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Gene Review

FOXL2  -  forkhead box L2

Homo sapiens

Synonyms: BPES, BPES1, Forkhead box protein L2, PFRK, PINTO, ...
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Disease relevance of FOXL2

  • The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome [1].
  • A new heterozygous mutation of the FOXL2 gene is associated with a large ovarian cyst and ovarian dysfunction in an adolescent girl with blepharophimosis/ptosis/epicanthus inversus syndrome [2].
  • This case describes the novel coexistence of sporadic blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and bilateral type I Duane syndrome in a female infant, with a FOXL2 mutation [3].
  • The role of FOXL2 in the development of infertility is still unclear, but several lines of evidence suggest that it plays a central role in follicle development [4].
  • Evidence was provided that BPES type I (eyelid abnormalities and female infertility) is caused by mutations resulting in a truncated FOXL2 protein [5].

Psychiatry related information on FOXL2

  • We report on a 3-year-old girl with the phenotype of BPES, mental retardation, facial dysmorphism and camptodactyly [6].
  • In addition, he has proposed an alternative account of whistleblowing, viz., the Complicity Theory. This paper examines the Complicity Theory. The supposed anomalies rest on misunderstandings of the received view or misreadings of model cases of whistleblowing, for example, the Challenger disaster and the Ford Pinto [7].

High impact information on FOXL2

  • This deletion affects the transcription of at least two genes: PISRT1, encoding a 1.5-kb mRNA devoid of open reading frame (ORF), and FOXL2, recently shown to be responsible for blepharophimosis ptosis epicanthus inversus syndrome (BPES) in humans [8].
  • Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary [1].
  • The discovery of FOXL2 may provide insight into the causes of idiopathic premature ovarian failure, a disease that burdens many infertile couples [9].
  • Here, Gene Shearer, Ligia Pinto and Mario Clerici raise the possibility that alloimmunization against a spectrum of HLA-disparate leukocytes be considered for immune-based therapy and as an AIDS vaccine [10].
  • Differentiation occurs when glucose is replaced by galactose in the culture medium (Pinto, M., M.D. Appay, P. Simon-Assman, G. Chevalier, N. Dracopoli, J. Fogh, and A. Zweibaum, 1982, Biol. Cell., 44:193-196) [11].

Chemical compound and disease context of FOXL2

  • We conclude that the FOXL2 mutation 904_939dup36 may account not only for blepharophimosis and ptosis but also for ovarian dysfunction and growth of the large corpus luteum cyst [2].
  • 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 [12].

Biological context of FOXL2

  • In addition, we report nine novel rearrangements encompassing FOXL2 that range from partial gene deletions to submicroscopic deletions [13].
  • FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long-range regulatory sequences [14].
  • The conserved sequences are candidates for models in which they are distant enhancers or otherwise affect higher order chromatin structure to impose long-range cis regulation of FOXL2 expression [14].
  • This genomic region is composed of at least two genes, FOXL2 and PISRT1, sharing a common transcriptional regulatory region, PIS [15].
  • To determine the linkage of this family to the FOXL2 locus, haplotype analysis was carried out using microsatellite markers from the BPES candidate region [16].

Anatomical context of FOXL2

  • We have transfected COS-7 cells with DNA constructs driving the expression of the wildtype and mutant FOXL2 proteins fused to the green fluorescent protein [17].
  • FOXL2 is a forkhead transcription factor expressed in the eye, ovary, and pituitary gland [18].
  • The FOXL2 mRNA is expressed in ovaries throughout development and adulthood and is localized to the undifferentiated granulosa cells in small and medium follicles as well as cumulus cells of preovulatory follicles [19].
  • The conservation of its sequence and pattern of expression suggests that FOXL2 might be a key factor in the early development of the vertebrate female gonad and involved later in adult ovarian function [20].
  • HT29-D4 clonal cells can be induced to differentiate by a simple alteration of the culture medium, that is, by the replacement of glucose by galactose [Fantini, J., et al. (1986) J. Cell Sci., 83:235-249] as reported for the nonclonal HT29 cells [Pinto, M., (1982) Biol. Cell, 44:193-196] [21].

Associations of FOXL2 with chemical compounds

  • Our study shows the existence of two mutational hotspots: 30% of FOXL2 mutations lead to polyalanine (poly-Ala) expansions, and 13% are a novel out-of-frame duplication [22].
  • We report that FOXL2 colocalizes with the glycoprotein hormone alpha-subunit (alphaGSU) in quiescent cells of the mouse pituitary from embryonic d 11.5 through adulthood [18].
  • We now show that DFMO can protect bean plants (Phaseolus vulgaris Linnaeus cv. Pinto) against infection by uredospores of the bean rust fungus, Uromyces phaseoli Linnaeus, race O [23].
  • Other studies indicate that in undifferentiated HT-29 Glc+ cells there is an accumulation of UDP-N-acetylhexosamine, which is involved in the glycosylation process (Wice, B. M., Trugnan, G., Pinto, M., Rousset, M., Chevalier, G., Dussaulx, E., Lacroix, B., and Zweibaum, A. (1985) J. Biol. Chem. 260, 139-146) [24].
  • The effects of substituting D178 in PDO with alanine or asparagine on the reactivity of the Rieske centers, phthalate hydroxylation, and coupling of Rieske center oxidation to DHD formation were studied previously [Pinto et al. (2006) Biochemistry 45, 9032-9041] [25].

Physical interactions of FOXL2


Other interactions of FOXL2

  • A translocation breakpoint 171 kb 5' of the transcription start of FOXL2 causes blepharophimosis/ptosis/epicanthus inversus syndrome (BPES) and associated premature ovarian failure [14].
  • Analyses using FOXL2 mutants also demonstrated the importance of the entire alanine/proline-rich carboxyl terminus of FOXL2 for transcriptional repression [19].
  • Overexpression of DP103 itself did not affect cell viability while its coexpression with FOXL2 led to the potentiation of cell death [26].
  • Mutational analysis of forkhead transcriptional factor 2 (FOXL2) in Korean patients with blepharophimosis-ptosis-epicanthus inversus syndrome [27].
  • Neuroglandular antigen (NGA) was identified as a human melanoma-associated antigen by a panel of murine monoclonal antibodies of both IgG2a (LS62, LS76, LS159) and IgG1 (LS113, LS140, LS152) subclasses, developed in this laboratory (L. Sikora, A. Pinto, D. Demetrick, W. Dixon, S. Urbanski, and L. M. Jerry, Int. J. Cancer, 39: 138-145, 1987) [28].

Analytical, diagnostic and therapeutic context of FOXL2

  • Interestingly, the human region orthologous to the 12-kb sequence deleted in the polled intersex syndrome in goat, which is an animal model for BPES, is contained in this SRO, providing evidence of human-goat conservation of FOXL2 expression and of the mutational mechanism [13].
  • Here, we describe 21 new FOXL2 mutations (16 novel ones) through sequencing of open reading frame, 5' untranslated region, putative core promoter, and fluorescence in situ hybridization analysis [22].
  • We investigated the expression of FOXL2 in the mouse ovary during follicular development and maturation by RT-PCR and in situ hybridization [19].
  • METHODS: PCR amplification and direct sequencing of the FOXL2 coding region in genomic DNA were performed in affected patients and 80 healthy controls [29].
  • Here we have performed a comparative sequence analysis of FOXL2 sequences of ten vertebrate species [20].


  1. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Crisponi, L., Deiana, M., Loi, A., Chiappe, F., Uda, M., Amati, P., Bisceglia, L., Zelante, L., Nagaraja, R., Porcu, S., Ristaldi, M.S., Marzella, R., Rocchi, M., Nicolino, M., Lienhardt-Roussie, A., Nivelon, A., Verloes, A., Schlessinger, D., Gasparini, P., Bonneau, D., Cao, A., Pilia, G. Nat. Genet. (2001) [Pubmed]
  2. A new heterozygous mutation of the FOXL2 gene is associated with a large ovarian cyst and ovarian dysfunction in an adolescent girl with blepharophimosis/ptosis/epicanthus inversus syndrome. Raile, K., Stobbe, H., Tröbs, R.B., Kiess, W., Pfäffle, R. Eur. J. Endocrinol. (2005) [Pubmed]
  3. Blepharophimosis and bilateral Duane syndrome associated with a FOXL2 mutation. Vincent, A.L., Watkins, W.J., Sloan, B.H., Shelling, A.N. Clin. Genet. (2005) [Pubmed]
  4. A novel 30 bp deletion in the FOXL2 gene in a phenotypically normal woman with primary amenorrhoea: case report. Gersak, K., Harris, S.E., Smale, W.J., Shelling, A.N. Hum. Reprod. (2004) [Pubmed]
  5. FOXL2-mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); challenges for genetic counseling in female patients. Fokstuen, S., Antonarakis, S.E., Blouin, J.L. Am. J. Med. Genet. A (2003) [Pubmed]
  6. Severe feeding problems and congenital laryngostenosis in a patient with 3q23 deletion. Chandler, K.E., de Die-Smulders, C.E., Engelen, J.J., Schrander, J.J. Eur. J. Pediatr. (1997) [Pubmed]
  7. On complicity theory. Kline, A.D. Science and engineering ethics. (2006) [Pubmed]
  8. A 11.7-kb deletion triggers intersexuality and polledness in goats. Pailhoux, E., Vigier, B., Chaffaux, S., Servel, N., Taourit, S., Furet, J.P., Fellous, M., Grosclaude, F., Cribiu, E.P., Cotinot, C., Vaiman, D. Nat. Genet. (2001) [Pubmed]
  9. A fork in the road to fertility. Prueitt, R.L., Zinn, A.R. Nat. Genet. (2001) [Pubmed]
  10. Alloimmunization for immune-based therapy and vaccine design against HIV/AIDS. Shearer, G.M., Pinto, L.A., Clerici, M. Immunol. Today (1999) [Pubmed]
  11. Absorptive and mucus-secreting subclones isolated from a multipotent intestinal cell line (HT-29) provide new models for cell polarity and terminal differentiation. Huet, C., Sahuquillo-Merino, C., Coudrier, E., Louvard, D. J. Cell Biol. (1987) [Pubmed]
  12. 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. Kosaki, K., Ogata, T., Kosaki, R., Sato, S., Matsuo, N. Ophthalmic Genet. (2002) [Pubmed]
  13. Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome. Beysen, D., Raes, J., Leroy, B.P., Lucassen, A., Yates, J.R., Clayton-Smith, J., Ilyina, H., Brooks, S.S., Christin-Maitre, S., Fellous, M., Fryns, J.P., Kim, J.R., Lapunzina, P., Lemyre, E., Meire, F., Messiaen, L.M., Oley, C., Splitt, M., Thomson, J., Peer, Y.V., Veitia, R.A., De Paepe, A., De Baere, E. Am. J. Hum. Genet. (2005) [Pubmed]
  14. FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long-range regulatory sequences. Crisponi, L., Uda, M., Deiana, M., Loi, A., Nagaraja, R., Chiappe, F., Schlessinger, D., Cao, A., Pilia, G. Genomics (2004) [Pubmed]
  15. Ovarian-specific expression of a new gene regulated by the goat PIS region and transcribed by a FOXL2 bidirectional promoter. Pannetier, M., Renault, L., Jolivet, G., Cotinot, C., Pailhoux, E. Genomics (2005) [Pubmed]
  16. Genetic analysis of a five generation Indian family with BPES: a novel missense mutation (p.Y215C). Kumar, A., Babu, M., Raghunath, A., Venkatesh, C.P. Mol. Vis. (2004) [Pubmed]
  17. A recurrent polyalanine expansion in the transcription factor FOXL2 induces extensive nuclear and cytoplasmic protein aggregation. Caburet, S., Demarez, A., Moumné, L., Fellous, M., De Baere, E., Veitia, R.A. J. Med. Genet. (2004) [Pubmed]
  18. FOXL2 in the Pituitary: Molecular, Genetic, and Developmental Analysis. Ellsworth, B.S., Egashira, N., Haller, J.L., Butts, D.L., Cocquet, J., Clay, C.M., Osamura, R.Y., Camper, S.A. Mol. Endocrinol. (2006) [Pubmed]
  19. Forkhead l2 is expressed in the ovary and represses the promoter activity of the steroidogenic acute regulatory gene. Pisarska, M.D., Bae, J., Klein, C., Hsueh, A.J. Endocrinology (2004) [Pubmed]
  20. Structure, evolution and expression of the FOXL2 transcription unit. Cocquet, J., De Baere, E., Gareil, M., Pannetier, M., Xia, X., Fellous, M., Veitia, R.A. Cytogenet. Genome Res. (2003) [Pubmed]
  21. Induction of polarized apical expression and vectorial release of carcinoembryonic antigen (CEA) during the process of differentiation of HT29-D4 cells. Fantini, J., Rognoni, J.B., Culouscou, J.M., Pommier, G., Marvaldi, J., Tirard, A. J. Cell. Physiol. (1989) [Pubmed]
  22. FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation. De Baere, E., Beysen, D., Oley, C., Lorenz, B., Cocquet, J., De Sutter, P., Devriendt, K., Dixon, M., Fellous, M., Fryns, J.P., Garza, A., Jonsrud, C., Koivisto, P.A., Krause, A., Leroy, B.P., Meire, F., Plomp, A., Van Maldergem, L., De Paepe, A., Veitia, R., Messiaen, L. Am. J. Hum. Genet. (2003) [Pubmed]
  23. Prevention of a plant disease by specific inhibition of fungal polyamine biosynthesis. Rajam, M.V., Weinstein, L.H., Galston, A.W. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  24. The processing of asparagine-linked oligosaccharides in HT-29 cells is a function of their state of enterocytic differentiation. An accumulation of Man9,8-GlcNAc2-Asn species is indicative of an impaired N-glycan trimming in undifferentiated cells. Ogier-Denis, E., Codogno, P., Chantret, I., Trugnan, G. J. Biol. Chem. (1988) [Pubmed]
  25. The "bridging" aspartate 178 in phthalate dioxygenase facilitates interactions between the Rieske center and the iron(II)--mononuclear center. Tarasev, M., Pinto, A., Kim, D., Elliott, S.J., Ballou, D.P. Biochemistry (2006) [Pubmed]
  26. Transcriptional factor FOXL2 interacts with DP103 and induces apoptosis. Lee, K., Pisarska, M.D., Ko, J.J., Kang, Y., Yoon, S., Ryou, S.M., Cha, K.Y., Bae, J. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  27. Mutational analysis of forkhead transcriptional factor 2 (FOXL2) in Korean patients with blepharophimosis-ptosis-epicanthus inversus syndrome. Cha, S.C., Jang, Y.S., Lee, J.H., Kim, H.K., Kim, S.C., Kim, S., Baek, S.H., Jung, W.S., Kim, J.R. Clin. Genet. (2003) [Pubmed]
  28. Biosynthesis, glycosylation and intracellular processing of the neuroglandular antigen, a human melanoma-associated antigen. Dixon, W.T., Demetrick, D.J., Ohyama, K., Sikora, L.K., Jerry, L.M. Cancer Res. (1990) [Pubmed]
  29. A novel mutation in the FOXL2 gene in a Chinese family with blepharophimosis, ptosis, and epicanthus inversus syndrome. Li, W.X., Wang, X.K., Sun, Y., Wang, Y.L., Lin, L.X., Tang, S.J. Zhonghua Yi Xue Yi Chuan Xue Za Zhi (2005) [Pubmed]
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