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Gene Review

FOXE1  -  forkhead box E1

Homo sapiens

Synonyms: FKHL15, FOXE2, Forkhead box protein E1, Forkhead box protein E2, Forkhead-related protein FKHL15, ...
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Disease relevance of FOXE1

  • FOXE1 is associated with two forms of nonsyndromic orofacial clefting: 1) cleft lip with or without cleft palate and 2) Isolated cleft palate. [1]
  • A genome wide association study identified significant association of several SNPs near FOXE1 and thyroid cancer. [2]
  • A second study replicated FOXE1 association with thyroid cancer showing increased risk for a specific haplotype containing rs1867277 that is subsequently shown, using in vitro experiments, to alter transcription activity [3]. It is possible that this variant is causal for increased risk for thyroid cancer, however there may be additional variants on the same haplotype with functional qualities. In vivo studies will be necessary to definitively link cause and effect for this variant.
  • FOXE1 expression is also found in basal keratinocytes of the human epidermis and basal cell carcinoma (BCC) [4].
  • Hitherto, two mutations in the human thyroid transcription factor 2 (TTF-2) gene have been described in unrelated cases of CH with cleft palate, spiky hair, variable choanal atresia, and complete thyroid agenesis [5].
  • FOXE1 gene mutation screening by multiplex PCR/DHPLC in CHARGE syndrome and syndromic and non-syndromic cleft palate [6].
  • A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate [7].
  • The map position of FKHL15 on 9q22 places the gene within the candidate regions for the cancer predisposition syndrome multiple self-healing squamous epitheliomata and the degenerative neurological disorder hereditary sensory neuropathy type I. This is a region frequently lost in squamous cell cancer [8].

Psychiatry related information on FOXE1


High impact information on FOXE1

  • Here we report that the transcription factor FKHL15 (ref. 11) is the human homologue of mouse TTF-2 (encoded by the Titf2 gene) and that two siblings with thyroid agenesis, cleft palate and choanal atresia are homozygous for a missense mutation (Ala65Val) within its forkhead domain [10].
  • Our findings provide a strong indication that the defect in Bamforth-Lazarus syndrome is due to altered FOXE1 function in the hair follicle, and is independent of systemic defects present in affected individuals [11].
  • Our observations support the role of TTF-2 in both thyroid and palate development but suggest phenotypic heterogeneity of this syndromic form of CH [7].
  • Two male siblings, born to consanguineous parents, presented with CH, athyreosis and cleft palate and were found to be homozygous for a mutation corresponding to a serine to asparagine substitution at codon 57 (S57N) in the forkhead DNA binding domain of TTF-2 [7].
  • Such incomplete loss of TTF-2 function may account for the absence of choanal atresia and bifid epiglottis in our patients, anomalies which were present together with CH and cleft palate in two other individuals with the only other, more deleterious, TTF-2 mutation (A65V) described previously [7].

Biological context of FOXE1


Anatomical context of FOXE1

  • Here, we describe a novel TTF-2 mutation in a female child resulting in syndromic CH in the absence of thyroid agenesis [5].
  • FOXE1 expression was detected in the oropharyngeal epithelium and thymus [9].
  • Production and application of polyclonal antibody to human thyroid transcription factor 2 reveals thyroid transcription factor 2 protein expression in adult thyroid and hair follicles and prepubertal testis [14].
  • Expression of HFKL5 in neurons is restricted to the fully differentiated neurons in fetal and adult brain as well as in the parasympathic ganglia of the small intestine [15].
  • Distribution of the titf2/foxe1 gene product is consistent with an important role in the development of foregut endoderm, palate, and hair [16].
  • In addition to the expression described above, we show that FOXE1 is expressed in the epithelium that will undergo fusion between the medial nasal and maxillary processes [1]

Associations of FOXE1 with chemical compounds

  • Results: The index case is homozygous for an arginine to cysteine mutation (R102C) of a highly conserved residue within the forkhead, DNA binding domain of TTF-2 [5].
  • The FKHL15 gene contains a region rich in alanine residues, frequently associated with transcriptional repression [8].

Regulatory relationships of FOXE1

  • We also studied the transcriptional activities of TITF2 by co-expressing the luciferase gene directed by the human thyroglobulin gene promoter [17].

Other interactions of FOXE1

  • These data point to a putative role of FOXE1 in mediating Hh signaling in the human epidermis downstream of GLI2 [4].
  • GLI family transcription factors then activate transcription of Hedgehog target genes, such as FOXE1 and FOXM1 encoding Forkhead-box transcription factors [18].
  • For the largest families, we likewise excluded a contribution of genes previously only associated with syndromic forms of RTSH, namely TITF1, GNAS, and FOXE1 [19].
  • Four girls with sporadic congenital hypothyroidism and hypoplastic thyroid glands were analyzed for mutations in PAX8 and TTF2 (FKHL15) [20].
  • TTF-1, TTF-2, Pax-8, Na-I symporter and thyroid peroxidase mRNA were detected [21].

Analytical, diagnostic and therapeutic context of FOXE1


  1. FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate. Moreno, L.M., Mansilla, M.A., Bullard, S.A., Cooper, M.E., Busch, T.D., Machida, J., Johnson, M.K., Brauer, D., Krahn, K., Daack-Hirsch, S., L'heureux, J., Valencia-Ramirez, C., Rivera, D., López, A.M., Moreno, M.A., Hing, A., Lammer, E.J., Jones, M., Christensen, K., Lie, R.T., Jugessur, A., Wilcox, A.J., Chines, P., Pugh, E., Doheny, K., Arcos-Burgos, M., Marazita, M.L., Murray, J.C., Lidral, A.C. Hum. Mol. Genet. (2009) [Pubmed]
  2. Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Gudmundsson, J., Sulem, P., Gudbjartsson, D.F., Jonasson, J.G., Sigurdsson, A., Bergthorsson, J.T., He, H., Blondal, T., Geller, F., Jakobsdottir, M., Magnusdottir, D.N., Matthiasdottir, S., Stacey, S.N., Skarphedinsson, O.B., Helgadottir, H., Li, W., Nagy, R., Aguillo, E., Faure, E., Prats, E., Saez, B., Martinez, M., Eyjolfsson, G.I., Bjornsdottir, U.S., Holm, H., Kristjansson, K., Frigge, M.L., Kristvinsson, H., Gulcher, J.R., Jonsson, T., Rafnar, T., Hjartarsson, H., Mayordomo, J.I., de la Chapelle, A., Hrafnkelsson, J., Thorsteinsdottir, U., Kong, A., Stefansson, K. Nat. Genet. (2009) [Pubmed]
  3. The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors. Landa, I., Ruiz-Llorente, S., Montero-Conde, C., Inglada-Pérez, L., Schiavi, F., Leskelä, S., Pita, G., Milne, R., Maravall, J., Ramos, I., Andía, V., Rodríguez-Poyo, P., Jara-Albarrán, A., Meoro, A., del Peso, C., Arribas, L., Iglesias, P., Caballero, J., Serrano, J., Picó, A., Pomares, F., Giménez, G., López-Mondéjar, P., Castello, R., Merante-Boschin, I., Pelizzo, M.R., Mauricio, D., Opocher, G., Rodríguez-Antona, C., González-Neira, A., Matías-Guiu, X., Santisteban, P., Robledo, M. PLoS. Genet. (2009) [Pubmed]
  4. FOXE1, a new transcriptional target of GLI2 is expressed in human epidermis and basal cell carcinoma. Eichberger, T., Regl, G., Ikram, M.S., Neill, G.W., Philpott, M.P., Aberger, F., Frischauf, A.M. J. Invest. Dermatol. (2004) [Pubmed]
  5. A Novel Missense Mutation in Human TTF-2 (FKHL15) Gene Associated with Congenital Hypothyroidism But Not Athyreosis. Baris, I., Arisoy, A.E., Smith, A., Agostini, M., Mitchell, C.S., Park, S.M., Halefoglu, A.M., Zengin, E., Chatterjee, V.K., Battaloglu, E. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  6. FOXE1 gene mutation screening by multiplex PCR/DHPLC in CHARGE syndrome and syndromic and non-syndromic cleft palate. Venza, M., Visalli, M., Venza, I., Torino, C., Saladino, R., Teti, D. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. (2006) [Pubmed]
  7. A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate. Castanet, M., Park, S.M., Smith, A., Bost, M., Léger, J., Lyonnet, S., Pelet, A., Czernichow, P., Chatterjee, K., Polak, M. Hum. Mol. Genet. (2002) [Pubmed]
  8. FKHL15, a new human member of the forkhead gene family located on chromosome 9q22. Chadwick, B.P., Obermayr, F., Frischauf, A.M. Genomics (1997) [Pubmed]
  9. PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations. Trueba, S.S., Augé, J., Mattei, G., Etchevers, H., Martinovic, J., Czernichow, P., Vekemans, M., Polak, M., Attié-Bitach, T. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  10. Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Clifton-Bligh, R.J., Wentworth, J.M., Heinz, P., Crisp, M.S., John, R., Lazarus, J.H., Ludgate, M., Chatterjee, V.K. Nat. Genet. (1998) [Pubmed]
  11. Requirement of the forkhead gene Foxe1, a target of sonic hedgehog signaling, in hair follicle morphogenesis. Brancaccio, A., Minichiello, A., Grachtchouk, M., Antonini, D., Sheng, H., Parlato, R., Dathan, N., Dlugosz, A.A., Missero, C. Hum. Mol. Genet. (2004) [Pubmed]
  12. Thyroid transcription factor-2 gene expression in benign and malignant thyroid lesions. Sequeira, M.J., Morgan, J.M., Fuhrer, D., Wheeler, M.H., Jasani, B., Ludgate, M. Thyroid (2001) [Pubmed]
  13. Cloning, chromosomal localization and identification of polymorphisms in the human thyroid transcription factor 2 gene (TITF2). Macchia, P.E., Mattei, M.G., Lapi, P., Fenzi, G., Di Lauro, R. Biochimie (1999) [Pubmed]
  14. Production and application of polyclonal antibody to human thyroid transcription factor 2 reveals thyroid transcription factor 2 protein expression in adult thyroid and hair follicles and prepubertal testis. Sequeira, M., Al-Khafaji, F., Park, S., Lewis, M.D., Wheeler, M.H., Chatterjee, V.K., Jasani, B., Ludgate, M. Thyroid (2003) [Pubmed]
  15. The novel human HNF-3/fork head-like 5 gene: chromosomal localization and expression pattern. Wiese, S., Emmerich, D., Schröder, B., Murphy, D.B., Grzeschik, K.H., Van Kessel, A.G., Thies, U. DNA Cell Biol. (1997) [Pubmed]
  16. Distribution of the titf2/foxe1 gene product is consistent with an important role in the development of foregut endoderm, palate, and hair. Dathan, N., Parlato, R., Rosica, A., De Felice, M., Di Lauro, R. Dev. Dyn. (2002) [Pubmed]
  17. Polymorphism of the polyalanine tract of thyroid transcription factor-2 gene in patients with thyroid dysgenesis. Hishinuma, A., Ohyama, Y., Kuribayashi, T., Nagakubo, N., Namatame, T., Shibayama, K., Arisaka, O., Matsuura, N., Ieiri, T. Eur. J. Endocrinol. (2001) [Pubmed]
  18. Identification and characterization of rat Desert hedgehog and Indian hedgehog genes in silico. Katoh, Y., Katoh, M. Int. J. Oncol. (2005) [Pubmed]
  19. Autosomal dominant resistance to thyrotropin as a distinct entity in five multigenerational kindreds: clinical characterization and exclusion of candidate loci. Grasberger, H., Mimouni-Bloch, A., Vantyghem, M.C., van Vliet, G., Abramowicz, M., Metzger, D.L., Abdullatif, H., Rydlewski, C., Macchia, P.E., Scherberg, N.H., van Sande, J., Mimouni, M., Weiss, R.E., Vassart, G., Refetoff, S. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  20. A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: evidence for phenotypic variability in mother and child. Congdon, T., Nguyen, L.Q., Nogueira, C.R., Habiby, R.L., Medeiros-Neto, G., Kopp, P. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  21. A case of primary mucoepidermoid carcinoma of the thyroid: molecular evidence of its origin. Minagawa, A., Iitaka, M., Suzuki, M., Yasuda, S., Kameyama, K., Shimada, S., Kitahama, S., Wada, S., Katayama, S. Clin. Endocrinol. (Oxf) (2002) [Pubmed]
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