| FOXL2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | FOXL2, BPES, BPES1, PFRK, PINTO, POF3, forkhead box L2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 605597 MGI: 1349428 HomoloGene: 74992 GeneCards: FOXL2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Forkhead box protein L2 is a protein that in humans is encoded by the FOXL2 gene.[5][6]
Function[edit]
FOXL2 (OMIM 605597) is a transcription factor belonging to the forkhead box (FOX) superfamily, characterized by the forkhead box/winged-helix DNA-binding domain. FOXL2 plays an important role in ovarian development and function.[6] In postnatal ovaries FOXL2 regulates granulosa cell differentiation and supports the growth of the pre-ovulatory follicles during adult life.[7] In addition, the FOXL2 protein will prevent the formation of testes by suppressing expression of SOX9.[8] In mice, FOXL2 is also expressed in pituitary cells[9] where it is required for FSH expression.[10]
Regulation[edit]
FOXL2 has several post-translational modifications that modulate its stability, subcellular localization and pro-apoptotic activity.[11] 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.[12]
Clinical significance[edit]
Sex determination[edit]
FOXL2 is involved in sex determination. 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.[13] Polled Intersex Syndrome in goats is caused by a biallelic loss-of-function in FOXL2 transcription and leads to in utero female-to-male sex-reversal.[14]
Eyebrow thickness[edit]
Several SNPs (Single Variant Polymorphisms) in the genomic region 3q23 overlapping the forkhead box L2 (FOXL2) were found associated with eyebrow thickness. In Europeans, East Asians, and South Asians, the derived allele is above ~90% frequency, and in Africans, it is above ~75%. Native Americans, particularly 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.[15]
Blepharophimosis–ptosis–epicanthus inversus syndrome[edit]
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.[16] 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.[17]
Adult granulosa cell tumors[edit]
A missense mutation in the FOXL2 gene, C134W, is typically found in adult granulosa cell tumors but not in other ovarian cancers nor in juvenile granulosa cell tumors.[7]
Endometriosis[edit]
In addition to ovarian expression of FOXL2, there have been recent studies to suggest that overexpression of FOXL2 has been implicated in endometriosis in addition to activin A.[18]
Other deregulations[edit]
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.[19]
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.[20]
See also[edit]
References[edit]
- ^ a b c GRCh38: Ensembl release 89: ENSG00000183770 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000050397 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ 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.
- ^ a b c "Entrez Gene: FOXL2 forkhead box L2".
- ^ 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.
- ^ 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.
- ^ Ellsworth BS, Egashira N, Haller JL, Butts DL, Cocquet J, Clay CM, et al. (November 2006). "FOXL2 in the pituitary: molecular, genetic, and developmental analysis". Mol Endocrinol. 20 (11): 2796–805. doi:10.1210/me.2005-0303. PMID 16840539.
- ^ Justice NJ, Blount AL, Pelosi E, Schlessinger D, Vale W, Bilezikjian LM (August 2011). "Impaired FSHbeta expression in the pituitaries of Foxl2 mutant animals". Mol Endocrinol. 25 (8): 1404–15. doi:10.1210/me.2011-0093. PMC 3146251. PMID 21700720.
- ^ 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. Bibcode:2011PLoSO...625463G. doi:10.1371/journal.pone.0025463. PMC 3192040. PMID 22022399.
- ^ L'Hôte D, Georges A, Todeschini AL, Kim JH, Benayoun BA, Bae J, et al. (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.
- ^ 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. S2CID 14305820.*Lay summary in: Borrell B (December 10, 2009). "Ovaries reveal their inner testes". Nature News.
- ^ Boulanger L, Pannetier M, Gall L, Allais-Bonnet A, Elzaiat M, Le Bourhis D, et al. (February 2014). "FOXL2 is a female sex-determining gene in the goat". Curr Biol. 24 (4): 404–8. Bibcode:2014CBio...24..404B. doi:10.1016/j.cub.2013.12.039. PMID 24485832. S2CID 12076748.
- ^ 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. Bibcode:2016NatCo...710815A. doi:10.1038/ncomms10815. PMC 4773514. PMID 26926045.
- ^ Dipietromaria A, Benayoun BA, Todeschini AL, Rivals I, Bazin C, Veitia RA (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.
- ^ 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.
- ^ 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. S2CID 25004354.
- ^ 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. Bibcode:2016PLoSO..1159112J. doi:10.1371/journal.pone.0159112. PMC 4944948. PMID 27414805.
- ^ 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. S2CID 31658647.
Further reading[edit]
- Vaiman D, Schibler L, Oustry-Vaiman A, Pailhoux E, Goldammer T, Stevanovic M, et al. (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. S2CID 1446666.
- 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. PMID 10702024. S2CID 26488600.
- Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, Amati P, et al. (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. S2CID 26750194.
- 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, et al. (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. S2CID 39171567.
- 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. S2CID 2502871.
- 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, et al. (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, et al. (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, et al. (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, et al. (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. S2CID 28855687.
- 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. S2CID 41583322.
- Dollfus H, Stoetzel C, Riehm S, Lahlou Boukoffa W, Bediard Boulaneb F, Quillet R, et al. (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. S2CID 19151109.
- 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. S2CID 24771690.
- Crisponi L, Uda M, Deiana M, Loi A, Nagaraja R, Chiappe F, et al. (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, et al. (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, et al. (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.
- 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. S2CID 30962804.
External links[edit]
- FOXL2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- GeneReviews/NCBI/NIH/UW entry on Blepharophimosis, Ptosis, and Epicanthus Inversus