Alternative titles; symbols
HGNC Approved Gene Symbol: FOXE1
SNOMEDCT: 722375007;
Cytogenetic location: 9q22.33 Genomic coordinates (GRCh38): 9:97,853,226-97,856,717 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q22.33 | {Thyroid cancer, nonmedullary, 4} | 616534 | Autosomal dominant | 3 |
| Bamforth-Lazarus syndrome | 241850 | Autosomal recessive | 3 |
FOXE1 belongs to a large family of forkhead box (FOX) transcription factors with a conserved winged-helix DNA-binding domain (Venza et al., 2011).
The 'forkhead' gene family, originally identified in Drosophila, encodes transcription factors with a conserved 100-amino acid DNA-binding motif called the 'forkhead domain'. Chadwick et al. (1997) isolated FKHL15 cDNAs from a cDNA library enriched for transcripts from 9q22. The predicted 376-amino acid FKHL15 protein contains a 19-residue polyalanine tract and 2 putative nuclear localization signals which flank the forkhead domain. Northern blot analysis detected a single 4.5-kb FKHL15 mRNA in a variety of tissues and multiple FKHL15 transcripts in others.
Clifton-Bligh et al. (1998) found by a database search against the rat TTF2 gene more than 90% homology with FKHL15. A probe specific to the 3-prime UTR of FKHL15 detected a 5.3-kb transcript that was highly expressed in thyroid tissues, and a second 3.2-kb transcript seen in both thyroid and testis.
Clifton-Bligh et al. (1998) found that the FKHL15 gene consists of a single exon.
Chadwick et al. (1997) localized the FKHL15 gene to 9q22 by somatic cell hybrid analysis and by its inclusion in cosmids that map to that region.
Thyroid gland organogenesis involves the dorso-caudal migration of a median endodermal bud that originates from the posterior region of the pharyngeal floor. The thyroid primordium migrates to the area located between the fourth pharyngeal pouches and eventually fuses with them. The adult thyroid gland is composed of cells derived from all 3 germ layers, but thyroid follicular cells (TFCs), which are responsible for thyroid hormone biosynthesis, appear to derive primarily from the median primordium, though a contribution from the endoderm of the pharyngeal pouches has also been proposed (Manley and Capecchi, 1998). Functional differentiation, as shown by the expression of thyroglobulin, occurs in TFCs following migration, suggesting that migration and functional differentiation may be mutually exclusive. Three transcription factors, TTF1 (NKX2-1; 600635), TTF2, and PAX8 (167415), are present from the start of thyroid morphogenesis. TTF2, which is also expressed in most of the foregut endoderm, in the craniopharyngeal ectoderm involved in palate formation and in the Rathke pouch, is transiently expressed at these sites from embryonic day (E) 8-8.5 to E13.5. The mRNA encoding TTF2 is downregulated in TFC precursors following their migration and just before their differentiation (summary by De Felice et al., 1998). De Felice et al. (1998) reported that Zannini et al. (1997) suggested that TTF2 is involved either in promoting the migration process or in repressing differentiation of the TFCs until migration has occurred. Thus, De Felice et al. (1998) predicted that the absence of TTF2 would result in alteration of thyroid primordium migration and/or precocious functional differentiation.
Brancaccio et al. (2004) reported that Foxe1 was specifically expressed in the lower undifferentiated compartment of hair follicles in mouse skin, at a time and site that parallel activation of the Shh (600725) signaling pathway. Foxe1 protein was also expressed in human and mouse basal cell carcinoma in which hedgehog signaling is constitutively activated, whereas it was undetectable in normal epidermis and squamous cell carcinoma. Expression of a dominant-negative form of Gli2 (165230) in mouse skin resulted in complete suppression of Foxe1 expression in hair follicles, whereas transcriptionally active Gli2 stimulated activity of the Foxe1 promoter. Foxe1-null skin that was grafted to immunodeficient mice displayed thin and curly pelage hairs, as well as disoriented, misaligned, and aberrantly shaped hair follicles. Brancaccio et al. (2004) concluded 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. They further hypothesized that Foxe1 is a downstream target of the Shh/Gli pathway in hair follicle morphogenesis and plays a crucial role in correct hair follicle orientation into the dermis and subcutis.
To gain insight into human thyroid development and thyroid dysgenesis-associated malformations, Trueba et al. (2005) studied the expression patterns of the PAX8, TITF1, and FOXE1 genes during human development. PAX8 and TITF1 were first expressed in the median thyroid primordium. Interestingly, PAX8 was also expressed in the thyroglossal duct and the ultimobranchial bodies. Human FOXE1 expression was detected later than in the mouse. PAX8 was also expressed in the developing central nervous system and kidney, including the ureteric bud and the main collecting ducts. TITF1 was expressed in the ventral forebrain and lung. FOXE1 expression was detected in the oropharyngeal epithelium and thymus. The expression patterns of these genes in human show some differences from those reported in the mouse; Pax8, Titf1, and Foxe1 are expressed in the mouse thyroid bud as soon as it differentiates on the pharyngeal floor. The authors concluded that the expression patterns of these 3 genes correlate well with the phenotypes observed in patients carrying mutations of the corresponding gene.
Venza et al. (2011) identified human MSX1 (142983) and TGFB3 (190230), which are required for proper palate formation, as direct FOXE1 target genes. Wildtype FOXE1, but not FOXE1 with forkhead domain mutations, directly bound FOXE1-binding motifs in the MSX1 and TGFB3 promoters and drove expression of MSX1 and TGFB3 reporter genes.
Bamforth-Lazarus Syndrome
Clifton-Bligh et al. (1998) demonstrated that the FKHL15 gene, which is the human homolog of the mouse Titf2 gene, was homozygously mutated (A65V; 602617.0001) in 2 sibs with thyroid agenesis, cleft palate, and choanal atresia, previously reported by Bamforth et al. (1989); see Bamforth-Lazarus syndrome (BAMLAZ; 241850). Spiky or curly hair was also a feature, as was bifid epiglottis. Polyhydramnios, which was present in the 2 pregnancies of the brothers and in another reported case of Bamforth-Lazarus syndrome, may have been caused by the choanal atresia.
In 2 brothers with congenital hypothyroidism, athyreosis, and cleft palate, Castanet et al. (2002) identified homozygosity for a missense mutation in the FOXE1 gene (S57N; 602617.0002). The authors noted that these patients had an incomplete clinical phenotype, lacking choanal atresia and bifid epiglottis.
In a girl with Bamforth-Lazarus syndrome, Baris et al. (2006) identified homozygosity for a missense mutation (R102C; 602617.0003) in the FOXE1 gene. The patient had congenital hypothyroidism, bilateral choanal atresia, cleft palate, and spiky hair, but was not athyreotic.
Using transfected 293 EBNA cells, Venza et al. (2011) showed that missense mutations within the FOXE1 forkhead domain associated with Bamforth-Lazarus syndrome, including A65V, S57N, and R102C, reduced or eliminated FOXE1-dependent upregulation of MSX1 (142983) and TGF-beta-3 (TGFB3; 190230), both of which are required for proper palate formation. In contrast, reducing the length of the FOXE1 polyalanine stretch to between 11 and 14 residues had no effect on its transcriptional activity. FOXE1 with forkhead domain mutations failed to bind FOXE1 motifs in the MSX1 and TGFB3 promoters.
In an 18-year-old man, born of consanguineous parents, with BAMLAZ, Sarma et al. (2022) identified a homozygous 1-bp duplication (c.141dupC; 602617.0005) in the FOXE1 gene. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in his parents and his unaffected sib.
Nonmedullary Thyroid Cancer 4
In a proband who presented with papillary thyroid carcinoma (PTC) and nodal metastases (NMTC4; 616534) at the age of 57 years, Pereira et al. (2015) identified a heterozygous ala248-to-gly (A248G; 602617.0004) mutation in the FOXE1 gene. The mutation segregated with disease in the family. In functional studies, the A248G mutation promoted cell proliferation and migration. Two affected family members also carried the BRAF V600E mutation (164757.0001). Pereira et al. (2015) also found the A248G mutation in 1 male patient among 80 unrelated Portuguese individuals with apparently sporadic NMTC. This patient had developed PTC with nodal metastases at the age of 24 years.
Associations Pending Confirmation
Thyroid Dysgenesis
Carre et al. (2007) analyzed FOXE1 alanine tract length in 115 patients with thyroid dysgenesis (see CHNG1, 275200) and 129 controls. They found that 16/16 and 16/14 genotypes were inversely associated with thyroid dysgenesis (OR, 0.39; p = 0.0005), suggesting that FOXE1 with 16 alanines protects against occurrence of thyroid dysgenesis; the protective effect was confirmed by transmission disequilibrium analysis in 39 parent-proband trios. Conversely, the 14/14 genotype was associated with an increased risk of thyroid dysgenesis (OR, 2.59; p = 0.0005). Expression studies showed that transcription activity of FOXE1 with 16 alanines was 1.55-fold higher than FOXE1 with 14 alanines (p less than 0.003); nuclear localization of FOXE1 was not affected. Carre et al. (2007) suggested that FOXE1 alanine tract length modulates genetic susceptibility to thyroid dysgenesis.
Nonsyndromic Orofacial Clefting
Nonsyndromic orofacial clefts are a common complex birth defect caused by genetic and environmental factors and/or their interactions. In a cohort of cleft lip and palate (CL/P; see 119530) families from Colombia, United States, and the Philippines, Moreno et al. (2009) tested 397 SNPs spanning 9q22-q33 for association. Significant SNP and haplotype association signals narrowed the interval to a 200-kb region containing FOXE1, C9ORF156, and HEMGN (610715). Association results were replicated in CL/P families of European descent; when all populations were combined, the 2 most associated SNPs, rs3758249 (P = 5.01E-13) and rs4460498 (P = 6.51E-12), were located inside a 70-kb high linkage disequilibrium block containing FOXE1. Association signals for Caucasians and Asians clustered 5-prime and 3-prime of FOXE1, respectively. Isolated cleft palate (CP) was also associated, indicating that FOXE1 may play a role in 2 phenotypes thought to be genetically distinct. Foxe1 expression was found in the epithelium undergoing fusion between the medial nasal and maxillary processes. Mutation screens of FOXE1 identified 2 family-specific missense mutations (ile59 to ser and pro208 to arg) at highly conserved amino acids. Although predicted to be benign by a computer program, both mutations are near previously identified deleterious mutations. The authors concluded that FOXE1 may be a major gene for CL/P and CP.
Many members of the forkhead/winged-helix transcription factor family are key regulators of embryogenesis (summary by Kaufmann and Knochel, 1996). Thyroid transcription factor-2 (TTF2), a forkhead domain-containing transcription factor, was cloned by Zannini et al. (1997) and the mouse gene, designated Titf2, was mapped to chromosome 4. De Felice et al. (1998) showed that Titf2-null mutant mice exhibit cleft palate and either a sublingual or completely absent thyroid gland. Thus, the Titf2-/- mutation results in neonatal hypothyroidism that showed similarity to thyroid dysgenesis in humans. Among the 1 in 3,000 or 4,000 newborns in which congenital hypothyroidism is detected, 80% have either an ectopic, small and sublingual thyroid, or have no thyroid tissue (Toublanc, 1992). Most of these cases appear sporadically, although a few cases of recurring familial thyroid dysgenesis (218700) have been reported.
Venza et al. (2011) found that 14-day Foxe1 -/- mouse embryos nearly lacked Msx1 and Tgfb3 expression in maxillary molar dental mesenchyme and in epithelial cells of the anterior palate shelves, respectively, compared with Foxe1 +/- embryos.
By screening a human fetal brain cDNA library with the forkhead domain of rat HNF3A (602294) as probe, Wiese et al. (1997) identified what they considered to be a novel member of the forkhead family of transcription factors, which they called HFKL5 and was later designated FOXE2 by the HUGO gene nomenclature committee. As described by Wiese et al. (1997), the full-length cDNA encodes a deduced 500-amino acid protein with a calculated molecular mass of approximately 55 kD. The protein shows little homology in the forkhead domain with other members of the forkhead family. Northern blot analysis detected a 4.4-kb transcript in all fetal and adult tissues tested. In situ hybridization studies detected expression in differentiated fetal and adult neurons but not in undifferentiated neurons, such as those in the periventricular matrix. Expression was also detected in neuron-derived cells in various tissues, such as the parasympathetic ganglia of the intestine, and in a subset of hepatocytes, lymphatic tissue cells, and kidney tubule cells. Although Wiese et al. (1997) stated that the HFKL5 gene maps to chromosome 22, Scott (2007) found that this mapping is not supported by the human genome build 36.2.
In 2 brothers with a syndrome of thyroid agenesis, cleft palate, and choanal atresia (BAMLAZ; 241850), originally reported by Bamforth et al. (1989), Clifton-Bligh et al. (1998) identified homozygosity for a missense mutation at nucleotide 196, causing an ala-to-val substitution at codon 65 (A65V) in the predicted structure of the TTF2 protein.
Using transfected 293 EBNA cells, Venza et al. (2011) showed that missense mutations within the FOXE1 forkhead domain, including A65V, reduced or eliminated FOXE1-dependent upregulation of MSX1 (142983) and TGF-beta-3 (TGFB3; 190230), both of which are required for proper palate formation.
Castanet et al. (2002) described 2 male sibs, born to consanguineous parents, with congenital hypothyroidism, athyreosis, and cleft palate (BAMLAZ; 241850). Unlike previous cases, these patients had an incomplete clinical phenotype, lacking choanal atresia and bifid epiglottis. They were homozygous for a 169G-A transition, which was predicted to result in a ser57-to-asn (S57N) substitution in the forkhead DNA binding domain of FOXE1. The mutant protein showed impaired DNA binding and partial loss of transcriptional function.
Using transfected 293 EBNA cells, Venza et al. (2011) showed that missense mutations within the FOXE1 forkhead domain, including S57N, reduced or eliminated FOXE1-dependent upregulation of MSX1 (142983) and TGF-beta-3 (TGFB3; 190230), both of which are required for proper palate formation.
Baris et al. (2006) reported a female child with Bamforth-Lazarus syndrome (BAMLAZ; 241850) who presented with congenital hypothyroidism, bilateral choanal atresia, cleft palate, and spiky hair but who was not athyreotic. Thyroid ultrasonography and computed tomography examination indicated thyroid tissue in a eutopic location, although biochemical measurements and radioisotope scanning showed that it was nonfunctional. The child was homozygous for a C-to-T transition at nucleotide 304 that resulted in an arginine-to-cysteine mutation at codon 102 (R102C), a highly conserved residue within the forkhead DNA-binding domain of FOXE1. Her consanguineous Turkish parents were unaffected heterozygotes, and the mutation was not detected in 100 control chromosomes. Consonant with its location, the R102C mutant FOXE1 protein showed loss of DNA binding and was transcriptionally inactive.
Using transfected 293 EBNA cells, Venza et al. (2011) showed that missense mutations within the FOXE1 forkhead domain, including R102C, reduced or eliminated FOXE1-dependent upregulation of MSX1 (142983) and TGF-beta-3 (TGFB3; 190230), both of which are required for proper palate formation.
In a proband who presented with papillary thyroid carcinoma (PTC) and nodal metastases (NMTC4; 616534) at the age of 57 years, Pereira et al. (2015) identified a heterozygous c.743C-G transversion in the FOXE1 gene, resulting in an ala248-to-gly (A248G) substitution. The variant was not identified in public databases. Three other family members also carried the variant: the proband's cousin was diagnosed with PTC at the age of 72 years, in addition to having other neoplasms; his consanguineous wife had an ovarian carcinoma; and the sister of the proband presented with PTC at the age of 57 and developed nodal metastases 2 years later. The proband's father was an obligate carrier but was deceased. The A248G mutation was also identified in an unrelated patient from a group of 80 unrelated persons with apparently sporadic NMTC. This patient developed PTC with nodal metastases at the age of 24 years. Functional studies showed increased cell growth and migration in the presence of the mutant protein. Pereira et al. (2015) also found the A248G mutation in 1 male patient among 80 unrelated Portuguese individuals with apparently sporadic NMTC. This patient had developed PTC with nodal metastases at the age of 24 years.
In an 18-year-old man, born to consanguineous parents, with Bamforth-Lazarus syndrome (BAMLAZ; 241850), Sarma et al. (2022) identified homozygosity for a 1-bp duplication (c.141dupC, NM_004473.4) in the FOXE1 gene, resulting in a frameshift and premature termination (Leu49ProfsTer75). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies were not performed.
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