Forkhead Transcription Factors in Genetic Disease

Abstract

Forkhead transcription factors represent an important family of proteins, for which more than 2000 family members have been identified so far, 26 of which can be found in humans. FOX genes exhibit many important functions in both development and adult life. Therefore, it is not surprising that alterations in these genes can cause of a broad range of developmental diseases and cancer. Today, 13 FOX genes are associated with developmental disorders. Mutations in five of them (FOXC1, FOXC2, FOXD3, FOXE3 and FOXL2) lead to an ocular phenotype, while mutations in three genes (FOXG1, FOXP1 and FOXP2) are a known cause for neurodevelopmental disorders, mutations in two (FOXL2 and FOXO3A) are associated with premature ovarian failure and mutation in other two genes (FOXN1 and FOXP3) are involved in immunodeficiency syndromes. Finally, FOXF1 mutations cause a lung development disorder. In this article, the different developmental disorders caused by mutations in FOX genes are reviewed. In addition, the article briefly touches cancers caused by genetic defects in FOX genes.

Key Concepts:

  • Forkhead transcription factor genes represent an important gene family, consisting out of more than 2000 members. In human, 26 family members have been identified and there are 8 FOX gene clusters.

  • The forkhead domain is built up by three α‐helices, two β‐sheets and two loops. These loops resemble wings of a butterfly, giving the family its nickname: winged helix transcription factors.

  • Forkhead transcription factors play important roles in a wide range of signalling pathways.

  • Mutations in FOX genes are known to cause hereditary developmental disorders. Five mutated FOX genes are associated with an ocular phenotype.

  • Forkhead transcription factors are also involved in cancer and ageing.

Keywords: forkhead transcription factors; forkhead domain; development; ocular phenotypes; cancer

Figure 1.

Overview of the forkhead gene clustering. In total, 21 of the 26 human forkhead genes are organised in 8 clusters.

Figure 2.

The FHD. (a) 3D‐structure of FOXO1 bound to DNA (Protein Database (PBD) accession: 3CO6). The DNA‐binding helix (H3) is coloured in blue. W1–W2 show the peculiar winged folding and are depicted in purple. The structure of FOXO1 was first resolved by Brent et al.. (b) 3D‐structure of FOXO3a (PDB accession: 2K86), with the 3 typical helices (H1–H3) and the 2 wings (W1–W2). This structure was first found by nuclear magnetic resonance by Wang et al..

Figure 3.

Ocular defects. (a–c) Ocular images from a patient carrying a partial FOXC1 deletion: (a) ectopic pupil, (b) right eye with iris strands and (c) peripheral polycoria and ectropion uveae.

Adapted from D'haene et al.2011. © Association for Research in Vision and Ophthalmology.
Figure 4.

Overview of copy number variations found in forkhead gene regions. Gene dosage is very important for forkhead transcription factor genes; this is underlined by the identification of copy number variations in several FOX genes, as demonstrated in panels (a–d). At the top of each panel, the chromosome ideogram is shown with a red box indicating the position of the corresponding FOX gene (marked with a blue box) region. (a) The FOXC1 region (chr 6:60 000–12 000 000, UCSC, Human Genome Browser, GRCh37/hg19) with custom tracks depicting FOXC1 deletions (red) and duplications (green) identified by Chanda et al.; D'haene et al.; Delahaye et al. and Reis et al.. (b) A regulatory duplication in the FOXC2 region (chr16: 86 533 617–86 669 777, UCSC, Human Genome Browser, GRCh37/hg19) described by Witte et al.. (c) The FOXF1 region (chr16:84 000 000–88 000 000, UCSC, Human Genome Browser, GRCh37/hg19) with custom tracks showing deletions of FOXF1 as described by Stankiewicz et al.. (d) The FOXL2 region (chr3:135 099 979–14 24 58 004, UCSC, Human Genome Browser, GRCh37/hg19) with custom tracks displaying the several FOXL2‐encompassing (light red) and FOXL2 regulatory (dark red) deletions found and delineated by Verdin et al.; D'haene et al.; D'haene et al. and Beysen et al..

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References

Adriani M, Martinez-Mir A, Fusco F et al. (2004) Ancestral founder mutation of the nude (FOXN1) gene in congenital severe combined immunodeficiency associated with alopecia in southern Italy population. Annals of Human Genetics 68: 265–268.

Al‐Agha OM, Huwait HF, Chow C et al. (2011) FOXL2 is a sensitive and specific marker for sex cord‐stromal tumors of the ovary. American Journal of Surgical Pathology 35: 484–494.

Alao MJ, Lalèyè A, Lalya F et al. (2012) Blepharophimosis, ptosis, epicanthus inversus syndrome with translocation and deletion at chromosome 3q23 in a black African female. European Journal of Medical Genetics 55: 630–634.

Anjum I, Eiberg H, Baig SM, Tommerup N and Hansen L (2010) A mutation in the FOXE3 gene causes congenital primary aphakia in an autosomal recessive consanguineous Pakistani family. Molecular Vision 16: 549–555.

Ariani F, Hayek G, Rondinella D et al. (2008) FOXG1 is responsible for the congenital variant of Rett syndrome. American Journal of Human Genetics 83: 89–93.

Bacon C and Rappold GA (2012) The distinct and overlapping phenotypic spectra of FOXP1 and FOXP2 in cognitive disorders. Human Genetics 131: 1687–1698.

Bae KW, Kim BE, Choi JH et al. (2011) A novel mutation and unusual clinical features in a patient with immune dysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX) syndrome. European Journal of Pediatrics 170: 1611–1615.

De Baere E, Dixon MJ, Small KW et al. (2001) Spectrum of FOXL2 gene mutations in blepharophimosis‐ptosis‐epicanthus inversus (BPES) families demonstrates a genotype – phenotype correlation. Human Molecular Genetics 10: 1591–1600.

De Baere E, Beysen D, Oley C et al. (2003) FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype–phenotype correlation. American Journal of Human Genetics 72: 478–487.

De Baere E, Lemercier B, Christin-Maitre S et al. (2002) FOXL2 mutation screening in a large panel of POF patients and XX males. Journal of Medical Genetics 7–10.

Bahi‐Buisson N, Nectoux J, Girard B et al. (2010) Revisiting the phenotype associated with FOXG1 mutations: two novel cases of congenital Rett variant. Neurogenetics 11: 241–249.

Bamforth JS, Hughest IA, Lazarust JH, Weavert CM and Harper PS (1989) Congenital hypothyroidism, spiky hair and cleft palate. Journal of Medical Genetics 26: 49–60.

Baris I, Arisoy AE, Smith A et al. (2006) A novel missense mutation in human TTF‐2 (FKHL15) gene associated with congenital hypothyroidism but not athyreosis. Journal of Clinical Endocrinology and Metabolism 91: 4183–4187.

Batista F, Vaiman D, Dausset J, Fellous M and Veitia RA (2007) Potential targets of FOXL2, a transcription factor involved in craniofacial and follicular development, identified by transcriptomics. Proceedings of the National Academy of Sciences of the USA 104: 3330–3335.

Benayoun A, Caburet S and Veitia RA (2011) Forkhead transcription factors: key players in health and disease. Trends in Genetics 27: 224–232.

Benayoun BA, Caburet S, Dipietromaria A et al. (2010) Functional exploration of the adult ovarian granulosa cell tumor‐associated somatic FOXL2 mutation p.Cys134Trp (c.402C>G). PloS One 5: e8789.

Bennett CL, Christie J and Ramsdell F et al. (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X‐linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genetics 27: 20–21.

Bennett CL and Ochs HD (2001) IPEX is a unique X‐linked syndrome characterized by immune dysfunction, polyendocrinopathy, enteropathy, and a variety of autoimmune phenomena. Current Opinion in Pediatrics 13: 533–538.

Beysen D, Moumné L, Veitia R et al. (2008) Missense mutations in the forkhead domain of FOXL2 lead to subcellular mislocalization, protein aggregation and impaired transactivation. Human Molecular Genetics 17: 2030–2038.

Beysen D, Raes J, Leroy BP et al. (2005) Deletions involving long‐range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease‐causing mechanism in blepharophimosis syndrome. American Journal of Human Genetics 77: 205–218.

Blixt Å, Mahlapuu M, Aitola M et al. (2000) A forkhead gen, FoxE3, is essential for lens epithelial proliferation and closure of the lens vesicle. Genes and Development 14: 245–254.

Bodega B, Porta C, Crosignani PG, Ginelli E and Marozzi A (2004) Mutations in the coding region of the FOXL2 gene are not a major cause of idiopathic premature ovarian failure. Molecular Human Reproduction 10: 555–557.

Bourguignon C, Li J and Papalopulu N (1998) XBF‐1, a winged helix transcription factor with dual activity, has a role in positioning neurogenesis in Xenopus competent ectoderm. Development 125: 4889–4900.

Brent MM, Anand R and Marmorstein R (2008) Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification. Structure 16: 1407–1416.

Caburet S, Demarez A, Moumné L et al. (2004) A recurrent polyalanine expansion in the transcription factor FOXL2 induces extensive nuclear and cytoplasmic protein aggregation. Journal of Medical Genetics 41: 932–936.

Carlsson P and Mahlapuu M (2002) Forkhead transcription factors: key players in development and metabolism. Developmental Biology 23: 1–23.

Carr CW, Moreno-De-Luca D, Parker C et al. (2010) Chiari I malformation, delayed gross motor skills, severe speech delay, and epileptiform discharges in a child with FOXP1 haploinsufficiency. European Journal of Human Genetics 18: 1216–1220.

Castanet M, Park SM, Smith A et al. (2002) A novel loss‐of‐function mutation in TTF‐2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate. Human Molecular Genetics 11: 2051–2059.

Castanet M and Polak M (2010) Spectrum of human Foxe1/TTF2 mutations. Hormone Research in Paediatrics 73: 423–429.

Castrillon DH, Miao L, Kollipara R, Horner JW and DePinho RA (2003) Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a. Science 301: 215–218.

Cederberg A, Gronning LM, Ahren B et al. (2001) FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet‐induced insulin resistance. Cell 106: 563–573.

Chanda B, Asai-Coakwell M, Ye M et al. (2008) A novel mechanistic spectrum underlies glaucoma‐associated chromosome 6p25 copy number variation. Human Molecular Genetics 17: 3446–3458.

Chatterjee S, Modi D, Maitra A et al. (2007) Screening for FOXL2 gene mutations in women with premature ovarian failure. Reproductive BioMedicine Online 15: 554–562.

Clark KL, Halay ED, Lai E and Burley SK (1993) Co‐crystal structure of the HNF‐3/fork head DNA‐recognition motif resembles histone H5. Nature 364: 412–420.

Clifton‐Bligh RJ, Wentworth JM, Heinz P et al. (1998) Mutation of the gene encoding human TTF‐2 associated with thyroid agenesis, cleft palate and choanal atresia. Nature Genetics 19: 399–401.

Crisponi L, Deiana M, Loi A et al. (2001) The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nature Genetics 27: 159–166.

Crisponi L, Uda M, Deiana M et al. (2004) FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long‐range regulatory sequences. Genomics 83: 757–764.

Cunningham MA, Zhu Q and Hammond JM (2004) FoxO1a can alter cell cycle progression by regulating the nuclear localization of p27kip in granulosa cells. Molecular Endocrinology 18: 1756–1767.

Dastidar SG, Landrieu PMZ and D'Mello SR (2011) FoxG1 promotes the survival of postmitotic neurons. Journal of Neuroscience 31: 402–413.

Decock CE, Claerhout I, Leroy BP et al. (2011) Correction of the lower eyelid malpositioning in the blepharophimosis‐ptosis‐epicanthus inversus syndrome. Ophthalmic Plastic and Reconstructive Surgery 27: 368–370.

Delahaye A, Khung-Savatovsky S, Aboura A et al. (2012) Pre‐ and postnatal phenotype of 6p25 deletions involving the FOXC1 gene. American Journal of Medical Genetics Part A 158A: 2430–2438.

Dipietromaria A, Benayoun BA, Todeshini AL et al. (2009) Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems. Human Molecular Genetics 18: 3324–3333.

D'Angelo E, Mosos A, Nakayama D et al. (2011) Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary. Modern Pathology 24: 1360–1367.

D'haene B, Attanasio C, Beysen D et al. (2009) Disease‐causing 7.4 kb cis‐regulatory deletion disrupting conserved non‐coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening. PLoS Genetics 5: e1000522.

D'haene B, Meire F, Claerhout I et al. (2011) Expanding the spectrum of FOXC1 and PITX2 mutations and copy number changes in patients with anterior segment malformations. Investigative Ophthalmology and Visual Science 52: 324–333.

D'haene B, Nevado J, Pugeat M et al. (2010) FOXL2 copy number changes in the molecular pathogenesis of BPES: unique cohort of 17 deletions. Human Mutation 31: E1332–E1347.

Fang J, Dagenais SL, Erickson RP et al. (2000) Mutations in FOXC2 (MFH‐1), a forkhead family transcription factor, are responsible for the hereditary lymphedema‐distichiasis syndrome. American Journal of Human Genetics 67: 1382–1388.

Feuk L, Kalervo A, Lipsanen-Nyman M et al. (2006) Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. American Journal of Human Genetics 79: 965–972.

Fisher SE and Scharff C (2009) FOXP2 as a molecular window into speech and language. Trends in Genetics 25: 166–177.

Fisher SE, Vargha‐Khadem F, Watkins KE, Monaco AP and Pembrey ME (1998) Localisation of a gene implicated in a severe speech and language disorder. Nature Genetics 168–170.

Flanagan SP (1966) Nude, a new hairless gene with pleiotropic effects in the mouse. Genetics Research 8: 295–309.

Gallardo TD, John GB, Bradshaw K et al. (2008) Sequence variation at the human FOXO3 locus: a study of premature ovarian failure and primary amenorrhea. Human Reproduction 23: 216–221.

Gersak K, Harris SE, Smale WJ and Shelling AN (2004) A novel 30 bp deletion in the FOXL2 gene in a phenotypically normal woman with primary amenorrhoea: case report. Human Reproduction 19: 2767–2770.

Gershon R, Aviel-Ronen S, Korach J et al. (2011) FOXL2 C402G mutation detection using MALDI‐TOF‐MS in DNA extracted from Israeli granulosa cell tumors. Gynecologic Oncology 122: 580–584.

Hamdan FF, Daoud H, Rochefort D et al. (2010) De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment. American Journal of Human Genetics 87: 671–678.

Hanashima C, Li SC, Shen L, Lai E and Fishell G (2004) Foxg1 suppresses early cortical cell fate. Science 303: 56–59.

Hanashima C, Shen L, Li SC and Lai E (2002) Brain factor‐1 controls the proliferation and differentiation of neocortical progenitor cells through independent mechanisms. Journal of Neuroscience 22: 6526–6536.

Harbuz R, Lespinasse J, Boulet S et al. (2010) Identification of new FOXP3 mutations and prenatal diagnosis of IPEX syndrome. Prenatal Diagnosis 30: 1072–1078.

Harris SE, Chand AL, Winship IM et al. (2002) Identification of novel mutations in FOXL2 associated with premature ovarian failure. Molecular Human Reproduction 8: 729–733.

Hes O, Vaněček T, Petersson F et al. (2011) Mutational analysis (c.402C>G) of the FOXL2 gene and immunohistochemical expression of the FOXL2 protein in testicular adult type granulosa cell tumors and incompletely differentiated sex cord stromal tumors. Applied Immunohistochemistry and Molecular Morphology 19: 347–351.

Hoodless PA,Pye M, Chazaud C et al. (2001) FoxH1 (Fast) functions to specify the anterior primitive streak in the mouse. Genes and Development 15: 1257–1271.

Horn D, Kapeller J, Rivera-Brugués N et al. (2010) Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits. Human Mutation 31: E1851–E1860.

Iida K, Koseki H, Kakinuma H et al. (1997) Essential roles of the winged helix transcription factor MFH‐1 in aortic arch patterning and skeletogenesis. Development 124: 4627–4638.

Iseri SU, Osborne RJ, Farrall M et al. (2009) Seeing clearly: the dominant and recessive nature of FOXE3 in eye developmental anomalies. Human Mutation 30: 1378–1386.

Jamieson S, Butzow R, Andersson N et al. (2010) The FOXL2 C134W mutation is characteristic of adult granulosa cell tumors of the ovary. Modern Pathology 23: 1477–1485.

Kaestner KH, Knöchel W, Martínez DE, Kno W and Martı DE (2000) Unified nomenclature for the winged helix/forkhead transcription factors. Genes and development 14: 142–146.

Katoh M, Igarashi M, Fukuda H, Nakagama H and Katoh M (2013) Cancer genetics and genomics of human FOX family genes. Cancer Letters 328: 198–206.

Kim J‐H, Yoon S, Park M et al. (2011) Differential apoptotic activities of wild‐type FOXL2 and the adult‐type granulosa cell tumor‐associated mutant FOXL2 (C134W). Oncogene 30: 1653–1663.

Kim MS, Hur SY, Yoo NJ and Lee SH (2010) Mutational analysis of FOXL2 codon 134 in granulosa cell tumour of ovary and other human cancers. Journal of Pathology 221: 147–152.

Kloss BAV, Reis LM, Brémond‐Gignac D, Glaser T and Semina EV (2012) Analysis of FOXD3 sequence variation in human ocular disease. Molecular Vision 18: 1740–1749.

Kume T, Deng K and Hogan BL (2000) Murine forkhead/winged helix genes Foxc1 (Mf1) and Foxc2 (Mfh1) are required for the early organogenesis of the kidney and urinary tract. Development 127: 1387–1395.

Kume T, Deng K and Hogan BLM (2000) Minimal phenotype of mice homozygous for a null mutation in the forkhead/winged minimal phenotype of mice homozygous for a null mutation in the forkhead/winged helix gene, Mf2. Molecular and Cellular Biology 20: 1419–1425.

Kume T, Deng KY, Winfrey V et al. (1998) The forkhead/winged helix gene Mf1 is disrupted in the pleiotropic mouse mutation congenital hydrocephalus. Cell 93: 985–996.

Kume T, Jiang H, Topczewska JM and Hogan BLM (2001) The murine winged helix transcription factors, Foxc1 and Foxc2, are both required for cardiovascular development and somitogenesis. Genes and Development 15: 2470–2482.

Lai CS, Fisher SE, Hurst JA et al. (2000) The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder. American Journal of Human Genetics 67: 357–368.

Lai CS, Fisher SE, Hurst JA, Vargha‐Khadem F and Monaco AP (2001) A forkhead‐domain gene is mutated in a severe speech and language disorder. Nature 413: 519–523.

Laissue P, Lakhal B, Benayoun BA et al. (2009) Functional evidence implicating FOXL2 in non‐syndromic premature ovarian failure and in the regulation of the transcription factor OSR2. Journal of Medical Genetics 46: 455–457.

Lehmann OJ, Ebenezer ND, Ekong R et al. (2002) Ocular developmental abnormalities and glaucoma associated with interstitial 6p25 duplications and deletions. Investigative Ophthalmology and Visual Science 43: 1843–1849.

Lehmann OJ, Ebenezer ND, Jordan T et al. (2000) Chromosomal duplication involving the forkhead transcription factor gene FOXC1 causes iris hypoplasia and glaucoma. American Journal of Human Genetics 67: 1129–1135.

Lehmann OJ, Sowden JC, Carlsson P, Jordan T and Bhattacharya SS (2003) Fox's in development and disease. Trends in Genetics 19: 339–344.

Le Lay J and Kaestner KH (2010) The Fox genes in the liver: from organogenesis to functional integration. Physiological Reviews 90: 1–22.

Lennon PA, Cooper ML, Peiffer DA et al. (2007) Deletion of 7q31. 1 supports involvement of FOXP2 in language impairment: clinical report and review. American Journal of Medical Genetics 143: 791–798.

MacDermot KD, Bonora E, Sykes N et al. (2005) Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. American Journal of Human Genetics 76: 1074–1080.

McMurchy AN, Gillies J, Allan SE et al. (2010) Point mutants of forkhead box P3 that cause immune dysregulation, polyendocrinopathy, enteropathy, X‐linked have diverse abilities to reprogram T cells into regulatory T cells. Journal of Allergy and Clinical Immunology 126: 1242–1251.

Mears AJ, Jordan T, Mirzayans F et al. (1998) Mutations of the forkhead/winged‐helix gene, FKHL7, in patients with Axenfeld–Rieger anomaly. American Journal of Human Genetics 63: 1316–1328.

Mencarelli MA, Spanhol-Rosseto A, Artuso R et al. (2010) Novel FOXG1 mutations associated with the congenital variant of Rett syndrome. Journal of Medical Genetics 47: 49–53.

Meng T, Shi JY, Wu M et al. (2012) Overexpression of mouse TTF‐2 gene causes cleft palate. Journal of Cellular and Molecular Medicine 16: 2362–2368.

Miranda J, Rocha G, Soares P et al. (2013) A novel mutation in FOXF1 Gene associated with alveolar capillary dysplasia with misalignment of pulmonary veins, intestinal malrotation and annular pancreas. Neonatology 103: 241–245.

Mirzayans F, Gould DB, Héon E et al. (2000) Axenfeld–Rieger syndrome resulting from mutation of the FKHL7 gene on chromosome 6p25. European Journal of Human Genetics 8: 71–74.

Moreno LM, Mansilla MA, Bullard SA et al. (2009) FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate. Human Molecular Genetics 18: 4879–4896.

Moumne L, Fellous M and Veitia RA (2005) Deletions in the polyAlanine‐containing transcription factor FOXL2 lead to intranuclear aggregation. Human Molecular Genetics 14: 3557–3564.

Murphy DB, Wiese S, Burfeind P et al. (1994) Human brain factor 1, a new member of the forkhead gene family. Genomics 21: 551–557.

Myatt SS and Lam EW (2007) The emerging roles of forkhead box (Fox) proteins in cancer. Nature Reviews Cancer 7: 847–859.

Myers AK, Perroni L, Costigan C and Reardon W (2006) Clinical and molecular findings in IPEX syndrome. Archives of Disease in Childhood 91: 63–64.

Nehls M, Pfeifer D, Schorpp M, Hedrich H and Boehm T (1994) New member of the winged‐helix protein family disrupted in mouse and rat nude mutations. Nature 372: 103–107.

Newbury DF and Monaco AP (2010) Genetic advances in the study of speech and language disorders. Neuron 68: 309–320.

Ni F, Wen Q, Wang B et al. (2010) Mutation analysis of FOXL2 gene in Chinese patients with premature ovarian failure. Gynecological Endocrinology 26: 246–249.

Nishimura DY Swiderski RE, Alward WL et al. (1998) The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nature Genetics 19: 140–147.

Nishimura DY, Searby CC, Alward WL et al. (2001) A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. American Journal of Human Genetics 68: 364–372.

Obsil T and Obsilova V (2008) Structure/function relationships underlying regulation of FOXO transcription factors. Oncogene 27: 2263–2275.

O'Roak BJ, Deriziotis P, Lee C et al. (2011) Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nature Genetics 43: 585–589.

Ottolenghi C, Omari S, Garcia-Ortiz JE et al. (2005) Foxl2 is required for commitment to ovary differentiation. Human Molecular Genetics 14: 2053–2062.

Pailhoux E, , Vigier B, Chaffaux S et al. (2001) A 11.7‐kb deletion triggers intersexuality and polledness in goats. Nature Genetics 29: 453–458.

Palka C, Alfonsi M, Mohn A et al. (2012) Mosaic 7q31 deletion involving FOXP2 gene associated with language impairment. Pediatrics 129: e183–e188.

Pariani MJ, Spencer A, Graham JM and Rimoin DL (2009) A 785 kb deletion of 3p14.1p13, including the FOXP1 gene, associated with speech delay, contractures, hypertonia and blepharophimosis. European Journal of Medical Genetics 52: 123–127.

Parris T, Nik AM, Kotecha S et al. (2013) Inversion upstream of FOXF1 in a case of lethal alveolar capillary dysplasia with misalignment of pulmonary veins. American Journal of Medical Genetics Part A doi:10.1002/ajmg.a.35832

Partridge L and Brüning JC (2008) Forkhead transcription factors and ageing. Oncogene 27: 2351–2363.

Philippe C, Amsallem D, Francannet C et al. (2010) Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females. Journal of Medical Genetics 47: 59–65.

Pignata C, Fiore M, Guzzetta V et al. (1996) Congenital alopecia and nail dystrophy associated with severe functional T‐cell immunodeficiency in two sibs. American Journal of Medical Genetics 65: 167–170.

Reis LM, Tyler RC, Schneider A et al. (2010) FOXE3 plays a significant role in autosomal recessive microphthalmia. American Journal of Medical Genetics Part A 152A: 582–590.

Reis LM, Tyler RC, Volkmann Kloss BA et al. (2012) PITX2 and FOXC1 spectrum of mutations in ocular syndromes. European Journal of Human Genetics 20: 1224–1233.

Rice GM, Raca G, Jakielski KJ et al. (2012) Phenotype of FOXP2 haploinsufficiency in a mother and son. American Journal of Medical Genetics Part A 158A: 174–181.

Sanyal S and Hawkins RK (1979) Dysgenetic lens (dyl) – a new gene in the mouse. Investigative Ophthalmology and Visual Science 18: 642–645.

Schlade‐Bartusiak K, Brown L, Lomax B et al. (2012) BPES with atypical premature ovarian insufficiency, and evidence of mitotic recombination, in a woman with trisomy X and a translocation t(3;11)(q22.3;q14.1). American Journal of Medical Genetics Part A 158A: 2322–2327.

Schmidt D, Ovitt CE, Anlag K et al. (2004) The murine winged‐helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development 131: 933–942.

Schrader KA, Gorbatcheva B, Senz J et al. (2009) The specificity of the FOXL2 c.402C>G somatic mutation: a survey of solid tumors. PloS One 4: e7988.

Semina EV, Brownell I, Mintz‐Hittner HA, Murray JC and Jamrich M (2001) Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts. Human Molecular Genetics 10: 231–236.

Sen P, Gerychova R, Janku P et al. (2013) A familial case of alveolar capillary dysplasia with misalignment of pulmonary veins supports paternal imprinting of FOXF1 in human. European Journal of Human Genetics 21: 474–477.

Shah SP, Köbel M, Senz J et al. (2009) Mutation of FOXL2 in granulosa‐cell tumors in the ovary. New England Journal of Medicine 360: 2719–2729.

Sheffield VC, Nishimura DY, Kanis AB et al. (1999) Gene dosage of the FKHL7 gene causes defects of the anterior chamber of the eye. Investigative Ophthalmology and Visual Science 40: 3127.

Shriberg LD, Ballard KJ, Tomblin JB et al. (2006) Speech, prosody, and voice characteristics of a mother and daughter with a 7;13 translocation affecting FOXP2. Journal of Speech, Language, and Hearing Research 49: 500–525.

Smith RS, Zabaleta A, Kume T et al. (2000) Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development. Human Molecular Genetics 9: 1021–1032.

Stankiewicz P, Sen P, Bhatt SS et al. (2009) Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. American Journal of Human Genetics 84: 780–791.

Talkowski ME, Rosenfeld JA, Blumenthal I et al. (2012) Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell 149: 525–537.

Tao W and Lai E (1992) Telencephalon‐restricted expression of BF‐1, a new member of the HNF‐3/fork head gene family, in the developing rat brain. Neuron 8: 957–966.

Todeschini A, Dipietromaria A, L'hôte D et al. (2011) Mutational probing of the forkhead domain of the transcription factor FOXL2 provides insights into the pathogenicity of naturally occurring mutations. Access 1–10. doi:10.1093/hmg/ddr244

Tomblin JB, O'Brien M, Shriberg LD et al. (2009) Language features in a mother and daughter of a chromosome 7;13 translocation involving FOXP2. Journal of Speech, Language, and Hearing Research 52: 1157–1175.

Torgerson TR, Linane A, Moes N et al. (2007) Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene. Gastroenterology 132: 1705–1717.

Tümer Z and Bach‐Holm D (2009) Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations. European Journal of Human Genetics 17: 1527–1539.

Uda M, Ottolenghi C, Crisponi L et al. (2004) Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development. Human Molecular Genetics 13: 1171–1181.

Uhlenhaut NH, Jakob S, Anlag K et al. (2009) Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell 139: 1130–1142.

Valleix S, Niel F, Nedelec B et al. (2006) Homozygous nonsense mutation in the FOXE3 gene as a cause of congenital primary aphakia in humans. American Journal of Human Genetics 79: 358–364.

Vargha‐Khadem F, Watkins K, Alcock K, Fletcher P and Passingham R (1995) Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder. Proceedings of the National Academy of Sciences of the USA 92: 930–933.

Verdin H, D'haene B, Beysen D et al. (2013) Microhomology‐mediated mechanisms underlie non‐recurrent disease‐causing microdeletions of the FOXL2 gene or its regulatory domain. PLoS Genetics 9: e1003358.

Verdin H and De Baere E (2012) FOXL2 impairment in human disease. Hormone Research in Paediatrics 77: 2–11.

Vernes SC, MacDermot KD, Monaco AP and Fisher SE (2009) Assessing the impact of FOXP1 mutations on developmental verbal dyspraxia. European Journal of Human Genetics 17: 1354–1358.

Vigliano I, Gorrese M, Fusco A et al. (2011) FOXN1 mutation abrogates prenatal T‐cell development in humans. Journal of Medical Genetics 48: 413–416.

De Vos M, Devroey P and Fauser BCJM (2010) Primary ovarian insufficiency. Lancet 376: 911–921.

Wang F, Marshall CB, Yamamoto K et al. (2008) Biochemical and structural characterization of an intramolecular interaction in FOXO3a and its binding with p53. Journal of Molecular Biology 384: 590–603.

Wang B, Mu Y, Ni F et al. (2010) Analysis of FOXO3 mutation in 114 Chinese women with premature ovarian failure. Reproductive Biomedicine Online 20: 499–503.

Watkins WJ, Umbers AJ, Woad KJ et al. (2006) Mutational screening of FOXO3A and FOXO1A in women with premature ovarian failure. Fertility and Sterility 86: 1518–1521.

Weigel D and Jackle H (1990) The fork head domain: a novel DNA binding motif of eukaryotic transcription factors. Cell 63: 455–456.

Weigel D, Jürgens G, Küttner F, Seifert E and Jäckle H (1989) The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo. Cell 57: 645–658.

Winnier GE, Kume T, Deng K et al. (1999) Roles for the winged helix transcription factors MF1 and MFH1 in cardiovascular development revealed by nonallelic noncomplementation of null alleles. Developmental Biology 213: 418–431.

Witte MH, Erickson RP, Khalil M et al. (2009) Lymphedema–distichiasis syndrome without FOXC2 mutation: evidence for chromosome 16 duplication upstream of FOXC2. Lymphology 42: 152–160.

Wotton KR and Shimeld SM (2006) Comparative genomics of vertebrate Fox cluster loci. BMC Genomics 7: 271.

Xuan S, Baptista CA, Balas G et al. (1995) Winged helix transcription factor BF‐1 is essential for the development of the cerebral hemispheres. Neuron 14: 1141–1152.

Yamamoto M, Meno C, Sakai Y, Shiratori H and Mochida K (2001) The transcription factor FoxH1 (FAST) mediates nodal signaling during anterior‐posterior patterning and node formation in the mouse. Genes and Development 15: 1242–1256.

Zeesman S, Nowaczyk MJ, Teshima I et al. (2006) Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2. American Journal of Medical Genetics 140: 509–514.

Zilina O, Reimand T, Zjablovskaja P et al. (2012) Maternally and paternally inherited deletion of 7q31 involving the FOXP2 gene in two families. American Journal of Medical Genetics Part A 158A: 254–256.

Further Reading

Katoh M, Igarashi M, Fukuda H, Nakagama H and Katoh M (2013) Cancer genetics and genomics of human FOX family genes. Cancer Letters 328: 198–206.

Lehmann OJ, Sowden JC, Carlsson P, Jordan T and Bhattacharya SS (2003) Fox's in Development and Disease. Trends in Genetics 19(6): 339–344.

Patridge L and Brüning JC (2008) Forkhead transcription factors and ageing. Oncogene 28: 2351–2363.

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Baetens, Dorien, Verdin, Hannah, Cools, Martine, and De Baere, Elfride(Sep 2013) Forkhead Transcription Factors in Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024256]