Q15475 (SIX1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Homeobox protein SIX1

Alternative name(s):
Sine oculis homeobox homolog 1

Gene names

Name:

SIX1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	284 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	May be involved in limb tendon and ligament development By similarity.
Subcellular location	Nucleus.
Tissue specificity	Specifically expressed in skeletal muscle.
Involvement in disease	Defects in SIX1 are the cause of deafness autosomal dominant type 23 (DFNA23) [MIM:605192]. A form of non-syndromic deafness characterized by prelingual, bilateral, symmetric hearing loss with a conductive component present in some but not all patients. Ref.4 Defects in SIX1 are the cause of branchiootic syndrome type 3 (BOS3) [MIM:608389]. BOS3 is a syndrome characterized by usually bilateral branchial cleft fistulas or cysts, sensorineural and/or conductive hearing loss, pre-auricular pits, and structural defects of the outer, middle or inner ear. Otic defects include malformed and hypoplastic pinnae, a narrowed external ear canal, bulbous internal auditory canal, stapes fixation, malformed and hypoplastic cochlea. Branchial and otic anomalies are as those seen in individuals with the branchiootorenal syndrome. However, renal anomalies are absent in branchiootic syndrome patients. Ref.4 Ref.5 Ref.6 Ref.7 Note=Defects in SIX1 could be a cause of branchiootorenal syndrome (BOR). 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.7
Sequence similarities	Belongs to the SIX/Sine oculis homeobox family. Contains 1 homeobox DNA-binding domain.

Ontologies

Keywords
Cellular component	Nucleus
Disease	Deafness Disease mutation Non-syndromic deafness
Domain	Homeobox
Ligand	DNA-binding
Molecular function	Developmental protein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	branching involved in ureteric bud morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB embryonic cranial skeleton morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB epithelial cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB inner ear morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB mesonephric tubule formation Inferred from sequence or structural similarity. Source: UniProtKB metanephric mesenchyme development Inferred from sequence or structural similarity. Source: UniProtKB myoblast migration Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of neuron apoptosis Inferred from sequence or structural similarity. Source: UniProtKB organ induction Inferred from sequence or structural similarity. Source: UniProtKB pattern specification process Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of branching involved in ureteric bud morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay Ref.4. Source: UniProtKB positive regulation of ureteric bud formation Inferred from sequence or structural similarity. Source: UniProtKB protein localization to nucleus Inferred from direct assay. Source: UniProtKB regulation of branch elongation involved in ureteric bud branching Inferred from sequence or structural similarity. Source: UniProtKB regulation of neuron differentiation Inferred from sequence or structural similarity. Source: UniProtKB skeletal muscle tissue development Inferred from sequence or structural similarity. Source: UniProtKB thymus development Inferred from sequence or structural similarity. Source: UniProtKB thyroid gland development Inferred from sequence or structural similarity. Source: UniProtKB transcription, DNA-dependent Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	nucleolus Inferred from direct assay. Source: HPA transcription factor complex Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	protein binding Inferred from physical interaction Ref.4. Source: UniProtKB sequence-specific DNA binding Inferred from direct assay Ref.4. Source: UniProtKB sequence-specific DNA binding transcription factor activity Inferred from sequence or structural similarity. Source: UniProtKB transcription regulatory region DNA binding Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
MDFI	Q99750	2	EBI-743675,EBI-724076

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 284	284	Homeobox protein SIX1		PRO_0000049295
Regions
	DNA binding	124 – 183	60	Homeobox
Natural variations
	Natural variant	17	1	V → E in BOS3. Ref.6		VAR_064948
	Natural variant	73	1	H → P in BOS3. Ref.6		VAR_064949
	Natural variant	106	1	V → G in BOS3. Ref.6		VAR_064950
	Natural variant	110	1	R → Q in BOS3. Ref.6		VAR_064951
	Natural variant	110	1	R → W in BOS3; crucial for EYA1-SIX1 interaction. Ref.4 Ref.6		VAR_031024
	Natural variant	112	1	R → C in BOS3. Ref.6		VAR_064952
	Natural variant	122	1	W → R in BOS3. Ref.5		VAR_064953
	Natural variant	129	1	Y → C in BOS3; crucial for EYA1-SIX1 interaction; crucial for SIX1-DNA protein-DNA binding. Ref.4 Ref.6 Ref.7		VAR_031025
	Natural variant	133	1	Missing in DFNA23; in addition to deafness the patient had renal anomalies suggesting a branchiootorenal syndrome; crucial for EYA1-SIX1 interaction; crucial for SIX1-DNA protein-DNA binding.		VAR_031026
	Natural variant	249	1	P → L in BOR; uncertain pathological significance. Ref.7		VAR_064954
Experimental info
	Sequence conflict	99	1	R → C in AAH08874. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Q15475 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: A4195376CFB9E3EA	FASTA	284	32,210
	10 20 30 40 50 60 MSMLPSFGFT QEQVACVCEV LQQGGNLERL GRFLWSLPAC DHLHKNESVL KAKAVVAFHR 70 80 90 100 110 120 GNFRELYKIL ESHQFSPHNH PKLQQLWLKA HYVEAEKLRG RPLGAVGKYR VRRKFPLPRT 130 140 150 160 170 180 IWDGEETSYC FKEKSRGVLR EWYAHNPYPS PREKRELAEA TGLTTTQVSN WFKNRRQRDR 190 200 210 220 230 240 AAEAKERENT ENNNSSSNKQ NQLSPLEGGK PLMSSSEEEF SPPQSPDQNS VLLLQGNMGH 250 260 270 280 ARSSNYSLPG LTASQPSHGL QTHQHQLQDS LLGPLTSSLV DLGS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning of the human SIX1 gene and its assignment to chromosome 14." Boucher C.A., Carey N., Edwards Y.H., Siciliano M.J., Johnson K.J. Genomics 33:140-142(1996) [PubMed: 8617500] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Muscle.
[2]	"Partial genomic sequence of human SIX1." Gallardo M.E., Rodriguez de Cordoba S. Submitted (NOV-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [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]. Tissue: Muscle.
[4]	"SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes." Ruf R.G., Xu P.-X., Silvius D., Otto E.A., Beekmann F., Muerb U.T., Kumar S., Neuhaus T.J., Kemper M.J., Raymond R.M. Jr., Brophy P.D., Berkman J., Gattas M., Hyland V., Ruf E.-M., Schwartz C., Chang E.H., Smith R.J.H. , Stratakis C.A., Weil D., Petit C., Hildebrandt F. Proc. Natl. Acad. Sci. U.S.A. 101:8090-8095(2004) [PubMed: 15141091] [Abstract] Cited for: VARIANTS BOS3 TRP-110 AND CYS-129, VARIANT DFNA23 GLU-133 DEL, CHARACTERIZATION OF VARIANTS BOS3 TRP-110 AND CYS-129, CHARACTERIZATION OF VARIANT DFNA23 GLU-133 DEL.
[5]	"Branchio-oto-renal syndrome: detection of EYA1 and SIX1 mutations in five out of six Danish families by combining linkage, MLPA and sequencing analyses." Sanggaard K.M., Rendtorff N.D., Kjaer K.W., Eiberg H., Johnsen T., Gimsing S., Dyrmose J., Nielsen K.O., Lage K., Tranebjaerg L. Eur. J. Hum. Genet. 15:1121-1131(2007) [PubMed: 17637804] [Abstract] Cited for: VARIANT BOS3 ARG-122.
[6]	"SIX1 mutation screening in 247 branchio-oto-renal syndrome families: a recurrent missense mutation associated with BOR." Kochhar A., Orten D.J., Sorensen J.L., Fischer S.M., Cremers C.W., Kimberling W.J., Smith R.J. Hum. Mutat. 29:565-565(2008) [PubMed: 18330911] [Abstract] Cited for: VARIANTS BOS3 GLU-17; PRO-73; GLY-106; GLN-110; TRP-110; CYS-112 AND CYS-129.
[7]	"Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations." Krug P., Moriniere V., Marlin S., Koubi V., Gabriel H.D., Colin E., Bonneau D., Salomon R., Antignac C., Heidet L. Hum. Mutat. 32:183-190(2011) [PubMed: 21280147] [Abstract] Cited for: VARIANT BOS3 CYS-129, VARIANT BOR LEU-249.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	X91868 mRNA. Translation: CAA62974.1. AF323497 Genomic DNA. Translation: AAK06772.1. BC008874 mRNA. Translation: AAH08874.1.
IPI	IPI00017506.
RefSeq	NP_005973.1. NM_005982.3.
UniGene	Hs.713114.
3D structure databases
ProteinModelPortal	Q15475.
SMR	Q15475. Positions 26-187.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q15475. 3 interactions.
MINT	MINT-140054.
STRING	Q15475.
PTM databases
PhosphoSite	Q15475.
Polymorphism databases
DMDM	2495290.
Proteomic databases
PRIDE	Q15475.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000247182; ENSP00000247182; ENSG00000126778.
GeneID	6495.
KEGG	hsa:6495.
UCSC	uc001xfb.2. human.
Organism-specific databases
CTD	6495.
GeneCards	GC14M061111.
H-InvDB	HIX0011712.
HGNC	HGNC:10887. SIX1.
HPA	HPA001893.
MIM	601205. gene. 605192. phenotype. 608389. phenotype.
neXtProt	NX_Q15475.
Orphanet	107. BOR syndrome. 52429. Branchio-otic syndrome.
PharmGKB	PA35787.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG15385.
HOGENOM	HBG443955.
HOVERGEN	HBG003609.
InParanoid	Q15475.
OMA	NTSSNKQ.
OrthoDB	EOG4RJG27.
PhylomeDB	Q15475.
Gene expression databases
ArrayExpress	Q15475.
Bgee	Q15475.
CleanEx	HS_SIX1.
Genevestigator	Q15475.
GermOnline	ENSG00000126778. Homo sapiens.
Family and domain databases
InterPro	IPR001356. Homeobox. IPR017970. Homeobox_CS. IPR009057. Homeodomain-like. IPR012287. Homeodomain-rel. [Graphical view]
Gene3D	G3DSA:1.10.10.60. Homeodomain-rel. 1 hit.
KO	K15614.
Pfam	PF00046. Homeobox. 1 hit. [Graphical view]
SMART	SM00389. HOX. 1 hit. [Graphical view]
SUPFAM	SSF46689. Homeodomain_like. 1 hit.
PROSITE	PS00027. HOMEOBOX_1. 1 hit. PS50071. HOMEOBOX_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	25247.
SOURCE	Search...

Entry information

Entry name

SIX1_HUMAN

Accession

Primary (citable) accession number: Q15475
Secondary accession number(s): Q96H64

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	November 1, 1996
Last modified:	January 25, 2012
This is version 104 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.