SIX3: A Key Homeobox Gene in Forebrain and Eye Development
SIX3 gene structure, function, and clinical significance in holoprosencephaly and related disorders
Gene Information Card
| Symbol | SIX3 |
|---|---|
| Full Name | SIX homeobox 3 |
| Gene Type | protein-coding |
| Chromosomal Location | 2p21 |
| NCBI Gene ID | 6496 ncbi.nlm.nih.gov/gene/6496 |
| Ensembl ID | ENSG00000138083 |
| UniProt ID | O95343 |
| OMIM ID | 603714 |
| HGNC ID | 10889 |
| Aliases | HPE2, SIX homeobox 3 |
Description
SIX3 is a homeobox-containing transcription factor essential for the development of the forebrain and eyes. It belongs to the SIX family of proteins, which are homologs of the Drosophila sine oculis gene. SIX3 regulates cell proliferation and differentiation during embryonic development, and its mutations are a major cause of holoprosencephaly type 2 (HPE2).
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Holoprosencephaly 2 (HPE2) | Loss-of-function mutations in SIX3 disrupt forebrain cleavage, leading to HPE2. | ClinVar, OMIM |
| Holoprosencephaly (non-syndromic) | Heterozygous missense or nonsense variants reduce SIX3 transcriptional activity. | NCBI Gene, OMIM |
| Microphthalmia / Anophthalmia | SIX3 haploinsufficiency or dominant-negative effects impair eye field specification. | ClinVar, OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | Medium |
| Eye | 8.3 | Medium |
| Testis | 2.1 | Low |
| Kidney | 1.0 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 5.4 | Neuronal model |
| HEK293 (embryonic kidney) | 2.8 | Low expression |
| ARPE-19 (retinal pigment epithelium) | 7.1 | Retinal model |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.253C>T (p.Arg85Trp) | Missense | Rare | Loss of DNA-binding; HPE2 |
| c.418_419del (p.Leu140fs) | Frameshift | Rare | Truncation; loss of function |
| c.1A>G (p.Met1Val) | Start loss | Rare | No protein; HPE2 |
Mutation functional classification
Loss of Function (LOF)
Most SIX3 mutations cause haploinsufficiency or loss of DNA-binding, leading to holoprosencephaly.
Gain of Function (GOF)
Not reported for SIX3.
Dominant Negative (DN)
Some missense variants (e.g., p.Arg85Trp) may act as dominant-negative by interfering with wild-type SIX3 function.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Hedgehog signaling pathway (Reactome: R-HSA-5358351)
• Forebrain development (KEGG: hsa05200)
Protein Summary
SIX3 is a 332-amino-acid protein containing a SIX domain (for DNA binding and protein interaction) and a homeodomain. It functions as a transcriptional repressor or activator depending on context, and interacts with co-repressors such as TLE/Groucho. SIX3 is critical for patterning the anterior neural plate and maintaining the boundary between the forebrain and midbrain.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SIX3 Knockout HEK293 Cell Line | EDJ-KQ5752 | Human | 6496 | Details Get a Quote |
| SIX3 Knockout HCT 116 Cell Line | EDJ-KQ29166 | Human | 6496 | Details Get a Quote |
| SIX3 Knockout HeLa Cell Line | EDJ-KQ54472 | Human | 6496 | Details Get a Quote |
| SIX3 Knockout A-549 Cell Line | EDJ-KQ62958 | Human | 6496 | Details Get a Quote |
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