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) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › 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	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 component	Nucleus
Disease	Deafness Disease mutation Non-syndromic deafness
Domain	Homeobox
Ligand	DNA-binding
Molecular function	Developmental protein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	aorta 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_component	nucleolus Inferred from direct assay. Source: HPA transcription factor complex Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	chromatin 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
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.7

VAR_064948

Natural variant

73

1

H → P in BOS3. Ref.7

VAR_064949

Natural variant

99

1

R → C. Ref.3 Ref.4
Corresponds to variant rs17850414 [ dbSNP | Ensembl ].

VAR_067446

Natural variant

106

1

V → G in BOS3. Ref.7

VAR_064950

Natural variant

110

1

R → Q in BOS3. Ref.7

VAR_064951

Natural variant

110

1

R → W in BOS3; crucial for EYA1-SIX1 interaction. Ref.5 Ref.7

VAR_031024

Natural variant

112

1

R → C in BOS3. Ref.7

VAR_064952

Natural variant

122

1

W → R in BOS3. Ref.6

VAR_064953

Natural variant

129

1

Y → C in BOS3; crucial for EYA1-SIX1 interaction; crucial for SIX1-DNA protein-DNA binding. Ref.5 Ref.7 Ref.8

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. Ref.5

VAR_031026

Natural variant

249

1

P → L in BOR; uncertain pathological significance. Ref.8

VAR_064954

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

284

Helix Strand Turn

Details...

Helix

11 – 23

13

Helix

27 – 36

10

Helix

47 – 60

14

Helix

63 – 72

10

Helix

77 – 79

3

Helix

80 – 99

20

Helix

105 – 114

10

Helix

135 – 145

11

Helix

151 – 161

11

Helix

165 – 184

20

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] [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. , 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.

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.
BT007083 mRNA. Translation: AAP35746.1.
BC008874 mRNA. Translation: AAH08874.1.

IPI

IPI00017506.

RefSeq

NP_005973.1. NM_005982.3.

UniGene

Hs.633506.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
4EGC	X-ray	1.99	A	1-189	[»]

ProteinModelPortal

Q15475.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q15475. 3 interactions.

MINT

MINT-140054.

STRING

9606.ENSP00000247182.

PTM databases

PhosphoSite

Q15475.

Polymorphism databases

DMDM

2495290.

Proteomic databases

PaxDb

Q15475.

PRIDE

Q15475.

Protocols and materials databases

DNASU

6495.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000247182; ENSP00000247182; ENSG00000126778.

GeneID

6495.

KEGG

hsa:6495.

UCSC

uc001xfb.4. human.

Organism-specific databases

CTD

6495.

GeneCards

GC14M061111.

HGNC

HGNC:10887. SIX1.

HPA

CAB058690.
HPA001893.

MIM

601205. gene.
605192. phenotype.
608389. phenotype.

neXtProt

NX_Q15475.

Orphanet

90635. Autosomal dominant nonsyndromic sensorineural deafness type DFNA.
107. BOR syndrome.
52429. Branchio-otic syndrome.

PharmGKB

PA35787.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG289502.

HOGENOM

HOG000261680.

HOVERGEN

HBG003609.

InParanoid

Q15475.

KO

K15614.

OMA

GNLSHAR.

OrthoDB

EOG4RJG27.

PhylomeDB

Q15475.

Enzyme and pathway databases

SignaLink

Q15475.

Gene expression databases

ArrayExpress

Q15475.

Bgee

Q15475.

CleanEx

HS_SIX1.

Genevestigator

Q15475.

GermOnline

ENSG00000126778. Homo sapiens.

Family and domain databases

Gene3D

1.10.10.60. 1 hit.

InterPro

IPR017970. Homeobox_CS.
IPR001356. Homeodomain.
IPR009057. Homeodomain-like.
[Graphical view]

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

GenomeRNAi

6495.

NextBio

25247.

SOURCE

Search...

Entry information

Entry name

SIX1_HUMAN

Accession

Primary (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 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.