SIX1 Gene - Sine Oculis Homeobox Homolog 1
Key regulator of embryonic development and organogenesis, implicated in cancer and congenital disorders
Gene Information Card
| Symbol | SIX1 |
|---|---|
| Full Name | Sine Oculis Homeobox Homolog 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 14q23.1 |
| NCBI Gene ID | 6495 ncbi.nlm.nih.gov/gene/6495 |
| Ensembl ID | ENSG00000126767 |
| UniProt ID | Q15475 |
| OMIM ID | 601205 |
| HGNC ID | 10887 |
| Aliases | BOS3, DFNA23, TIP39 |
Description
The SIX1 gene encodes a homeobox-containing transcription factor that plays a critical role in embryonic development, particularly in the formation of sensory organs, kidney, and muscle. It is a member of the SIX family of proteins, which are homologs of the Drosophila sine oculis gene. SIX1 regulates cell proliferation, survival, and differentiation by binding to DNA as part of a transcriptional complex. Dysregulation of SIX1 is associated with branchio-oto-renal syndrome, hearing loss, and multiple cancer types including breast, ovarian, and rhabdomyosarcoma.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Branchio-oto-renal syndrome 3 (BOS3) | Loss-of-function mutations in SIX1 disrupt normal development of branchial arches, ear, and kidney, leading to characteristic malformations. | OMIM #608389; ClinVar |
| Autosomal dominant deafness 23 (DFNA23) | Missense mutations in the homeodomain impair DNA binding and transcriptional activity, causing sensorineural hearing loss. | OMIM #605192; ClinVar |
| Breast cancer | Overexpression of SIX1 promotes epithelial-mesenchymal transition (EMT), metastasis, and poor prognosis. | COSMIC; PMID: 19029980 |
| Rhabdomyosarcoma | SIX1 is highly expressed and drives myogenic progenitor cell proliferation; fusion with EYA1 enhances oncogenic activity. | COSMIC; PMID: 24755471 |
| Ovarian cancer | SIX1 overexpression correlates with aggressive tumor features and resistance to chemotherapy. | COSMIC; PMID: 21746835 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Skeletal muscle | 28.5 | High |
| Kidney | 15.2 | Medium |
| Thyroid | 12.8 | Medium |
| Breast | 6.3 | Low |
| Lung | 4.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| RD (rhabdomyosarcoma) | 35.7 | High expression; consistent with muscle lineage |
| MCF7 (breast cancer) | 18.4 | Moderate expression; associated with EMT |
| HEK293 (embryonic kidney) | 22.1 | High expression; reflects developmental role |
| A549 (lung cancer) | 5.2 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.328C>T (p.Arg110Cys) | Missense | Rare | Impairs DNA binding; associated with DFNA23 and BOS3 |
| c.332G>A (p.Arg111His) | Missense | Rare | Reduces transcriptional activity; linked to BOS3 |
| c.514A>G (p.Thr172Ala) | Missense | Rare | Alters homeodomain stability; DFNA23 |
| Amplification | Copy number gain | Frequent in breast cancer | Overexpression drives tumor progression |
Mutation functional classification
Loss of Function (LOF)
Missense mutations in the homeodomain (e.g., p.Arg110Cys, p.Arg111His) reduce or abolish DNA binding and transcriptional activation, leading to branchio-oto-renal syndrome and hearing loss.
Gain of Function (GOF)
Gene amplification and overexpression in cancers (breast, ovarian, rhabdomyosarcoma) enhance SIX1 activity, promoting EMT, metastasis, and cell proliferation.
Dominant Negative (DN)
Some missense variants may act in a dominant-negative manner by forming non-functional dimers, though evidence is limited; further studies needed.
View complete mutation data：
Gene Ontology (GO)
Pathways
• SIX1/EYA transcriptional complex pathway
• Epithelial-mesenchymal transition (EMT) in cancer
• PAX-SIX-EYA-DACH signaling network
• Organogenesis and developmental gene regulation
Protein Summary
The SIX1 protein (UniProt Q15475) is a 284-amino acid transcription factor containing a conserved homeodomain and a SIX domain that mediates protein-protein interactions. It forms a transcriptional complex with EYA proteins and DACH, regulating target genes involved in cell cycle, apoptosis, and differentiation. SIX1 is essential for the development of the kidney, inner ear, and skeletal muscle. In cancer, aberrant SIX1 expression drives metastasis and therapy resistance, making it a potential therapeutic target.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SIX1 Knockout HEK293 Cell Line | EDJ-KQ15269 | Human | 6495 | Details Get a Quote |
| SIX1 Knockout A-549 Cell Line | EDJ-KQ45960 | Human | 6495 | Details Get a Quote |
| SIX1 Knockout HCT 116 Cell Line | EDJ-KQ45961 | Human | 6495 | Details Get a Quote |
| SIX1 Knockout HeLa Cell Line | EDJ-KQ45962 | Human | 6495 | Details Get a Quote |
| SIX1 Knockout Hep-G2 Cell Line | EDJ-KZ468 | Human | 6495 | Details Get a Quote |
| SIX1 Knockout ZR-75-1 Cell Line | EDJ-KZ469 | Human | 6495 | Details Get a Quote |
