Definition: FOXL2 encodes a forkhead transcription factor. The protein FOXL2 contains a fork-head DNA-binding domain and may play a role in ovarian development and function.
Mutations in FOXL2 are a cause of blepharophimosis syndrome (BPES) and premature ovarian failure type 3 (MIM.608996).
Functions
FOXL2 represses the transcription of aromatase, cholesterol side-chain cleavage enzyme P450scc and cyclin D2 in granulosa cells.
FoxL2 plays a key role in activin induction of the FSHbeta gene, by binding to sites conserved across multiple species.
Human FOXL2 and SF-1 proteins interact in human granulosa cells and that FOXL2 negatively regulates the transcriptional activation of a steroidogenic enzyme, CYP17, by SF-1.
Pathology
Defects in FOXL2 underlies some types of female infertility and premature ovarian failure. (FOXL2-associated premature ovarian failure)
FOXL2 germline mutations in
- blepharophimosis syndrome (BPES), an autosomal dominant syndrome in which an eyelid malformation is associated (type I) or not (type II) with premature ovarian failure (12529855) (polyalanine repeat expansion)
- premature ovarian failure type 3 (MIM.608996)
FOXL2 germline mutations in blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES)(MIM.110100)
- BPES type 1
- BPES type 2
Mutation of FOXL2 in adult-type granulosa-cell tumor of the ovary. (19516027, 19996294, 19956657)
- FOXL2 showed a p.C134W missense point mutation in 18 of 20 adult granulosa-cell tumors.
- FOXL2 codon 134 mutation occurs exclusively in granulosa cell tumor (GCT) and thecoma. It suggest the possibility that the development of most GCTs and a fraction of thecomas may be dependent on this mutation.
References
FOXL2 is a sensitive and specific marker for sex cord-stromal tumors of the ovary. Al-Agha OM, Huwait HF, Chow C, Yang W, Senz J, Kalloger SE, Huntsman DG, Young RH, Gilks CB. Am J Surg Pathol. 2011 Apr;35(4):484-94. PMID: 21378549
FOXL2 and SOX9 as parameters of female and male gonadal differentiation in patients with various forms of disorders of sex development (DSD). Hersmus R, Kalfa N, de Leeuw B, Stoop H, Oosterhuis JW, de Krijger R, Wolffenbuttel KP, Drop SL, Veitia RA, Fellous M, Jaubert F, Looijenga LH. J Pathol. 2008 May;215(1):31-8. PMID: 18348162
Adult-type granulosa cell tumors and FOXL2 mutation. Köbel M, Gilks CB, Huntsman DG. Cancer Res. 2009 Dec 15;69(24):9160-2. PMID: 19996294
A new FOXL2 gene mutation in a woman with premature ovarian failure and sporadic blepharophimosis-ptosis-epicanthus inversus syndrome. Silva Corrêa FJ, Tavares AB, Pereira RW, Abrão MS. Fertil Steril. 2009 Dec 5. PMID: 19969293
The specificity of the FOXL2 c.402C>G Somatic mutation: a survey of solid tumors. Schrader KA, Gorbatcheva B, Senz J, Heravi-Moussavi A, Melnyk N, Salamanca C, Maines-Bandiera S, Cooke SL, Leung P, Brenton JD, Gilks CB, Monahan J, Huntsman DG. PLoS One. 2009 Nov 24;4(11):e7988. PMID: 19956657
Identification of a Novel Mutation in FOXL2 Gene That Leads to Blepharophimosis Ptosis Epicanthus Inversus and Telecanthus Syndrome in a Tunisian Consanguineous Family. Chouchene I, Derouiche K, Chaabouni A, Cherif L, Amouri A, Largueche L, Abdelhak S, Matri LE. Genet Test Mol Biomarkers. 2009 Nov 23. PMID: 19929410
FOXL2 mutations lead to different ovarian phenotypes in BPES patients: Case Report. Méduri G, Bachelot A, Duflos C, Bständig B, Poirot C, Genestie C, Veitia R, De Baere E, Touraine P. Hum Reprod. 2010 Jan;25(1):235-43. Epub 2009 Oct 9. PMID: 19819892
The forkhead factor FOXL2: A novel tumor suppressor? Benayoun BA, Kalfa N, Sultan C, Veitia RA. Biochim Biophys Acta. 2009 Sep 10. PMID: 19747961
The new molecular biology of granulosa cell tumors of the ovary. Kalfa N, Veitia RA, Benayoun BA, Boizet-Bonhoure B, Sultan C. Genome Med. 2009 Aug 25;1(8):81. PMID: 19725933
Mutation of FOXL2 in granulosa-cell tumors of the ovary. Shah SP, Köbel M, Senz J, Morin RD, Clarke BA, Wiegand KC, Leung G, Zayed A, Mehl E, Kalloger SE, Sun M, Giuliany R, Yorida E, Jones S, Varhol R, Swenerton KD, Miller D, Clement PB, Crane C, Madore J, Provencher D, Leung P, DeFazio A, Khattra J, Turashvili G, Zhao Y, Zeng T, Glover JN, Vanderhyden B, Zhao C, Parkinson CA, Jimenez-Linan M, Bowtell DD, Mes-Masson AM, Brenton JD, Aparicio SA, Boyd N, Hirst M, Gilks CB, Marra M, Huntsman DG. N Engl J Med. 2009 Jun 25;360(26):2719-29. PMID: 19516027
