FOXL2 (forkhead box L2)

Gene

• Entrez ID: 668
• Gene name: Forkhead box L2
• Gene symbol: FOXL2
• Synonyms (NCBI Gene): BPES, BPES1, PFRK, PINTO, POF3
• Chromosome: 3
• Chromosome location: 3q22.3
• Summary: This gene encodes a forkhead transcription factor. The protein contains a fork-head DNA-binding domain and may play a role in ovarian development and function. Expansion of a polyalanine repeat region and other mutations in this gene are a cause of blepha

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT438580	hsa-miR-133b	ChIP-seq, Luciferase reporter assay, qRT-PCR, Western blot	23810756
MIRT438580	hsa-miR-133b	ChIP-seq, Luciferase reporter assay, qRT-PCR, Western blot	23810756
MIRT438580	hsa-miR-133b	ChIP-seq, Luciferase reporter assay, qRT-PCR, Western blot	23810756
MIRT438580	hsa-miR-133b	ChIP-seq, Luciferase reporter assay, qRT-PCR, Western blot	23810756
MIRT458211	hsa-miR-8084	PAR-CLIP	23592263
MIRT458210	hsa-miR-5197-3p	PAR-CLIP	23592263
MIRT458209	hsa-miR-141-5p	PAR-CLIP	23592263
MIRT458208	hsa-miR-1253	PAR-CLIP	23592263
MIRT458207	hsa-miR-3928-3p	PAR-CLIP	23592263
MIRT458206	hsa-miR-520a-5p	PAR-CLIP	23592263
MIRT458205	hsa-miR-525-5p	PAR-CLIP	23592263
MIRT458204	hsa-miR-3915	PAR-CLIP	23592263
MIRT458203	hsa-miR-3180-5p	PAR-CLIP	23592263
MIRT458211	hsa-miR-8084	PAR-CLIP	23592263
MIRT458210	hsa-miR-5197-3p	PAR-CLIP	23592263
MIRT458209	hsa-miR-141-5p	PAR-CLIP	23592263
MIRT458208	hsa-miR-1253	PAR-CLIP	23592263
MIRT458207	hsa-miR-3928-3p	PAR-CLIP	23592263
MIRT458206	hsa-miR-520a-5p	PAR-CLIP	23592263
MIRT458205	hsa-miR-525-5p	PAR-CLIP	23592263
MIRT458204	hsa-miR-3915	PAR-CLIP	23592263
MIRT458203	hsa-miR-3180-5p	PAR-CLIP	23592263
MIRT1002469	hsa-miR-1538	CLIP-seq
MIRT1002470	hsa-miR-23a	CLIP-seq
MIRT1002471	hsa-miR-23b	CLIP-seq
MIRT1002472	hsa-miR-23c	CLIP-seq
MIRT1002473	hsa-miR-3194-5p	CLIP-seq
MIRT1002474	hsa-miR-3667-3p	CLIP-seq
MIRT1002475	hsa-miR-4279	CLIP-seq
MIRT1002476	hsa-miR-4455	CLIP-seq
MIRT1002477	hsa-miR-4662a-5p	CLIP-seq
MIRT1002478	hsa-miR-4676-5p	CLIP-seq
MIRT1002479	hsa-miR-4745-3p	CLIP-seq
MIRT1002480	hsa-miR-4761-5p	CLIP-seq
MIRT1002481	hsa-miR-575	CLIP-seq
MIRT2230952	hsa-miR-665	CLIP-seq

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000122	Process	Negative regulation of transcription by RNA polymerase II	IEA
GO:0000785	Component	Chromatin	ISA
GO:0000978	Function	RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA
GO:0000978	Function	RNA polymerase II cis-regulatory region sequence-specific DNA binding	IEA
GO:0000981	Function	DNA-binding transcription factor activity, RNA polymerase II-specific	IBA
GO:0000981	Function	DNA-binding transcription factor activity, RNA polymerase II-specific	ISA
GO:0001228	Function	DNA-binding transcription activator activity, RNA polymerase II-specific	IEA
GO:0001541	Process	Ovarian follicle development	IEA
GO:0001541	Process	Ovarian follicle development	IMP	12161610
GO:0001541	Process	Ovarian follicle development	ISS
GO:0001555	Process	Oocyte growth	IEA
GO:0002074	Process	Extraocular skeletal muscle development	IMP	12630957
GO:0003677	Function	DNA binding	IDA	16720712
GO:0003677	Function	DNA binding	IEA
GO:0003677	Function	DNA binding	TAS	11175783
GO:0003700	Function	DNA-binding transcription factor activity	IEA
GO:0003700	Function	DNA-binding transcription factor activity	ISS
GO:0003700	Function	DNA-binding transcription factor activity	NAS	11175783, 12471206
GO:0005515	Function	Protein binding	IPI	16153597
GO:0005634	Component	Nucleus	IDA	12471206
GO:0005634	Component	Nucleus	IEA
GO:0005654	Component	Nucleoplasm	IDA
GO:0005654	Component	Nucleoplasm	TAS
GO:0006309	Process	Apoptotic DNA fragmentation	IMP	16153597
GO:0006355	Process	Regulation of DNA-templated transcription	IEA
GO:0006357	Process	Regulation of transcription by RNA polymerase II	IBA
GO:0007338	Process	Single fertilization	IEA
GO:0008585	Process	Female gonad development	IEA
GO:0009653	Process	Anatomical structure morphogenesis	IBA
GO:0019101	Process	Female somatic sex determination	IEA
GO:0030154	Process	Cell differentiation	IBA
GO:0030154	Process	Cell differentiation	IEA
GO:0030154	Process	Cell differentiation	NAS	12471206
GO:0030331	Function	Nuclear estrogen receptor binding	IEA
GO:0031624	Function	Ubiquitin conjugating enzyme binding	IPI	19744555
GO:0033686	Process	Positive regulation of luteinizing hormone secretion	IEA
GO:0043028	Function	Cysteine-type endopeptidase regulator activity involved in apoptotic process	IMP	16153597
GO:0043065	Process	Positive regulation of apoptotic process	IGI	16153597
GO:0043065	Process	Positive regulation of apoptotic process	IMP	16153597
GO:0043565	Function	Sequence-specific DNA binding	IEA
GO:0045892	Process	Negative regulation of DNA-templated transcription	IDA	19744555
GO:0045892	Process	Negative regulation of DNA-templated transcription	IEA
GO:0045893	Process	Positive regulation of DNA-templated transcription	ISS
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	IEA
GO:0046881	Process	Positive regulation of follicle-stimulating hormone secretion	IEA
GO:0048048	Process	Embryonic eye morphogenesis	IEA
GO:0048048	Process	Embryonic eye morphogenesis	IEA
GO:0060014	Process	Granulosa cell differentiation	IEA
GO:0060065	Process	Uterus development	IEA
GO:0090543	Component	Flemming body	IDA
GO:1990837	Function	Sequence-specific double-stranded DNA binding	IDA	28473536

Other IDs

• MIM: 605597
• HGNC: 1092
• e!Ensembl: ENSG00000183770

Protein

• UniProt ID: P58012
• Protein name: Forkhead box protein L2
• Protein function: Transcriptional regulator. Critical factor essential for ovary differentiation and maintenance, and repression of the genetic program for somatic testis determination. Prevents trans-differentiation of ovary to testis through transcriptional rep
• PDB: 7VOU, 7VOV
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00250	Forkhead	53 → 139	Forkhead domain	Domain

• Tissue specificity: TISSUE SPECIFICITY: In addition to its expression in the developing eyelid, it is transcribed very early in somatic cells of the developing gonad (before sex determination) and its expression persists in the follicular cells of the adult ovary.
• Sequence:

  MMASYPEPEDAAGALLAPETGRTVKEPEGPPPSPGKGGGGGGGTAPEKPDPAQKPPYSYV
  ALIAMAIRESAEKRLTLSGIYQYIIAKFPFYEKNKKGWQNSIRHNLSLNECFIKVPREGG
  GERKGNYWTLDPACEDMFEKGNYRRRRRMKRPFRPPPAHFQPGKGLFGAGGAAGGCGVAG
  AGADGYGYLAPPKYLQSGFLNNSWPLPQPPSPMPYASCQMAAAAAAAAAAAAAAGPGSPG
  AAAVVKGLAGPAASYGPYTRVQSMALPPGVVNSYNGLGGPPAAPPPPPHPHPHPHAHHLH
  AAAAPPPAPPHHGAAAPPPGQLSPASPATAAPPAPAPTSAPGLQFACARQPELAMMHCSY
  WDHDSKTGALHSRLDL

• Sequence length: 376

Pathways

Reactome:

SUMOylation of transcription factors

Associated diseases

Causal
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession
Blepharophimosis, ptosis, and epicanthus inversus syndrome	Likely pathogenic; Pathogenic	rs201840174, rs2107743541, rs1057516159, rs2473812496, rs2473815062, rs672601358, rs672601359, rs672601357, rs797044529, rs797044531, rs797044527, rs104893741, rs387906321, rs863225452, rs797044528, rs797044532, rs104893738, rs387906322, rs104893739, rs2473811785, rs2473815051, rs2473812186, rs2473814801, rs1057516185, rs1057516184, rs1057516183, rs1057516182, rs1057516181, rs1057516179, rs1057516180, rs1057516178, rs1057516176, rs1057516175, rs1057516174, rs1057516173, rs1057516172, rs764243782, rs1057516170, rs1057516166, rs1057516168, rs1057516167, rs1057516165, rs1057516164, rs1057516163, rs1057516161, rs1553752890, rs1057516158, rs1057516157, rs1057516156, rs1057516153, rs1057516151, rs1057516150, rs1057516149, rs387906920, rs1057516145, rs1057516144, rs1057516142, rs1057516141, rs1057516140, rs1057516139, rs1553752945, rs1060499717, rs1553752849, rs1559921677, rs1559921797, rs1559921800, rs1576469579, rs1559921849, rs1559921874, rs1559921944, rs1559921973, rs1559922013, rs1559922026, rs1559922033, rs1559922136, rs1559922257, rs1559922261, rs1559922308, rs1559922381, rs1559922462, rs1559922470, rs1559922472, rs1559922473, rs1559922476, rs1559922498, rs1559922528, rs1226344391, rs1559922558, rs1559922577, rs1559922621, rs1315073489, rs1559922628, rs1559922634, rs1559922647, rs1559922657, rs759236439, rs1559922782, rs1559922829	RCV005409620 RCV002251230 RCV002273098 RCV002283805 RCV002283948 RCV000149461 RCV000149462 RCV000149460 RCV000192037 RCV000192039 RCV000192032 RCV000192033 RCV000408801 RCV000785831 RCV000192036 RCV000192041 RCV002496265 RCV002490318 RCV000005141 RCV000192040 RCV003314082 RCV003984388 RCV003991932 RCV004555293 RCV000408792 RCV000408893 RCV000408828 RCV000408783 RCV000408867 RCV000408869 RCV000408840 RCV000408820 RCV000408862 RCV000408754 RCV000408856 RCV000408791 RCV000408895 RCV000408845 RCV000408883 RCV000408843 RCV000408822 RCV000408786 RCV000408870 RCV000408781 RCV000408864 RCV000408815 RCV000408857 RCV000408885 RCV000408861 RCV000408795 RCV000408897 RCV000408833 RCV000408824 RCV000408814 RCV000408774 RCV000408873 RCV000408818 RCV000408759 RCV000408860 RCV000408770 RCV000408854 RCV000408789 RCV000408892 RCV000504566 RCV000449613 RCV000677693 RCV000785840 RCV000785839 RCV000785859 RCV000785862 RCV000785861 RCV000785860 RCV000785858 RCV000785857 RCV000785856 RCV000785855 RCV000785853 RCV000785852 RCV000785851 RCV000785850 RCV000785849 RCV000785848 RCV000785847 RCV000785846 RCV000785845 RCV000785844 RCV000785843 RCV000785838 RCV000785837 RCV000785836 RCV000785835 RCV000785834 RCV000785833 RCV000785832 RCV000785829 RCV000785830 RCV000785828 RCV000785827 RCV000785826 RCV000785825 RCV000785842 RCV000785841 RCV001029899
BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I	Pathogenic	rs104893741, rs863225450, rs863225451, rs797044528, rs104893737, rs104893738, rs28937884, rs121908358, rs797044532, rs863225453, rs387906322	RCV000005126 RCV000005129 RCV000005130 RCV000005133 RCV000005135 RCV000005136 RCV000005139 RCV000005140 RCV000005142 RCV000005143 RCV000005146
BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II	Pathogenic; Likely pathogenic	rs387906321, rs863225452, rs797044528, rs797044532, rs104893738, rs387906322, rs387906920	RCV000005127 RCV000005131 RCV000005132 RCV000005134 RCV000005137 RCV000005138 RCV000023464
Blepharophimosis, ptosis, and epicanthus inversus, type II with Duane retraction syndrome	Pathogenic	rs387906321	RCV000005128
FOXL2-related disorder	Likely pathogenic; Pathogenic	rs672601359, rs28937884, rs1057516168	RCV003415986 RCV003894790 RCV003392224
Genetic non-acquired premature ovarian failure	Likely pathogenic; Pathogenic	rs2107743526, rs1373284153, rs2107743381, rs201840174	RCV001661755 RCV001661781 RCV001663371 RCV001657762
Premature ovarian failure 3	Likely pathogenic; Pathogenic	rs201840174, rs2107743381, rs672601359, rs104893741, rs797044528, rs104893738, rs387906322, rs764243782, rs1553752779, rs1553752894	RCV005409620 RCV002290263 RCV003398794 RCV004795376 RCV004795377 RCV002496265 RCV002490318 RCV000005144 RCV000596083 RCV000625747

Unknown
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession
Duane retraction syndrome	Uncertain significance	rs1935946242	RCV004577405
See cases	Uncertain significance; Conflicting classifications of pathogenicity	rs1309298600, rs121908359	RCV004584535 RCV002251877

Associations from Text Mining
Disease Name	Relationship Type	References
ACTH Secreting Pituitary Adenoma	Associate	21478824
Adenoma	Associate	21478824
Amblyopia	Associate	22312189
Amenorrhea	Associate	36793102
Anisometropia	Associate	37932670
Ascites	Inhibit	17430735
Blepharophimosis	Associate	27414805, 29471425, 30029625, 31366388, 37932670, 40102860
Blepharophimosis Ptosis and Epicanthus Inversus	Associate	12529855, 15257268, 17277738, 17360647, 18642388, 19543368, 19969293, 20222838, 21321671, 21862621, 22312189, 23441113, 24817949, 25086333, 26323275, 27414805, 29339661, 29378385, 30029625, 31221094, 31366388, 31823134, 35574016, 36338666, 36793102, 37932670, 37938073, 40102860
Blepharophimosis Ptosis and Epicanthus Inversus	Inhibit	23516377
Blepharophimosis syndrome type 1	Associate	19969293
Cakut	Associate	34473308
Carcinoma Squamous Cell	Associate	28377632
Cataract	Associate	37932670
Cerebellar Ataxia and Hypogonadotropic Hypogonadism	Associate	31366388
Disease	Associate	19543368
Disorder of Sex Development 46 XY	Associate	39285472
Endocrine System Diseases	Associate	31366388
Endodermal Sinus Tumor	Associate	26076062
Endometrial Neoplasms	Associate	32555395
Eyelid Diseases	Associate	12529855, 27414805, 34473308
Genetic Diseases Inborn	Associate	21862621, 23516377
Gliosarcoma	Associate	34856571
Gonadoblastoma	Associate	19513096
Granulosa Cell Tumor	Associate	19516027, 19956657, 20693978, 21188138, 22742556, 23029457, 23372819, 24416423, 25297715, 25884336, 26076062, 26893359, 27297428, 27810330, 28347324, 28852190, 29471425, 30166312, 32203090, 33428330, 33639972, 34083028, 36881092, 37565864, 37634867, 38429437
Granulosa cell tumor of the ovary	Associate	19516027, 19956657, 20693978, 21623383, 21761343, 23029457, 23372819, 23674259, 25884336, 27810330, 28594898, 29950560, 33428330, 36399188
Heart Septal Defects Atrial	Associate	29505555
Hemorrhage	Associate	17430735
Hypersensitivity Delayed	Associate	36793102
Hypogonadism	Associate	19969293
Infertility	Associate	29339661, 31823134
Inflammation	Associate	30304016
Laryngeal Neoplasms	Associate	37875354
Mouth Diseases	Associate	19513096
Multicystic renal dysplasia bilateral	Associate	34473308
Myopia	Associate	37932670
Myopia Degenerative	Associate	37932670
Neoplasm Metastasis	Associate	29060929
Neoplasms	Associate	21623383, 24671188, 25297715, 25884336, 26428316, 26893359, 27810330, 28377632, 28594898, 30166312, 31221094, 33428330, 34083028, 34396573, 37565864
Neoplasms Squamous Cell	Associate	24817949
Ovarian Diseases	Associate	34845303
Ovarian Neoplasms	Associate	17430735, 19956657, 19969293, 20098707, 24416423, 24817949, 25884336, 26428316, 26893359, 29882921, 30066910, 30166312, 30304016, 31464709, 34238613, 36793102, 36881092
Personality Disorders	Associate	30166312
Pituitary Neoplasms	Associate	21478824
Polydactyly	Associate	37938073
Primary Ovarian Insufficiency	Associate	12529855, 17277738, 17360647, 19969293, 20222838, 21862621, 24817949, 26323275, 27414805, 29339661, 29378385, 29471425, 29916099, 30029625, 31366388, 32962729, 36338666, 40102860
Ptosis Hereditary Congenital 2	Associate	22312189, 27414805, 29471425, 30029625, 31366388, 37932670, 40102860
Sertoli Leydig Cell Tumor	Associate	26428316
Sex Cord Gonadal Stromal Tumors	Associate	26428316
Situs Inversus	Associate	29471425
Stomach Neoplasms	Associate	29060929
Thecoma	Associate	19516027
Uterine Cervical Neoplasms	Associate	24817949