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FOXL2

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FOXL2
Identifiers
AliasesFOXL2, BPES, BPES1, PFRK, PINTO, POF3, forkhead box L2
External IDsOMIM: 605597; MGI: 1349428; HomoloGene: 74992; GeneCards: FOXL2; OMA:FOXL2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

668

26927

Ensembl

ENSG00000183770

ENSMUSG00000050397

UniProt

P58012

O88470

RefSeq (mRNA)

NM_023067

NM_012020

RefSeq (protein)

NP_075555

NP_036150

Location (UCSC)Chr 3: 138.94 – 138.95 MbChr 9: 98.84 – 98.84 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Forkhead box protein L2 is a protein that in humans is encoded by the FOXL2 gene.[5][6]

Function

FOXL2 is a forkhead transcription factor. The protein contains a fork-head DNA-binding domain and plays a role in ovarian development and function.[6] FoxL2 is a marker for ovarian differentiation and is required for granulosa cell differentiation. In addition, the foxl2 protein will prevent the formation of testes by suppressing expression of SOX9.[7]

In postnatal ovaries, FOXL2 regulates granulosa cell differentiation and also supports the growth of the pre-ovulatory follicles during adult life.[8]

Regulation

FOXL2 has several post-translational modifications that modulate its stability, subcellular localization and pro-apoptotic activity.[9] By a yeast-two-hybrid screening, 10 novel protein partners of FOXL2 were discovered. The interactions were confirmed by co-immunoprecipitation experiments between FOXL2 and CXXC4 (IDAX), CXXC5 (RINF/WID), CREM, GMEB1 (P96PIF), NR2C1 (TR2), SP100, RPLP1, BAF (BANF1), XRCC6 (KU70) and SIRT1.[10]

Clinical significance

Sex determination

FOXL2 is involved in sex determination. Females missing the FOXL2 gene appear male. FOXL2 knockout in mature mouse ovaries appears to cause the ovary's somatic cells to transdifferentiate to the equivalent cell types ordinarily found in the testes.[11]

Eyebrow thickness

A variant on FOXL2 is the single most significant in producing thicker than average eyebrows. In Europeans, East Asians, and South Asians, the derived allele is above ~90% frequency, and in Africans, it is above ~75%. Native Americans, particularity Peruvians, have a relatively high frequency of the homozygous ancestral allele, which significantly decreases eyebrow thickness. All primates and archaic humans share the ancestral allele.[12]

Blepharophimosis–ptosis–epicanthus inversus syndrome

Mutations in this gene are a cause of blepharophimosis, ptosis, epicanthus inversus syndrome and/or premature ovarian failure (POF) 3.[6] Predicting the occurrence of POF based on the nature of the missense mutations in FOXL2 was a medical challenge. However, a correlation between the transcriptional activity of FOXL2 variants and the type of BPES was found.[13] Moreover, by studying the effects of natural and artificial mutations in the forkhead domain of FOXL2, a clear correlation between the orientation of amino-acid side chains in the DNA-binding domain and transcriptional activity is founded, providing the first (in silico) predictive tool of the effects of FOXL2 missense mutations.[14]

Adult granulosa cell tumors

A missense mutation in the FOXL2 gene, C134W, is found in adult granulosa cell tumors but not in other ovarian cancers nor in juvenile granulosa cell tumors.[8]

Endometriosis

In addition to ovarian expression of FOXL2, there has been recent studies to suggest that overexpression of FOXL2 has been implicated in endometriosis in addition to activin A.[15]

Other deregulations

One study has found that FOXL2 is required for SF-1-induced ovarian AMH regulation by interactions between FOXL2 protein and SF-1; a mutated FOXL2 could not interact with SF-1 normally and thus could not regulate ovarian AMH as normal.[16]

In a knockout study in mice, the granulosa cells of the ovaries failed to undergo the squamous-to-cuboidal transition, which led to the arrest of folliculogenesis.[17]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000183770 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000050397 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ de Die-Smulders CE, Engelen JJ, Donk JM, Fryns JP (October 1991). "Further evidence for the location of the BPES gene at 3q2". Journal of Medical Genetics. 28 (10): 725. doi:10.1136/jmg.28.10.725. PMC 1017067. PMID 1941972.
  6. ^ a b c "Entrez Gene: FOXL2 forkhead box L2".
  7. ^ Yang YJ, Wang Y, Li Z, Zhou L, Gui JF (April 2017). "Sequential, Divergent, and Cooperative Requirements of Foxl2a and Foxl2b in Ovary Development and Maintenance of Zebrafish". Genetics. 205 (4): 1551–1572. doi:10.1534/genetics.116.199133. PMC 5378113. PMID 28193729.
  8. ^ a b Leung DT, Fuller PJ, Chu S (March 2016). "Impact of FOXL2 mutations on signaling in ovarian granulosa cell tumors". The International Journal of Biochemistry & Cell Biology. 72: 51–4. doi:10.1016/j.biocel.2016.01.003. PMID 26791928.
  9. ^ Georges A, Benayoun BA, Marongiu M, Dipietromaria A, L'Hôte D, Todeschini AL, et al. (Oct 2011). "SUMOylation of the Forkhead transcription factor FOXL2 promotes its stabilization/activation through transient recruitment to PML bodies". PLOS ONE. 6 (10): e25463. doi:10.1371/journal.pone.0025463. PMC 3192040. PMID 22022399.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ L'Hôte D, Georges A, Todeschini AL, Kim JH, Benayoun BA, Bae J, Veitia RA (July 2012). "Discovery of novel protein partners of the transcription factor FOXL2 provides insights into its physiopathological roles". Human Molecular Genetics. 21 (14): 3264–74. doi:10.1093/hmg/dds170. PMID 22544055.
  11. ^ Uhlenhaut NH, Jakob S, Anlag K, Eisenberger T, Sekido R, Kress J, et al. (December 2009). "Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation". Cell. 139 (6): 1130–42. doi:10.1016/j.cell.2009.11.021. PMID 20005806. {{cite journal}}: Unknown parameter |lay-url= ignored (help); Unknown parameter |laysource= ignored (help)
  12. ^ Adhikari K, Fontanil T, Cal S, Mendoza-Revilla J, Fuentes-Guajardo M, Chacón-Duque JC, et al. (March 2016). "A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features". Nature Communications. 7: 10815. doi:10.1038/ncomms10815. PMC 4773514. PMID 26926045.
  13. ^ Dipietromaria A, Benayoun BA, Todeschini AL, Rivals I, Bazin C, Veitia RA, et al. (September 2009). "Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems". Human Molecular Genetics. 18 (17): 3324–33. CiteSeerX 10.1.1.615.6877. doi:10.1093/hmg/ddp273. PMID 19515849.
  14. ^ Todeschini AL, Dipietromaria A, L'hôte D, Boucham FZ, Georges AB, Pandaranayaka PJ, et al. (September 2011). "Mutational probing of the forkhead domain of the transcription factor FOXL2 provides insights into the pathogenicity of naturally occurring mutations". Human Molecular Genetics. 20 (17): 3376–85. doi:10.1093/hmg/ddr244. PMID 21632871.
  15. ^ Governini L, Carrarelli P, Rocha AL, Leo VD, Luddi A, Arcuri F, et al. (October 2014). "FOXL2 in human endometrium: hyperexpressed in endometriosis". Reproductive Sciences. 21 (10): 1249–55. doi:10.1177/1933719114522549. PMID 24520083.
  16. ^ Jin H, Won M, Park SE, Lee S, Park M, Bae J (2016-07-14). "FOXL2 Is an Essential Activator of SF-1-Induced Transcriptional Regulation of Anti-Müllerian Hormone in Human Granulosa Cells". PLOS ONE. 11 (7): e0159112. doi:10.1371/journal.pone.0159112. PMC 4944948. PMID 27414805.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  17. ^ Schmidt D, Ovitt CE, Anlag K, Fehsenfeld S, Gredsted L, Treier AC, et al. (February 2004). "The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance". Development. 131 (4): 933–42. doi:10.1242/dev.00969. PMID 14736745.

Further reading

  • Vaiman D, Schibler L, Oustry-Vaiman A, Pailhoux E, Goldammer T, Stevanovic M, Furet JP, Schwerin M, Cotinot C, Fellous M, Cribiu EP (February 1999). "High-resolution human/goat comparative map of the goat polled/intersex syndrome (PIS): the human homologue is contained in a human YAC from HSA3q23". Genomics. 56 (1): 31–9. doi:10.1006/geno.1998.5691. PMID 10036183.
  • Kaestner KH, Knochel W, Martinez DE (January 2000). "Unified nomenclature for the winged helix/forkhead transcription factors". Genes & Development. 14 (2): 142–6. doi:10.1101/gad.14.2.142 (inactive 2020-01-22). PMID 10702024.{{cite journal}}: CS1 maint: DOI inactive as of January 2020 (link)
  • Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, Amati P, Bisceglia L, Zelante L, Nagaraja R, Porcu S, Ristaldi MS, Marzella R, Rocchi M, Nicolino M, Lienhardt-Roussie A, Nivelon A, Verloes A, Schlessinger D, Gasparini P, Bonneau D, Cao A, Pilia G (February 2001). "The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome". Nature Genetics. 27 (2): 159–66. doi:10.1038/84781. PMID 11175783.
  • De Baere E, Dixon MJ, Small KW, Jabs EW, Leroy BP, Devriendt K, et al. (July 2001). "Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation". Human Molecular Genetics. 10 (15): 1591–600. doi:10.1093/hmg/10.15.1591. PMID 11468277.
  • Dollfus H, Kumaramanickavel G, Biswas P, Stoetzel C, Quillet R, Denton M, Maw M, Perrin-Schmitt F (July 2001). "Identification of a new TWIST mutation (7p21) with variable eyelid manifestations supports locus homogeneity of BPES at 3q22". Journal of Medical Genetics. 38 (7): 470–2. doi:10.1136/jmg.38.7.470. PMC 1757180. PMID 11474656.
  • Yamada T, Hayasaka S, Matsumoto M, Esa T, Hayasaka Y, Endo M (2002). "Heterozygous 17-bp deletion in the forkhead transcription factor gene, FOXL2, in a Japanese family with blepharophimosis-ptosis-epicanthus inversus syndrome". Journal of Human Genetics. 46 (12): 733–6. doi:10.1007/s100380170009. PMID 11776388.
  • Kosaki K, Ogata T, Kosaki R, Sato S, Matsuo N (March 2002). "A novel mutation in the FOXL2 gene in a patient with blepharophimosis syndrome: differential role of the polyalanine tract in the development of the ovary and the eyelid". Ophthalmic Genetics. 23 (1): 43–7. doi:10.1076/opge.23.1.43.2202. PMID 11910558.
  • Bell R, Murday VA, Patton MA, Jeffery S (2002). "Two families with blepharophimosis/ptosis/epicanthus inversus syndrome have mutations in the putative forkhead transcription factor FOXL2". Genetic Testing. 5 (4): 335–8. doi:10.1089/109065701753617499. PMID 11960581.
  • Harris SE, Chand AL, Winship IM, Gersak K, Aittomäki K, Shelling AN (August 2002). "Identification of novel mutations in FOXL2 associated with premature ovarian failure". Molecular Human Reproduction. 8 (8): 729–33. doi:10.1093/molehr/8.8.729. PMID 12149404.
  • De Baere E, Lemercier B, Christin-Maitre S, Durval D, Messiaen L, Fellous M, Veitia R (August 2002). "FOXL2 mutation screening in a large panel of POF patients and XX males". Journal of Medical Genetics. 39 (8): 43e–43. doi:10.1136/jmg.39.8.e43. PMC 1735205. PMID 12161610.
  • Ramírez-Castro JL, Pineda-Trujillo N, Valencia AV, Muñetón CM, Botero O, Trujillo O, Vásquez G, Mora BE, Durango N, Bedoya G, Ruiz-Linares A (November 2002). "Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian families". American Journal of Medical Genetics. 113 (1): 47–51. doi:10.1002/ajmg.10741. PMID 12400065.
  • Cocquet J, Pailhoux E, Jaubert F, Servel N, Xia X, Pannetier M, De Baere E, Messiaen L, Cotinot C, Fellous M, Veitia RA (December 2002). "Evolution and expression of FOXL2". Journal of Medical Genetics. 39 (12): 916–21. doi:10.1136/jmg.39.12.916. PMC 1757225. PMID 12471206.
  • De Baere E, Beysen D, Oley C, Lorenz B, Cocquet J, De Sutter P, Devriendt K, Dixon M, Fellous M, Fryns JP, Garza A, Jonsrud C, Koivisto PA, Krause A, Leroy BP, Meire F, Plomp A, Van Maldergem L, De Paepe A, Veitia R, Messiaen L (February 2003). "FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation". American Journal of Human Genetics. 72 (2): 478–87. doi:10.1086/346118. PMC 379240. PMID 12529855.
  • Mazumdar A, Kumar R (January 2003). "Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells". FEBS Letters. 535 (1–3): 6–10. doi:10.1016/S0014-5793(02)03846-2. PMID 12560069.
  • Fokstuen S, Antonarakis SE, Blouin JL (March 2003). "FOXL2-mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); challenges for genetic counseling in female patients". American Journal of Medical Genetics. Part A. 117A (2): 143–6. doi:10.1002/ajmg.a.10024. PMID 12567411.
  • Dollfus H, Stoetzel C, Riehm S, Lahlou Boukoffa W, Bediard Boulaneb F, Quillet R, Abu-Eid M, Speeg-Schatz C, Francfort JJ, Flament J, Veillon F, Perrin-Schmitt F (February 2003). "Sporadic and familial blepharophimosis -ptosis-epicanthus inversus syndrome: FOXL2 mutation screen and MRI study of the superior levator eyelid muscle". Clinical Genetics. 63 (2): 117–20. doi:10.1034/j.1399-0004.2003.00011.x. PMID 12630957.
  • Udar N, Yellore V, Chalukya M, Yelchits S, Silva-Garcia R, Small K (September 2003). "Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients". Human Mutation. 22 (3): 222–8. doi:10.1002/humu.10251. PMID 12938087.
  • Crisponi L, Uda M, Deiana M, Loi A, Nagaraja R, Chiappe F, Schlessinger D, Cao A, Pilia G (May 2004). "FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long-range regulatory sequences". Genomics. 83 (5): 757–64. doi:10.1016/j.ygeno.2003.11.010. PMID 15081106.
  • L'Hôte D, Georges A, Todeschini AL, Kim JH, Benayoun BA, Bae J, Veitia RA (July 2012). "Discovery of novel protein partners of the transcription factor FOXL2 provides insights into its physiopathological roles". Human Molecular Genetics. 21 (14): 3264–74. doi:10.1093/hmg/dds170. PMID 22544055.
  • Georges A, L'Hôte D, Todeschini AL, Auguste A, Legois B, Zider A, Veitia RA (November 2014). "The transcription factor FOXL2 mobilizes estrogen signaling to maintain the identity of ovarian granulosa cells". eLife. 3. doi:10.7554/eLife.04207. PMC 4356143. PMID 25369636.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Elzaiat M, Todeschini AL, Caburet S, Veitia RA (February 2017). "The genetic make-up of ovarian development and function: the focus on the transcription factor FOXL2". Clinical Genetics. 91 (2): 173–182. doi:10.1111/cge.12862. PMID 27604691.
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