic dystrophy." Winchester C.L., Ferrier R.K., Sermoni A., Clark B.J., Johnson K.J. Hum. Mol. Genet. 8:481-492(1999) [PubMed: 9949207] [Abstract] Cited for: TISSUE SPECIFICITY.
[8]	"Functional analysis of the homeodomain protein SIX5." Harris S.E., Winchester C.L., Johnson K.J. Nucleic Acids Res. 28:1871-1878(2000) [PubMed: 10756185] [Abstract] Cited for: DNA-BINDING.
[9]	"Six and Eya expression during human somitogenesis and MyoD gene family activation." Fougerousse F., Durand M., Lopez S., Suel L., Demignon J., Thornton C., Ozaki H., Kawakami K., Barbet P., Beckmann J.S., Maire P. J. Muscle Res. Cell Motil. 23:255-264(2002) [PubMed: 12500905] [Abstract] Cited for: SUBCELLULAR LOCATION, DEVELOPMENTAL STAGE.
[10]	"Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome." Hoskins B.E., Cramer C.H., Silvius D., Zou D., Raymond R.M., Orten D.J., Kimberling W.J., Smith R.J.H., Weil D., Petit C., Otto E.A., Xu P.-X., Hildebrandt F. Am. J. Hum. Genet. 80:800-804(2007) [PubMed: 17357085] [Abstract] Cited for: VARIANTS BOR2 THR-158; THR-296; ARG-365 AND MET-552, CHARACTERIZATION OF VARIANTS BOR2 THR-158 AND MET-552.

Cross-references

Sequence databases
EMBLGenBankDDBJ	X84813 Genomic DNA. No translation available. AC074212 Genomic DNA. No translation available. BC033204 mRNA. Translation: AAH33204.1. BU859227 mRNA. No translation available. AK074826 mRNA. No translation available.
IPI	IPI00166124. IPI00410575.
UniGene	Hs.43314
3D structure databases
ModBase	Search...
Protein-protein interaction databases
IntAct	Q8N196. 1 interaction.
Genome annotation databases
Ensembl	ENSG00000177045. Homo sapiens. [Contig view]
NMPDR	fig|9606.3.peg.16708.
UCSC	uc002pdb.1. human.
Organism-specific databases
GeneCards	GC19M050959.
H-InvDB	HIX0015240.
HGNC	HGNC:10891. SIX5.
MIM	600963. gene. 610896. phenotype.
Orphanet	107. BOR syndrome.
PharmGKB	PA35791.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	Q8N196.
HOVERGEN	Q8N196.
OMA	Q8N196. LRARYHE.
Gene expression databases
ArrayExpress	Q8N196.
Bgee	Q8N196.
CleanEx	HS_SIX5.
GermOnline	ENSG00000177045. Homo sapiens.
Family and domain databases
InterPro	IPR001356. Homeobox. IPR017970. Homeobox_CS. IPR012287. Homeodomain-rel. [Graphical view]
Gene3D	G3DSA:1.10.10.60. Homeodomain-rel. 1 hit.
Pfam	PF00046. Homeobox. 1 hit. [Graphical view]
ProDom	PD000010. Homeobox. 1 hit. [Graphical view] [Entries sharing at least one domain]
SMART	SM00389. HOX. 1 hit. [Graphical view]
PROSITE	PS00027. HOMEOBOX_1. 1 hit. PS50071. HOMEOBOX_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
SOURCE	Search...

Entry information

Entry name

SIX5_HUMAN

Accession

Primary (citable) accession number: Q8N196

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 13, 2004
Last sequence update:	June 26, 2007
Last modified:	July 7, 2009
This is version 60 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)