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GeneE
25 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
FOXL2
forkhead box L2
Chromosome 3 Β· 3q22.3
NCBI Gene: 668Ensembl: ENSG00000183770.7HGNC: HGNC:1092UniProt: P58012
219PubMed Papers
22Diseases
0Drugs
176Pathogenic Variants
FUNCTIONAL ROLE
Transcription Factor
RESEARCH IMPACT
Variant-Rich
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
positive regulation of apoptotic processDNA bindingprotein bindingubiquitin conjugating enzyme bindingblepharophimosis, ptosis, and epicanthus inversus syndromeprimary ovarian insufficiencyblepharophimosis-ptosis-epicanthus inversus syndrome type 2Opitz G/BBB syndrome
✦AI Summary

FOXL2 is a transcriptional regulator critical for ovarian development and maintenance 1. As a class 1 forkhead box protein 2, FOXL2 coordinates multiple biological processes essential for female reproductive function. It prevents ovarian-to-testis transdifferentiation by repressing SOX9 expression and regulates follicle-stimulating hormone Ξ² (FSHΞ²) subunit transcription through cooperative binding with SMAD3 and SMAD4 at intronic regulatory elements 34. FOXL2 controls steroidogenic capacity in granulosa cells and can reprogram fibroblasts into functional granulosa-like cells, offering potential therapeutic applications for polycystic ovary syndrome 5. Functionally, FOXL2 participates in cell-cycle regulation, apoptosis, and follistatin transcription regulation 14. Germline FOXL2 variants cause blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES), characterized by premature ovarian insufficiency and eyelid abnormalities 12. Reduced FOXL2 expression correlates with premature ovarian insufficiency in human ovarian tissue 6, suggesting its importance in follicle pool maintenance. Somatic FOXL2 variants drive adult granulosa cell tumors 1, highlighting its role in proliferation control. STAT3 regulates FOXL2 expression upstream 7, indicating integration into broader cellular signaling networks.

Sources cited
1
FOXL2 regulates sex development, ovarian function, eyelid development, and cellular pathways including apoptosis and proliferation; over 100 germline variants cause BPES with ovarian dysgenesis; somatic variants cause adult granulosa cell tumors
PMID: 34727551
2
FOXL2 is a class 1 FOX protein; FOXL2 mutations are associated with BPES and congenital disorders
PMID: 15492844
3
FOXL2 and SMAD4 are essential for human FSHB expression in response to activins via signaling in pituitary gonadotrope cells
PMID: 32191302
4
FOXL2 binds forkhead-binding elements and coordinates with SMAD3 to drive follistatin gene transcription
PMID: 19106105
5
FOXL2 overexpression with NR5A1 induces fibroblasts into steroidogenic granulosa-like cells; transplantation alleviates PCOS in mouse models
PMID: 38192172
6
FOXL2 mRNA expression is significantly reduced in ovarian tissue from women with premature ovarian insufficiency compared to controls
PMID: 31637660
7
STAT3 regulates FOXL2 promoter activity and FOXL2 expression
PMID: 28677787
8
FOXL2 is associated with blepharophimosis, ptosis, and epicanthus inversus syndrome
PMID: 15492844
Disease Associationsβ“˜22
blepharophimosis, ptosis, and epicanthus inversus syndromeOpen Targets
0.84Strong
primary ovarian insufficiencyOpen Targets
0.73Strong
blepharophimosis-ptosis-epicanthus inversus syndrome type 2Open Targets
0.60Moderate
Opitz G/BBB syndromeOpen Targets
0.52Moderate
genetic disorderOpen Targets
0.51Moderate
genetic non-acquired premature ovarian failureOpen Targets
0.44Moderate
ovarian granulosa cell tumorOpen Targets
0.37Weak
Ovarian Sertoli-Leydig Cell TumorOpen Targets
0.37Weak
ovarian epithelial tumorOpen Targets
0.36Weak
BlepharophimosisOpen Targets
0.34Weak
neurodegenerative diseaseOpen Targets
0.34Weak
non-small cell lung carcinomaOpen Targets
0.30Weak
androgenetic alopeciaOpen Targets
0.28Weak
hepatocellular carcinomaOpen Targets
0.28Weak
Ovarian GynandroblastomaOpen Targets
0.28Weak
squamous cell lung carcinomaOpen Targets
0.28Weak
head and neck squamous cell carcinomaOpen Targets
0.28Weak
esophageal squamous cell carcinomaOpen Targets
0.28Weak
gastric carcinomaOpen Targets
0.28Weak
cervical squamous cell carcinomaOpen Targets
0.28Weak
Blepharophimosis, ptosis, and epicanthus inversus syndromeUniProt
Premature ovarian failure 3UniProt
Pathogenic Variants176
NM_023067.4(FOXL2):c.672_701dup (p.Ala225_Ala234dup)Pathogenic
Blepharophimosis, ptosis, and epicanthus inversus, type II with Duane retraction syndrome|BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II|Blepharophimosis, ptosis, and epicanthus inversus syndrome|not provided|Inborn genetic diseases
β˜…β˜…β˜†β˜†2025β†’ Residue 225
NM_023067.4(FOXL2):c.843_859dup (p.Pro287fs)Pathogenic
Blepharophimosis, ptosis, and epicanthus inversus syndrome|not provided|Premature ovarian failure 3|FOXL2-related disorder
β˜…β˜…β˜†β˜†2025β†’ Residue 287
NM_023067.4(FOXL2):c.855_871dup (p.His291fs)Pathogenic
BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I|Blepharophimosis, ptosis, and epicanthus inversus syndrome|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 291
NM_023067.4(FOXL2):c.663_692dup (p.Ala225_Ala234dup)Pathogenic
Blepharophimosis, ptosis, and epicanthus inversus syndrome|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 225
NM_023067.4(FOXL2):c.775_778del (p.Thr259fs)Pathogenic
Blepharophimosis, ptosis, and epicanthus inversus syndrome|not provided
β˜…β˜…β˜†β˜†2024β†’ Residue 259
NM_023067.4(FOXL2):c.319A>G (p.Ser107Gly)Likely pathogenic
Blepharophimosis, ptosis, and epicanthus inversus syndrome|not provided
β˜…β˜…β˜†β˜†2024β†’ Residue 107
NM_023067.4(FOXL2):c.804dup (p.Gly269fs)Pathogenic
BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II|BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I|Blepharophimosis, ptosis, and epicanthus inversus syndrome|not provided|Premature ovarian failure 3;Blepharophimosis, ptosis, and epicanthus inversus syndrome|Inborn genetic diseases
β˜…β˜…β˜†β˜†2024β†’ Residue 269
NM_023067.4(FOXL2):c.223C>T (p.Leu75Phe)Pathogenic
not provided|Blepharophimosis, ptosis, and epicanthus inversus syndrome
β˜…β˜…β˜†β˜†2024β†’ Residue 75
NM_023067.4(FOXL2):c.586C>T (p.Gln196Ter)Pathogenic
Blepharophimosis, ptosis, and epicanthus inversus syndrome
β˜…β˜…β˜†β˜†2023β†’ Residue 196
NM_023067.4(FOXL2):c.650C>T (p.Ser217Phe)Pathogenic
Blepharophimosis, ptosis, and epicanthus inversus syndrome|not provided
β˜…β˜…β˜†β˜†2023β†’ Residue 217
NM_023067.4(FOXL2):c.644A>G (p.Tyr215Cys)Pathogenic
Blepharophimosis, ptosis, and epicanthus inversus syndrome|not provided|FOXL2-related disorder
β˜…β˜…β˜†β˜†2023β†’ Residue 215
NM_023067.4(FOXL2):c.612G>A (p.Trp204Ter)Pathogenic
Blepharophimosis, ptosis, and epicanthus inversus syndrome|not provided
β˜…β˜…β˜†β˜†2023β†’ Residue 204
NM_023067.4(FOXL2):c.576dup (p.Lys193fs)Pathogenic
Blepharophimosis, ptosis, and epicanthus inversus syndrome|not provided|Inborn genetic diseases
β˜…β˜…β˜†β˜†2023β†’ Residue 193
NM_023067.4(FOXL2):c.195G>A (p.Met65Ile)Likely pathogenic
Blepharophimosis, ptosis, and epicanthus inversus syndrome|not provided
β˜…β˜…β˜†β˜†2023β†’ Residue 65
NM_023067.4(FOXL2):c.193A>G (p.Met65Val)Pathogenic
Blepharophimosis, ptosis, and epicanthus inversus syndrome|not provided
β˜…β˜…β˜†β˜†2023β†’ Residue 65
NM_023067.4(FOXL2):c.655C>T (p.Gln219Ter)Pathogenic
BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I|Blepharophimosis, ptosis, and epicanthus inversus syndrome|not provided|Premature ovarian failure 3;Blepharophimosis, ptosis, and epicanthus inversus syndrome
β˜…β˜…β˜†β˜†2023β†’ Residue 219
NM_023067.4(FOXL2):c.860del (p.Pro287fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2026β†’ Residue 287
NM_023067.4(FOXL2):c.369dup (p.Lys124fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2026β†’ Residue 124
NM_023067.4(FOXL2):c.1032dup (p.Phe345fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2026β†’ Residue 345
NM_023067.4(FOXL2):c.1095del (p.Ser365fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 365
View on ClinVar β†—
Related Genes
SMAD4Protein interaction100%FIGLAProtein interaction96%NR5A1Protein interaction95%NOBOXProtein interaction94%SOX9Protein interaction92%POF1BProtein interaction88%
Tissue Expression6 tissues
Ovary
100%
Brain
0%
Bone Marrow
0%
Liver
0%
Heart
0%
Lung
0%
Gene Interaction Network
Click a node to explore
FOXL2SMAD4FIGLANR5A1NOBOXSOX9POF1B
PROTEIN STRUCTURE
Preparing viewer…
PDB7VOU Β· 3.10 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
1.91LoF Tolerant
pLIβ“˜
0.03Tolerant
Observed/Expected LoF1.31 [0.52–1.91]
RankingsWhere FOXL2 stands among ~20K protein-coding genes
  • #1,875of 20,598
    Most Researched219 Β· top 10%
  • #408of 5,498
    Most Pathogenic Variants176 Β· top 10%
  • #17,342of 17,882
    Most Constrained (LOEUF)1.91
Genes detectedFOXL2
Sources retrieved25 papers
Response timeβ€”
πŸ“„ Sources
25β–Ό
1
Human FOX gene family (Review).
PMID: 15492844
Int J Oncol Β· 2004
1.00
2
The Genetics and Biology of FOXL2.
PMID: 34727551
Sex Dev Β· 2022
0.90
3
FOXL2 drives the differentiation of supporting gonadal cells in early ovarian development.
PMID: 40102860
Reprod Biol Endocrinol Β· 2025
0.84
4
Sex determination and maintenance: the role of DMRT1 and FOXL2.
PMID: 28091399
Asian J Androl Β· 2017
0.80
5
Granulosa cells from human primordial and primary follicles show differential global gene expression profiles.
PMID: 29506120
Hum Reprod Β· 2018
0.72