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Q15475 (SIX1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified May 29, 2013. Version 118. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Homeobox protein SIX1
Alternative name(s):
Sine oculis homeobox homolog 1
Gene names
Name:SIX1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length284 AA.
Sequence statusComplete.
Protein existenceEvidence 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

Deafness, autosomal dominant, 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.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.5

Branchiootic syndrome 3 (BOS3) [MIM:608389]: 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 overlap with those seen in individuals with the branchiootorenal syndrome. However renal anomalies are absent in branchiootic syndrome patients.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.5 Ref.6 Ref.7 Ref.8

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.8

Sequence similarities

Belongs to the SIX/Sine oculis homeobox family.

Contains 1 homeobox DNA-binding domain.

Ontologies

Keywords
   Cellular componentNucleus
   DiseaseDeafness
Disease mutation
Non-syndromic deafness
   DomainHomeobox
   LigandDNA-binding
   Molecular functionDevelopmental protein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processaorta morphogenesis

Inferred from electronic annotation. Source: Compara

branching involved in ureteric bud morphogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

cochlea morphogenesis

Inferred from electronic annotation. Source: Compara

embryonic cranial skeleton morphogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

epithelial cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

facial nerve morphogenesis

Inferred from electronic annotation. Source: Compara

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

middle ear morphogenesis

Inferred from electronic annotation. Source: Compara

myoblast migration

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of branching involved in ureteric bud morphogenesis

Inferred from electronic annotation. Source: Compara

negative regulation of neuron apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of transcription from RNA polymerase II promoter

Inferred from electronic annotation. Source: Compara

organ induction

Inferred from sequence or structural similarity. Source: UniProtKB

otic vesicle development

Inferred from electronic annotation. Source: Compara

outflow tract morphogenesis

Inferred from electronic annotation. Source: Compara

pattern specification process

Inferred from sequence or structural similarity. Source: UniProtKB

pharyngeal system development

Inferred from electronic annotation. Source: Compara

positive regulation of branching involved in ureteric bud morphogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of mesenchymal cell proliferation involved in ureter development

Inferred from electronic annotation. Source: Compara

positive regulation of secondary heart field cardioblast proliferation

Inferred from electronic annotation. Source: Compara

positive regulation of transcription from RNA polymerase II promoter

Inferred from direct assay Ref.5. Source: UniProtKB

positive regulation of ureteric bud formation

Inferred from sequence or structural similarity. Source: UniProtKB

protein localization to nucleus

Inferred from direct assay PubMed 19497856. 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

regulation of protein localization

Inferred from electronic annotation. Source: Compara

regulation of synaptic growth at neuromuscular junction

Inferred from electronic annotation. Source: Compara

sensory perception of sound

Inferred from electronic annotation. Source: Compara

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

ureter smooth muscle cell differentiation

Inferred from electronic annotation. Source: Compara

   Cellular_componentnucleolus

Inferred from direct assay. Source: HPA

transcription factor complex

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionchromatin binding

Inferred from electronic annotation. Source: Compara

sequence-specific DNA binding

Inferred from direct assay Ref.5. 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 PubMed 16670092. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

MDFIQ997502EBI-743675,EBI-724076

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 284284Homeobox protein SIX1
PRO_0000049295

Regions

DNA binding124 – 18360Homeobox

Natural variations

Natural variant171V → E in BOS3. Ref.7
VAR_064948
Natural variant731H → P in BOS3. Ref.7
VAR_064949
Natural variant991R → C. Ref.3 Ref.4
Corresponds to variant rs17850414 [ dbSNP | Ensembl ].
VAR_067446
Natural variant1061V → G in BOS3. Ref.7
VAR_064950
Natural variant1101R → Q in BOS3. Ref.7
VAR_064951
Natural variant1101R → W in BOS3; crucial for EYA1-SIX1 interaction. Ref.5 Ref.7
VAR_031024
Natural variant1121R → C in BOS3. Ref.7
VAR_064952
Natural variant1221W → R in BOS3. Ref.6
VAR_064953
Natural variant1291Y → C in BOS3; crucial for EYA1-SIX1 interaction; crucial for SIX1-DNA protein-DNA binding. Ref.5 Ref.7 Ref.8
VAR_031025
Natural variant1331Missing 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. Ref.5
VAR_031026
Natural variant2491P → L in BOR; uncertain pathological significance. Ref.8
VAR_064954

Secondary structure

.................... 284
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q15475 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: A4195376CFB9E3EA

FASTA28432,210
        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 

« Hide

References

« Hide '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] [Europe PMC] [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]"Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT CYS-99.
[4]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT CYS-99.
Tissue: Muscle.
[5]"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. expand/collapse author list , Stratakis C.A., Weil D., Petit C., Hildebrandt F.
Proc. Natl. Acad. Sci. U.S.A. 101:8090-8095(2004) [PubMed] [Europe PMC] [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.
[6]"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] [Europe PMC] [Abstract]
Cited for: VARIANT BOS3 ARG-122.
[7]"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] [Europe PMC] [Abstract]
Cited for: VARIANTS BOS3 GLU-17; PRO-73; GLY-106; GLN-110; TRP-110; CYS-112 AND CYS-129.
[8]"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] [Europe PMC] [Abstract]
Cited for: VARIANT BOS3 CYS-129, VARIANT BOR LEU-249.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X91868 mRNA. Translation: CAA62974.1.
AF323497 Genomic DNA. Translation: AAK06772.1.
BT007083 mRNA. Translation: AAP35746.1.
BC008874 mRNA. Translation: AAH08874.1.
IPIIPI00017506.
RefSeqNP_005973.1. NM_005982.3.
UniGeneHs.633506.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
4EGCX-ray1.99A1-189[»]
ProteinModelPortalQ15475.
ModBaseSearch...

Protein-protein interaction databases

IntActQ15475. 3 interactions.
MINTMINT-140054.
STRING9606.ENSP00000247182.

PTM databases

PhosphoSiteQ15475.

Polymorphism databases

DMDM2495290.

Proteomic databases

PaxDbQ15475.
PRIDEQ15475.

Protocols and materials databases

DNASU6495.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000247182; ENSP00000247182; ENSG00000126778.
GeneID6495.
KEGGhsa:6495.
UCSCuc001xfb.4. human.

Organism-specific databases

CTD6495.
GeneCardsGC14M061111.
HGNCHGNC:10887. SIX1.
HPACAB058690.
HPA001893.
MIM601205. gene.
605192. phenotype.
608389. phenotype.
neXtProtNX_Q15475.
Orphanet90635. Autosomal dominant nonsyndromic sensorineural deafness type DFNA.
107. BOR syndrome.
52429. Branchio-otic syndrome.
PharmGKBPA35787.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG289502.
HOGENOMHOG000261680.
HOVERGENHBG003609.
InParanoidQ15475.
KOK15614.
OMAGNLSHAR.
OrthoDBEOG4RJG27.
PhylomeDBQ15475.

Enzyme and pathway databases

SignaLinkQ15475.

Gene expression databases

ArrayExpressQ15475.
BgeeQ15475.
CleanExHS_SIX1.
GenevestigatorQ15475.
GermOnlineENSG00000126778. Homo sapiens.

Family and domain databases

Gene3D1.10.10.60. 1 hit.
InterProIPR017970. Homeobox_CS.
IPR001356. Homeodomain.
IPR009057. Homeodomain-like.
[Graphical view]
PfamPF00046. Homeobox. 1 hit.
[Graphical view]
SMARTSM00389. HOX. 1 hit.
[Graphical view]
SUPFAMSSF46689. Homeodomain_like. 1 hit.
PROSITEPS00027. HOMEOBOX_1. 1 hit.
PS50071. HOMEOBOX_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GenomeRNAi6495.
NextBio25247.
SOURCESearch...

Entry information

Entry nameSIX1_HUMAN
AccessionPrimary (citable) accession number: Q15475
Secondary accession number(s): Q53Y16, Q96H64
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1996
Last modified: May 29, 2013
This is version 118 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

Human chromosome 14

Human chromosome 14: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families