FOXL2: Forkhead Box L2 Gene in Ovarian Development and Granulosa Cell Tumors
A critical transcription factor for ovarian function and a key driver in adult-type granulosa cell tumors
Gene Information Card
| Symbol | FOXL2 |
|---|---|
| Full Name | Forkhead Box L2 |
| Gene Type | Protein coding |
| Chromosomal Location | 3q22.3 |
| NCBI Gene ID | 668 ncbi.nlm.nih.gov/gene/668 |
| Ensembl ID | ENSG00000183770 |
| UniProt ID | P58012 |
| OMIM ID | 605597 |
| HGNC ID | 1092 |
| Aliases | BPES, BPES1, PFRK, PINTO, POF3 |
Description
FOXL2 encodes a forkhead transcription factor essential for ovarian development and function. It is expressed predominantly in the eyelids and ovaries. Mutations in FOXL2 cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and premature ovarian failure. A recurrent somatic missense mutation (c.402C>G, p.Cys134Trp) is a hallmark of adult-type granulosa cell tumors (AGCTs).
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES) | Loss-of-function mutations in FOXL2 disrupt eyelid and ovarian development; type I includes ovarian failure, type II is isolated to eyelids. | OMIM #110100; NCBI Gene; ClinVar |
| Premature Ovarian Failure 3 (POF3) | Heterozygous FOXL2 mutations impair granulosa cell function leading to early menopause. | OMIM #608996; NCBI Gene |
| Adult Granulosa Cell Tumor (AGCT) | Recurrent somatic c.402C>G (p.Cys134Trp) mutation in the forkhead domain drives tumorigenesis via altered transcriptional activity. | COSMIC; ClinVar; PMID 19234473 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Ovary | 12.5 | Medium |
| Fallopian Tube | 3.2 | Low |
| Adipose Tissue | 1.8 | Low |
| Eye | 2.1 | Low |
| Testis | 0.5 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| KGN (granulosa cell tumor line) | 45.3 | High; derived from AGCT; carries endogenous FOXL2 C134W mutation |
| COV434 (granulosa cell tumor line) | 28.7 | Moderate; wild-type FOXL2 |
| HeLa | 0.2 | Not detected |
| MCF7 | 0.1 | Not detected |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.402C>G (p.Cys134Trp) | Missense | >95% in AGCT | Alters DNA-binding specificity; gain-of-function in granulosa cells |
| c.250C>T (p.Arg84Trp) | Missense | Rare in BPES | Loss of nuclear localization and transactivation |
| c.672_701dup (p.Ala224_Ala233dup) | In-frame duplication | Rare in BPES | Disrupts polyalanine tract; loss of function |
Mutation functional classification
Loss of Function (LOF)
Most BPES-associated mutations (nonsense, frameshift, polyalanine expansions) lead to haploinsufficiency or impaired DNA binding.
Gain of Function (GOF)
The C134W mutation in AGCT alters FOXL2 target gene specificity, promoting proliferation and inhibiting apoptosis in granulosa cells.
Dominant Negative (DN)
Some missense mutations in the forkhead domain (e.g., p.Ile80Thr) can interfere with wild-type FOXL2 activity in a dominant-negative manner.
View complete mutation data：
Gene Ontology (GO)
Pathways
• TGF-beta signaling pathway (via regulation of inhibin/activin subunits)
• Steroidogenesis (regulation of CYP19A1/aromatase)
• FOXL2 transcription factor network
Protein Summary
FOXL2 is a 376-amino-acid forkhead transcription factor with a conserved DNA-binding domain. It regulates genes involved in ovarian granulosa cell differentiation, steroidogenesis, and eyelid development. The protein localizes to the nucleus and binds to forkhead response elements. The recurrent C134W mutation in the forkhead domain confers a neomorphic activity that drives adult granulosa cell tumorigenesis.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| FOXL2 Knockout HEK293 Cell Line | EDJ-KQ2444 | Human | 668 | Details Get a Quote |
| FOXL2NB Knockout HEK293 Cell Line | EDJ-KQ11616 | Human | 401089 | Details Get a Quote |
| FOXL2 Knockout A-549 Cell Line | EDJ-KQ22960 | Human | 668 | Details Get a Quote |
| FOXL2 Knockout HeLa Cell Line | EDJ-KQ22961 | Human | 668 | Details Get a Quote |
| FOXL2NB Knockout A-549 Cell Line | EDJ-KQ39959 | Human | 401089 | Details Get a Quote |
| FOXL2NB Knockout HeLa Cell Line | EDJ-KQ39960 | Human | 401089 | Details Get a Quote |
| FOXL2 Knockout HCT 116 Cell Line | EDJ-KQ69695 | Human | 668 | Details Get a Quote |
| FOXL2NB Knockout HCT 116 Cell Line | EDJ-KQ77117 | Human | 401089 | Details Get a Quote |
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