SIX3 SIX homeobox 3 [Homo sapiens (human)] - Gene

Summary

Official Symbol: SIX3provided by HGNC
Official Full Name: SIX homeobox 3provided by HGNC
Primary source: HGNC:HGNC:10889
See related: Ensembl:ENSG00000138083 MIM:603714; AllianceGenome:HGNC:10889
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: HPE2
Summary: This gene encodes a member of the sine oculis homeobox transcription factor family. The encoded protein plays a role in eye development. Mutations in this gene have been associated with holoprosencephaly type 2. [provided by RefSeq, Oct 2009]
Expression: Low expression observed in reference dataset See more
Orthologs: mouse all
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Genomic context

Location:: 2p21

Exon count:: 2

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	2	NC_000002.12 (44941702..44946071)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	2	NC_060926.1 (44946967..44951332)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	2	NC_000002.11 (45168841..45173210)

Chromosome 2 - NC_000002.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Heterozygous variants in SIX3 and POU1F1 cause pituitary hormone deficiency in mouse and man.
Title: Heterozygous variants in SIX3 and POU1F1 cause pituitary hormone deficiency in mouse and man.
RNA interference-mediated knockdown of the Drosophila ortholog of SIX3 in insulin-producing cells, a model for mammalian beta cells, conferred reduced insulin output.
Title: Discovering human diabetes-risk gene function with genetics and physiological assays.
TRIM27 acts as an oncogene and regulates cell proliferation and metastasis in non-small cell lung cancer through SIX3-beta-catenin signaling.
Title: TRIM27 acts as an oncogene and regulates cell proliferation and metastasis in non-small cell lung cancer through SIX3-β-catenin signaling.
The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically.
Title: The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically.
Upregulation of sine oculis homeobox homolog 3 is associated with proliferation, invasion, migration, as well as poor prognosis of esophageal cancer.
Title: Upregulation of sine oculis homeobox homolog 3 is associated with proliferation, invasion, migration, as well as poor prognosis of esophageal cancer.
The authors demonstrate that the SIX3/LSD1/NuRD(MTA3) complex inhibits carcinogenesis in breast cancer cells and suppresses metastasis in breast cancer.
Title: The Homeotic Protein SIX3 Suppresses Carcinogenesis and Metastasis through Recruiting the LSD1/NuRD(MTA3) Complex.
SIX3 deletions and incomplete penetrance in families affected by holoprosencephaly have been described.
Title: SIX3 deletions and incomplete penetrance in families affected by holoprosencephaly.
Results demonstrate that Six3 silence or loss in glioma is induced by its promoter hypermethylation and Six3 down-regulation contributes to proliferation and invasion of glioma. And this process is involved in activation of Wnt/beta-catenin pathway. Six3 play a suppressor role in the initiation and progression of human glioma and potentially serve as a target for the diagnosis and treatment of human glioma.
Title: Epigenetically controlled Six3 expression regulates glioblastoma cell proliferation and invasion alongside modulating the activation levels of WNT pathway members.
SIX3 is a novel negative transcriptional regulator and acts as a tumor suppressor that directly represses the transcription of AURKA and AURKB in astrocytoma.
Title: SIX3, a tumor suppressor, inhibits astrocytoma tumorigenesis by transcriptional repression of AURKA/B.
SIX2, SIX3, and SIX4 were correlated with higher TNM stages in lung neoplasms
Title: The expression profile and clinic significance of the SIX family in non-small cell lung cancer.

Submit: New GeneRIF Correction See all GeneRIFs (31)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Anophthalmia-microphthalmia syndrome MedGen: C5680330 GeneReviews: Not available	Compare labs
Holoprosencephaly 2 MedGen: C1834877 OMIM: 157170 GeneReviews: Holoprosencephaly Overview	Compare labs
Schizencephaly MedGen: C0266484 OMIM: 269160 GeneReviews: Not available	Compare labs

Copy number response

Description
Copy number response Triplosensitivity No evidence available (Last evaluated 2020-09-23) ClinGen Genome Curation Page Haploinsufficency Sufficient evidence for dosage pathogenicity (Last evaluated 2020-09-23) ClinGen Genome Curation PagePubMed

EBI GWAS Catalog

Description
Genome-wide association meta-analysis identifies novel variants associated with fasting plasma glucose in East Asians. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide search for replicable risk gene regions in alcohol and nicotine co-dependence. EBI GWAS Catalog EBI GWAS CatalogPubMed
Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

NoName (e-PCR)
- UniSTS:495216

Six3 (e-PCR), detects polymorphism
- UniSTS:536466

RH94877 (e-PCR)
- UniSTS:88751

RH143896 (e-PCR)
- UniSTS:233142

G65690 (e-PCR)
- UniSTS:225483

D2S4014 (e-PCR)
- UniSTS:226021

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables DNA-binding transcription activator activity, RNA polymerase II-specific	ISS Inferred from Sequence or Structural Similarity more info
enables DNA-binding transcription factor activity, RNA polymerase II-specific	IBA Inferred from Biological aspect of Ancestor more info
enables DNA-binding transcription factor activity, RNA polymerase II-specific	ISA Inferred from Sequence Alignment more info
enables RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA Inferred from Biological aspect of Ancestor more info
enables RNA polymerase II cis-regulatory region sequence-specific DNA binding	IDA Inferred from Direct Assay more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables sequence-specific double-stranded DNA binding	IDA Inferred from Direct Assay more info	PubMed
enables signaling receptor binding	IEA Inferred from Electronic Annotation more info
enables transcription corepressor binding	IPI Inferred from Physical Interaction more info	PubMed

Process	Evidence Code	Pubs
involved_in apoptotic process involved in development	ISS Inferred from Sequence or Structural Similarity more info
involved_in brain development	IBA Inferred from Biological aspect of Ancestor more info
involved_in cell proliferation in forebrain	ISS Inferred from Sequence or Structural Similarity more info
involved_in epithelial cell maturation	ISS Inferred from Sequence or Structural Similarity more info
involved_in eye development	IBA Inferred from Biological aspect of Ancestor more info
involved_in eye development	IDA Inferred from Direct Assay more info	PubMed
involved_in forebrain dorsal/ventral pattern formation	IDA Inferred from Direct Assay more info	PubMed
involved_in lens development in camera-type eye	ISS Inferred from Sequence or Structural Similarity more info
involved_in lens fiber cell apoptotic process	ISS Inferred from Sequence or Structural Similarity more info
involved_in lens fiber cell differentiation	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of DNA-templated transcription	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of neuron differentiation	ISS Inferred from Sequence or Structural Similarity more info
involved_in neuroblast differentiation	ISS Inferred from Sequence or Structural Similarity more info
involved_in neuroblast migration	ISS Inferred from Sequence or Structural Similarity more info
involved_in optic vesicle morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in pituitary gland development	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of transcription by RNA polymerase II	IEA Inferred from Electronic Annotation more info
involved_in proximal/distal axis specification	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of cell cycle phase transition	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of cell population proliferation	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of neural precursor cell proliferation	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of neural retina development	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of neuroblast proliferation	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of transcription by RNA polymerase II	IBA Inferred from Biological aspect of Ancestor more info
involved_in telencephalon development	ISS Inferred from Sequence or Structural Similarity more info
involved_in telencephalon regionalization	ISS Inferred from Sequence or Structural Similarity more info
involved_in visual perception	TAS Traceable Author Statement more info	PubMed

Component	Evidence Code	Pubs
part_of chromatin	ISA Inferred from Sequence Alignment more info
is_active_in nucleus	IBA Inferred from Biological aspect of Ancestor more info
part_of transcription regulator complex	IBA Inferred from Biological aspect of Ancestor more info

General protein information

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Preferred Names: homeobox protein SIX3

Names: sine oculis homeobox homolog 3; sine oculis homeobox-like protein 3

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_016222.1 RefSeqGene

Range

4805..9174

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_005413.4 → NP_005404.1 homeobox protein SIX3

See identical proteins and their annotated locations for NP_005404.1

Status: REVIEWED

Source sequence(s)

AC012354, AJ012611, BF570321, CD673488, EL952320

Consensus CDS

CCDS1821.1

UniProtKB/Swiss-Prot

D6W5A5, O95343, Q53T42

UniProtKB/TrEMBL

A0A127AXB2

Related

ENSP00000260653.3, ENST00000260653.5

Conserved Domains (2) summary

cd00086
Location:208 → 256

homeodomain; Homeodomain; DNA binding domains involved in the transcriptional regulation of key eukaryotic developmental processes; may bind to DNA as monomers or as homo- and/or heterodimers, in a sequence-specific manner.

pfam16878
Location:87 → 200

SIX1_SD; Transcriptional regulator, SIX1, N-terminal SD domain