GLI3: A Key Transcriptional Regulator in Hedgehog Signaling and Development
Comprehensive genomic and clinical overview of the GLI3 gene, its role in development, associated diseases, and mutational landscape.
Gene Information Card
| Symbol | GLI3 |
|---|---|
| Full Name | GLI family zinc finger 3 |
| Gene Type | protein-coding |
| Chromosomal Location | 7p14.1 |
| NCBI Gene ID | 2737 ncbi.nlm.nih.gov/gene/2737 |
| Ensembl ID | ENSG00000106571 |
| UniProt ID | P10071 |
| OMIM ID | 165240 |
| HGNC ID | 4319 |
| Aliases | GCPS, PAP-A, PAPA, PAPB, PHS, GLI3-190, GLI3FL |
Description
GLI3 (GLI family zinc finger 3) encodes a zinc finger transcription factor that is a key mediator of the Hedgehog (Hh) signaling pathway. It functions primarily as a transcriptional repressor of Hh target genes, but can also act as an activator depending on proteolytic processing. GLI3 is critical for embryonic development, including limb patterning, neural tube formation, and craniofacial development. Mutations in GLI3 cause several developmental disorders, including Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS).
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Greig cephalopolysyndactyly syndrome (GCPS) | Haploinsufficiency or loss-of-function mutations in GLI3 disrupt normal limb and craniofacial development, leading to polysyndactyly and macrocephaly. | OMIM #175700; multiple case reports in ClinVar |
| Pallister-Hall syndrome (PHS) | Dominant-negative or frameshift mutations in the middle third of GLI3 produce a truncated protein that retains repressor function but lacks activator function, causing hypothalamic hamartoma, polydactyly, and bifid epiglottis. | OMIM #146510; functional studies in PMID: 9215672 |
| Acrocallosal syndrome | Mutations in GLI3 can cause overlapping features with GCPS, including agenesis of the corpus callosum and polydactyly. | OMIM #200990; rare variants reported in ClinVar |
| Postaxial polydactyly type A/B | GLI3 missense or nonsense mutations lead to isolated polydactyly without other syndromic features. | OMIM #174200; PMID: 15793702 |
| Hypothalamic hamartoma | GLI3 mutations (especially in PHS) result in abnormal development of the hypothalamus, leading to hamartomas and seizures. | OMIM #146510; confirmed in multiple families |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 5.2 | Low |
| Lung | 3.8 | Low |
| Kidney | 4.1 | Low |
| Testis | 6.7 | Medium |
| Placenta | 3.5 | Low |
| Skin | 2.9 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 4.5 | Embryonic kidney cell line; moderate expression |
| SH-SY5Y | 6.1 | Neuroblastoma cell line; higher expression |
| A549 | 3.2 | Lung carcinoma cell line; low expression |
| MCF7 | 2.8 | Breast cancer cell line; low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.2023G>A (p.Gly675Arg) | Missense | Rare | Alters DNA-binding affinity; associated with GCPS |
| c.2179C>T (p.Arg727*) | Nonsense | Rare | Premature stop; loss-of-function; GCPS |
| c.3499_3500insC (p.Leu1167Profs*12) | Frameshift | Rare | Truncation; dominant-negative; PHS |
| c.1441C>T (p.Arg481Cys) | Missense | Rare | Reduced repressor activity; postaxial polydactyly |
Mutation functional classification
Loss of Function (LOF)
Nonsense, frameshift, and splice-site mutations that lead to haploinsufficiency or complete loss of GLI3 repressor function, primarily causing Greig cephalopolysyndactyly syndrome.
Gain of Function (GOF)
Not commonly described; GLI3 is primarily a repressor, and gain-of-function is rare. Some missense variants may increase activator function but are not well characterized.
Dominant Negative (DN)
Frameshift or nonsense mutations in the middle third of the gene (e.g., c.3499_3500insC) produce a truncated protein that retains repressor activity but lacks activator function, leading to Pallister-Hall syndrome.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Hedgehog signaling pathway (KEGG hsa04340)
• Developmental Biology (Reactome R-HSA-1266738)
• Signaling by Hedgehog (Reactome R-HSA-5358351)
Protein Summary
GLI3 is a 1580-amino acid zinc finger transcription factor that localizes to the nucleus and cytoplasm. It contains an N-terminal repressor domain, a central DNA-binding domain with five zinc fingers, and a C-terminal activator domain. Full-length GLI3 (GLI3FL) can be proteolytically cleaved to generate a repressor form (GLI3R) that lacks the C-terminal activator domain. In the absence of Hedgehog ligand, GLI3R accumulates and represses target genes; upon pathway activation, processing is inhibited, allowing GLI3FL to activate transcription. Mutations disrupting this balance cause developmental disorders.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| GLI3 Knockout HEK293 Cell Line | EDJ-KQ898 | Human | 2737 | Details Get a Quote |
| GLI3 Knockout HeLa Cell Line | EDJ-KQ19743 | Human | 2737 | Details Get a Quote |
| GLI3 Knockout A-549 Cell Line | EDJ-KQ61833 | Human | 2737 | Details Get a Quote |
| GLI3 Knockout HCT 116 Cell Line | EDJ-KQ70317 | Human | 2737 | Details Get a Quote |
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