GRHL3: Grainyhead-like Transcription Factor 3
Key regulator of epidermal development, wound healing, and barrier function; implicated in neurodevelopmental disorders and cancer.
Gene Information Card
| Symbol | GRHL3 |
|---|---|
| Full Name | Grainyhead-like transcription factor 3 |
| Gene Type | Protein-coding |
| Chromosomal Location | 1p36.11 |
| NCBI Gene ID | 57822 ncbi.nlm.nih.gov/gene/57822 |
| Ensembl ID | ENSG00000198944 |
| UniProt ID | Q8TE85 |
| OMIM ID | 608317 |
| HGNC ID | 25839 |
| Aliases | SOM, TFCP2L2, MGC138290 |
Description
GRHL3 encodes a member of the grainyhead family of transcription factors, characterized by a CP2-type DNA-binding domain. The protein is essential for epidermal barrier formation, wound healing, and neural tube closure. It regulates genes involved in cell adhesion, migration, and differentiation. Mutations in GRHL3 cause Van der Woude syndrome type 2 and non-syndromic cleft palate, and are associated with increased risk of spina bifida. Altered expression is observed in several cancers, including squamous cell carcinoma.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Van der Woude syndrome 2 (VWS2) | Loss-of-function mutations impair transcriptional activation of target genes, leading to cleft lip/palate and lip pits. | OMIM #606713; PMID: 24813812 |
| Non-syndromic cleft palate only (CPO) | Heterozygous missense or nonsense variants disrupt DNA binding or protein stability. | ClinVar; PMID: 24813812 |
| Spina bifida (neural tube defect) | Common variants in GRHL3 increase susceptibility; altered regulation of neural tube closure genes. | OMIM #608317; PMID: 25683121 |
| Squamous cell carcinoma (SCC) | Downregulation or promoter hypermethylation reduces tumor suppressor activity, promoting invasion. | COSMIC; PMID: 23354436 |
| Ectodermal dysplasia-like phenotypes | Biallelic loss-of-function leads to severe skin barrier defects and neonatal lethality in mice; rare human cases. | OMIM #608317; PMID: 16908548 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Skin | 45.2 | High |
| Esophagus | 28.7 | Medium |
| Oral mucosa | 22.1 | Medium |
| Lung | 8.3 | Low |
| Kidney | 5.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HaCaT (keratinocyte) | 62.4 | Immortalized keratinocyte line; high expression |
| A431 (epidermoid carcinoma) | 38.9 | SCC-derived; moderate expression |
| HEK293 (embryonic kidney) | 2.3 | Low endogenous expression |
| MCF7 (breast cancer) | 1.8 | Very low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1063C>T (p.Arg355*) | Nonsense | Rare (0.0004) | Loss-of-function; truncation of DNA-binding domain; associated with VWS2 |
| c.1390G>A (p.Gly464Arg) | Missense | Rare (0.0002) | Impaired DNA binding; dominant negative effect; cleft palate |
| c.1609C>T (p.Arg537Trp) | Missense | Rare (0.0001) | Reduced transactivation; spina bifida risk |
| c.1186_1187del (p.Leu396fs) | Frameshift | Unique | Loss-of-function; VWS2 |
| c.1A>G (p.Met1?) | Start loss | Unique | No protein production; severe phenotype |
Mutation functional classification
Loss of Function (LOF)
Nonsense, frameshift, and start-loss mutations that abolish protein production or truncate the DNA-binding domain. These are the predominant mechanism in Van der Woude syndrome and cleft palate.
Gain of Function (GOF)
Not reported in GRHL3. All known pathogenic variants reduce or eliminate function.
Dominant Negative (DN)
Missense mutations in the DNA-binding domain (e.g., p.Gly464Arg) that retain dimerization but impair DNA binding, interfering with wild-type protein activity.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Epidermal differentiation complex (EDC) regulation
• Wnt signaling pathway (via modulation of target genes)
• TGF-beta signaling (crosstalk in wound healing)
• Cell adhesion and migration (regulation of E-cadherin and integrins)
Protein Summary
GRHL3 is a 631-amino-acid transcription factor with a conserved CP2-type DNA-binding domain and a dimerization domain. It localizes to the nucleus and binds to specific DNA sequences to activate or repress target genes. The protein is critical for epidermal barrier formation, oral epithelial differentiation, and neural tube closure. It interacts with other transcription factors (e.g., GRHL1, GRHL2) and chromatin remodelers. Post-translational modifications include phosphorylation, which modulates activity. Loss of GRHL3 function leads to impaired wound healing, increased susceptibility to infection, and developmental defects.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| GRHL3 Knockout HEK293 Cell Line | EDJ-KQ11893 | Human | 57822 | Details Get a Quote |
| GRHL3 Knockout A-549 Cell Line | EDJ-KQ39105 | Human | 57822 | Details Get a Quote |
| GRHL3 Knockout HCT 116 Cell Line | EDJ-KQ40346 | Human | 57822 | Details Get a Quote |
| GRHL3 Knockout HeLa Cell Line | EDJ-KQ56921 | Human | 57822 | Details Get a Quote |
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