FOXE1 (forkhead box E1 (thyroid transcription factor 2))

2010-05-01   Isabella Venza , Maria Visalli , Diana Teti , Mario Venza 

Identity

HGNC
LOCATION
9q22.33
LOCUSID
ALIAS
FKHL15,FOXE2,HFKH4,HFKL5,NMTC4,TITF2,TTF-2,TTF2

DNA/RNA

Atlas Image
Schematic diagram of the human FOXE1 gene.

Description

The gene consists of 1 exon and is intronless; the 5 and the 3 parts of the exon are non-coding.

Transcription

3461 bp transcript with a 1121 bp of coding sequence.

Proteins

Atlas Image
Diagrammatic representation of the functional domains of human FOXE1 protein.

Description

The FOXE1 protein is 373-amino acid long and its molecular weight is 42 kDa. It contains a forkhead DNA-binding domain, 2 putative nuclear localization signals (NLS) which flank the DNA-binding domain, and a polyalanine (polyA) stretch of variable length. Population-based studies found polymorphism of the polyA tract lengths varying from 11 to 19 residues with the 14 as the most frequent allele (Venza et al., 2006; Macchia et al., 1999; Hishinuma et al., 2001; Tonacchera et al., 2004; Santarpia et al., 2007; Carre et al., 2007).

Expression

In humans, FOXE1 is expressed at the embryonic Carnegie stage (CS) 15 in the thyroid primordium and persists in the thyroid gland throughout development. At the same embryonic stage, FOXE1 is also detectable in the thymus and in the oropharyngeal epithelium. At 11 weeks of development it is present in the tracheal and esophageal epithelium (Trueba et al., 2005).
In mice, FOXE1 is expressed at embryonic day E8.5 in the endoderm corresponding to the floor of the foregut, at E9.2-9.3 in the epithelium lining the anterior foregut and the posterior stomodeum, including the pharyngeal membrane, and in the migrating thyroid primordium and at E9.5 in the craniopharyngeal ectoderm involved in palate formation. Later, at E10.5 FOXE1 expression is transcribed along all the endoderm of the foregut lining the visceral pouch of the branchial arches (Zannini et al., 1997; Dathan et al., 2002).

Localisation

Nuclear.

Function

FOXE1 regulates the transcription of thyroglobulin (Tg) and thyroid peroxidase (TPO), and represses transcriptional activation of TTF-1 and PAX8 on the Tg and TPO promoters. The gene plays an important role in thyroid development, secondary palate closure and hair follicle morphogenesis. FOXE1 is also implicated in malignancy.

Homology

Member of the forkhead box E (FOXE) subfamily which itself is a part of the large FOX gene family of transcription factors, characterized by sharing a common 100 amino acid forkhead domain. FOXE proteins (FOXE-1, -2, -3, -4) are widely expressed in a range of tissues, have diverse roles in development and metabolism and have been implicated in various forms of cancer and disease.

Implicated in

Entity name
Thyroid carcinoma
Disease
Genome-wide association studies (GWAS) showed a significant correlation of the rs965513 variant located 57-kb upstream to FOXE1 with follicular thyroid carcinoma (FTC) (Gudmundsson et al., 2009) as well as with sporadic or radiation-related papillary thyroid carcinoma (PTC) (Gudmundsson et al., 2009; Takahashi et al., 2010). A detailed analysis of the PTC-risk conferring haplotype identified rs1867277 as a highly correlated putative functional variant within the FOXE1 promoter (Landa et al., 2009). Functional assays revealed that the rs1867277 G allele partially impairs the recruitment of USF1 and USF2 factors to the FOXE1 promoter and alters the expression status of the FOXE1 gene (Landa et al., 2009).
Entity name
Pancreatic cancer
Disease
Aberrant CpG methylation of FOXE1 was detected in pancreatic cancer cell lines and in a series of resected primary pancreatic carcinomas (Sato et al., 2003) as well as in familial and sporadic pancreatic adenocarcinoma specimens (Brune et al., 2008). FOXE1 was also prevalently methylated in the surgical pancreatic juice of patients with pancreatic ductal adenocarcinoma, less frequently in samples of intraductal papillary mucinous neoplasms, but never in patients with chronic pancreatitis (Matsubayashi et al., 2006).
Entity name
Breast cancer
Disease
DNA hypermethylation events in the CpG islands of FOXE1 promoter were present in plasma samples from breast cancer patients (Weisenberger et al., 2008).
Entity name
Cutaneous squamous cell carcinoma (SCC)
Disease
A higher frequency of FOXE1 promoter hypermethylation was found in cutaneous SCCs (55%), as compared with the adjacent uninvolved skin (12%) and blood control samples (9%). FOXE1 methylation was frequently seen in association with a complete absence or downregulation of gene expression. Treatment with the demethylating agent 5-Aza-2-deoxycytidine resulted in profound reactivation of FOXE1 expression (Venza et al., 2010a). It was also reported that expansions of the polyA tract (16 alanine) of FOXE1 predisposes to cutaneous SCC (Venza et al., 2010b).
Entity name
Bamforth-lazarus syndrome
Disease
Homozygous, human loss-of-function mutations located within the forkhead domain of FOXE1 (A65V, S57N and R72S) cause the Bamforth-Lazarus syndrome, which includes congenital hypothyroidism, cleft palate and spiky hair, with or without choanal atresia, bifid epiglottis, and ocular hypertelorism, depending on the severity of the mutation (Clifton-Bligh et al., 1998; Castanet et al., 2002; Baris et al., 2006). In vitro studies showed the complete lack of DNA binding and transcriptional activity of A65V (Clifton-Bligh et al., 1998) and R102C (Baris et al., 2006), and the partial preservation of function with the S57N (Castanet et al., 2002) mutant FOXE1 proteins, respectively.
Entity name
Non-syndromic cleft lip with or without cleft palate (NS CL/P)
Disease
Rare missense mutations in FOXE1 (A207V and D285V) have been associated with isolated clefting (Vieira et al., 2005). Fine-mapping association studies showed genome-wide significant SNPs in or near FOXE1 region (rs3758249, rs4460498, rs1443434, rs993501) in CLP patients (Marazita et al., 2009; Moreno et al., 2009). Recently, the novel homozygous polymorphism C(-1204)G in the FOXE1 promoter region that prevented the binding of MYF-5, a myogenic regulatory factor essential for the muscle-dependent craniofacial skeletal development and the fusion of primary and secondary palate, was found in non-syndromic CP patients (Venza et al., 2009).
Entity name
Premature ovarian failure (POF)
Disease
Variation in FOXE1 polyalanine length from the most frequently occurring 14 alanine allele to the 16 allele increases the risk of developing POF (Watkins et al., 2006).

Bibliography

Pubmed IDLast YearTitleAuthors
168827472006A novel missense mutation in human TTF-2 (FKHL15) gene associated with congenital hypothyroidism but not athyreosis.Baris I et al
190645682008Genetic and epigenetic alterations of familial pancreatic cancers.Brune K et al
177177072007Polymorphic length of FOXE1 alanine stretch: evidence for genetic susceptibility to thyroid dysgenesis.Carré A et al
121655662002A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate.Castanet M et al
96977051998Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia.Clifton-Bligh RJ et al
122037372002Distribution of the titf2/foxe1 gene product is consistent with an important role in the development of foregut endoderm, palate, and hair.Dathan N et al
191986132009Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations.Gudmundsson J et al
115809932001Polymorphism of the polyalanine tract of thyroid transcription factor-2 gene in patients with thyroid dysgenesis.Hishinuma A et al
197306832009The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.Landa I et al
104031721999Cloning, chromosomal localization and identification of polymorphisms in the human thyroid transcription factor 2 gene (TITF2).Macchia PE et al
195210982009Genome scan, fine-mapping, and candidate gene analysis of non-syndromic cleft lip with or without cleft palate reveals phenotype-specific differences in linkage and association results.Marazita ML et al
164240602006DNA methylation alterations in the pancreatic juice of patients with suspected pancreatic disease.Matsubayashi H et al
197790222009FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate.Moreno LM et al
173180172007TTF-2/FOXE1 gene polymorphisms in Sicilian patients with permanent primary congenital hypothyroidism.Santarpia L et al
128399672003Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays.Sato N et al
203509372010The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl.Takahashi M et al
153209692004Genetic analysis of TTF-2 gene in children with congenital hypothyroidism and cleft palate, congenital hypothyroidism, or isolated cleft palate.Tonacchera M et al
154944582005PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations.Trueba SS et al
199304422010Investigation into FOXE1 genetic variations in cutaneous squamous cell carcinoma.Venza I et al
191920462009Altered binding of MYF-5 to FOXE1 promoter in non-syndromic and CHARGE-associated cleft palate.Venza M et al
163278842005Medical sequencing of candidate genes for nonsyndromic cleft lip and palate.Vieira AR et al
164814062006An investigation into FOXE1 polyalanine tract length in premature ovarian failure.Watkins WJ et al
186282962008DNA methylation analysis by digital bisulfite genomic sequencing and digital MethyLight.Weisenberger DJ et al
92146351997TTF-2, a new forkhead protein, shows a temporal expression in the developing thyroid which is consistent with a role in controlling the onset of differentiation.Zannini M et al

Other Information

Locus ID:

NCBI: 2304
MIM: 602617
HGNC: 3806
Ensembl: ENSG00000178919

Variants:

dbSNP: 2304
ClinVar: 2304
TCGA: ENSG00000178919
COSMIC: FOXE1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000178919ENST00000375123O00358

Expression (GTEx)

0
50
100
150
200

References

Pubmed IDYearTitleCitations
191986132009Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations.134
163278842005Medical sequencing of candidate genes for nonsyndromic cleft lip and palate.70
197306832009The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.59
197306832009The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.59
197790222009FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate.57
197790222009FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate.57
203509372010The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl.56
203509372010The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl.56
224936912012Novel associations for hypothyroidism include known autoimmune risk loci.52
235121052013Confirming genes influencing risk to cleft lip with/without cleft palate in a case-parent trio study.39

Citation

Isabella Venza ; Maria Visalli ; Diana Teti ; Mario Venza

FOXE1 (forkhead box E1 (thyroid transcription factor 2))

Atlas Genet Cytogenet Oncol Haematol. 2010-05-01

Online version: http://atlasgeneticsoncology.org/gene/47197/foxe1