FOXE1

Summary

FOXE1 (forkhead box E1, HGNC:3806) is a protein-coding gene on chromosome 9q22.33, encoding Forkhead box protein E1 (O00358). Transcription factor that binds consensus sites on a variety of gene promoters and activate their transcription.

This intronless gene encodes a protein that belongs to the forkhead family of transcription factors. Members of this family contain a conserved 100-amino acid DNA-binding ‘forkhead’ domain. The encoded protein functions as a thyroid transcription factor that plays a role in thyroid morphogenesis. Mutations in this gene are associated with the Bamforth-Lazarus syndrome, and with susceptibility to nonmedullary thyroid cancer-4.

Source: NCBI Gene 2304 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Bamforth-Lazarus syndrome (Definitive, ClinGen)
• GWAS associations: 25
• Clinical variants (ClinVar): 116 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 63
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_004473

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3806
Approved symbol	FOXE1
Name	forkhead box E1
Location	9q22.33
Locus type	gene with protein product
Status	Approved
Aliases	TTF-2, HFKH4
Ensembl gene	ENSG00000178919
Ensembl biotype	protein_coding
OMIM	602617
Entrez	2304

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000375123

RefSeq mRNA: 1 — MANE Select: NM_004473 NM_004473

CCDS: CCDS35078

Canonical transcript exons

ENST00000375123 — 1 exons

Exon	Start	End
ENSE00001465823	97853226	97856717

Expression profiles

Bgee: expression breadth broad, 94 present calls, max score 96.53.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.3306 / max 400.4059, expressed in 181 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
97578	1.0878	135
97580	0.1616	77
97579	0.0812	40

Top tissues by expression

261 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of thyroid gland	UBERON:0001119	96.53	gold quality
left lobe of thyroid gland	UBERON:0001120	95.07	gold quality
thyroid gland	UBERON:0002046	94.96	gold quality
gingival epithelium	UBERON:0001949	94.29	gold quality
gingiva	UBERON:0001828	92.56	gold quality
epithelium of nasopharynx	UBERON:0001951	88.77	gold quality
oral cavity	UBERON:0000167	83.90	gold quality
amniotic fluid	UBERON:0000173	83.22	gold quality
squamous epithelium	UBERON:0006914	81.90	gold quality
esophagus squamous epithelium	UBERON:0006920	79.91	gold quality
pharyngeal mucosa	UBERON:0000355	77.65	gold quality
epithelium of esophagus	UBERON:0001976	75.90	gold quality
buccal mucosa cell	CL:0002336	75.61	gold quality
tongue squamous epithelium	UBERON:0006919	75.31	silver quality
tonsil	UBERON:0002372	74.66	gold quality
stromal cell of endometrium	CL:0002255	73.15	gold quality
esophagus mucosa	UBERON:0002469	72.57	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	71.08	gold quality
lower esophagus mucosa	UBERON:0035834	70.75	gold quality
superior surface of tongue	UBERON:0007371	70.53	gold quality
tongue	UBERON:0001723	69.50	gold quality
hair follicle	UBERON:0002073	69.34	silver quality
cervix squamous epithelium	UBERON:0006922	69.27	silver quality
mammalian vulva	UBERON:0000997	68.12	gold quality
body of tongue	UBERON:0011876	68.11	gold quality
vagina	UBERON:0000996	64.87	gold quality
cervix epithelium	UBERON:0004801	63.79	silver quality
trachea	UBERON:0003126	63.00	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	61.36	gold quality
pancreatic ductal cell	CL:0002079	60.41	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

9 targets.

Target	Regulation
CCND1	Repression
ESR1	Repression
MSX1	Activation
SLC5A5	Unknown
TG	Unknown
TGFB3	Activation
TPM1
TPO	Unknown
TSHR	Unknown

JASPAR motifs

Motif	Name	Family
MA1487.1	FOXE1	FOX
MA1487.2	FOXE1	FOX
MA1487.3	FOXE1	FOX

JASPAR matrix evidence (PMIDs): PMID:23675434

Upstream regulators (CollecTRI, top): GLI2, MYF5, PAX8

miRNA regulators (miRDB)

59 targeting FOXE1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5193	100.00	67.26	1744
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Compared with normal thyroids, transcripts were more abundant in 24% of thyroid lesions (PMID:11762722)
• Loss of function mutation of TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate (PMID:12165566)
• By means of a polyclonal antibody, TTF2 is identified in adult human thyroid and hair follicles and prepubertal testis. (PMID:14611701)
• a basic amino acid stretch present at both ends of the DNA-binding domain is a bona fide nuclear localization signal, able to bind the nuclear import receptor importin alpha (PMID:14654228)
• a putative role of FOXE1 in mediating hedgehog signaling in the human epidermis downstream of GLI2. (PMID:15140221)
• no genetic alteration was present in the TTF-2 gene of congenital hypothyroid and cleft palate patients, suggesting that defects in the TTF-2 gene are a rare event. (PMID:15320969)
• FOXE1 is required for hair follicle morphogenesis. (PMID:15367491)
• Foxe1 expression in the hair follicle is dependent on the Shh pathway. Loss of Foxe1 expression in skin causes aberrant hair formation with disoriented, misalignment and aberrantly shaped hair follicles. (PMID:15367491)
• Results provided evidence to suggest that variation in FOXE1 polyalanine tract length predisposes to premature ovarian failure. (PMID:16481406)
• FOXE1 through its alanine containing stretch modulates significantly the risk of thyroid dysgenesis occurrence, enhancing a mechanism linking an alanine containing transcription factor to disease. (PMID:17717707)
• A novel homozygous polymorphism that prevented the binding of MYF-5 to FOXE1 promoter and affected the FOXE1 expression was found in 45% nonsyndromic cleft palate. (PMID:19192046)
• USF1 and USF2 regulate transcriptional activity of the FOXE1 promoter. (PMID:19730683)
• These data indicate that FOXE1 is a major gene for cleft lip with or without cleft palate and provides new insights for improved counseling and genetic interaction studies. (PMID:19779022)
• given the seemingly relevant role that FOXE1 plays in the development of cutaneous SCC, these results may lead to the development of novel therapies that replace or mimic FOXE1 function to treat this form of cancer. (PMID:19845668)
• results imply that another tumour suppressor gene at this locus may be more important than FOXE1 in skin carcinogenesis and suggest that variation in the FOXE1 polyalanine tract length predisposes to cutaneous squamous cell carcinoma. (PMID:19930442)
• Binding ability of mutant FOXE1 protein to the human thyroperoxidase promoter is reduced compared with the wild-type FOXE1 in patients with thyroid diseases. (PMID:20094846)
• FOXE1 is unlikely to be the only key player in radiation-related thyroid carcinogenesis. (PMID:20350937)
• Review. Describes spectrum of human Foxe1/TTF2 mutations. (PMID:20453517)
• MSX1 and TGF-beta3 are direct targets of FOXE1. (PMID:21177256)
• FOXE1-polyAla tract expansion may contribute to the molecular background of familial but not sporadic forms of thyroid hemiagenesis. (PMID:21311165)
• Effects of genetic variation in FOXE1 on serum free thyroxine (FT4) levels in Caucasian populations are demonstrated, as well as borderline significant effects on serum thyroid hormone (TSH) levels. (PMID:21367965)
• Polymorphisms in TIMP2 and WNT9B are novel loci predisposing to cleft palate. (PMID:21462296)
• Both FOXE1 and NKX2-1 were associated with the increased risk of sporadic Japanese PTC. (PMID:21730105)
• these results excluded the association of poly (Ala) polymorphism with autoimmune thyroid diseases; however it confirms the involvement of FOXE1 in the genesis of thyroid carcinoma. (PMID:21896990)
• Polyalanine repeat expansions in FOXE1 is associated with the genetic aetiology of POF in Chinese women. (PMID:22177572)
• Novel associations for hypothyroidism and autoimmune risk loci include SNPs near the FOXE1 gene. (PMID:22493691)
• these data suggest that TTF-2 may modulate the function of ERalpha as a corepressor and play a role in ER-dependent proliferation of mammary cells. (PMID:22521644)
• coding polyalanine expansion in FOXE1 may be responsible for the observed association between FOXE1 and papillary thyroid cancer (PMID:22736773)
• FOXE1 genes suggest a role for orofacial clefting in hispanic polulation. (PMID:22753311)
• study showed evidence of association between forkhead box E1 (FOXE1) variants and thyroid cancer risk in the Portuguese population (PMID:22882326)
• Nuclear FOXE1 expression in tumor cells in vicinity of the PTC border is associated with presence of a risk allele of rs1867277 (c.-238G>A) in the 5’ untranslated region of the FOXE1 gene, as well as with pathological characteristics of PTC. (PMID:23327367)
• In addition, eight genes classified as ‘second tier’ hits in the original study (PAX7, THADA, COL8A1/FILIP1L, DCAF4L2, GADD45G, NTN1, RBFOX3 and FOXE1) showed evidence of linkage and association in this replication sample. (PMID:23512105)
• the FOXE1 gene exhibits significant differential expression levels between PTC tissues and adjacent non-tumor thyroid tissues. (PMID:23715628)
• Significant association with PTC was found for rs1801516 (D1853N) in ATM and rs1867277 in the promoter region of FOXE1 (OR = 1.55, 95% CI 1.03, 2.34). (PMID:24105688)
• single nucleotide polymorphisms at 9q22.33 near FOXE1 showed convincing evidence of association with nonmedullary thyroid carcinoma risk in high-risk families (PMID:24127282)
• study identifies probable susceptibility variants of FOXE1 for oral clefts in the Thai population (PMID:24252547)
• FOXE1 and SYNE1 hypermethylation markers demonstrated significantly increased expression in neoplastic tissue. (PMID:24280874)
• genetic association studies in population in Germany: Data suggest that an SNP in FOXE1 (rs965513) is associated with increased risk for differentiated thyroid cancer (of an aggressive nature) in the population studied. (PMID:24325646)
• Common variations of FOXE1 are a risk factor associated with increased thyroid cancer susceptibility. (PMID:24489898)
• These results strongly support the FOXE1 locus as a risk factor for nsOFC. With the data of the initial study, there is now considerable evidence that this locus is the first conclusive risk factor shared between nsCL/P and nsCPO. (PMID:24563486)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxe3	ENSDARG00000062892
mus_musculus	Foxe1	ENSMUSG00000070990
rattus_norvegicus	Foxe1	ENSRNOG00000023497

Paralogs (41): FOXP3 (ENSG00000049768), FOXC1 (ENSG00000054598), FOXJ2 (ENSG00000065970), FOXF1 (ENSG00000103241), FOXN1 (ENSG00000109101), FOXM1 (ENSG00000111206), FOXP1 (ENSG00000114861), FOXO3 (ENSG00000118689), FOXA2 (ENSG00000125798), FOXA1 (ENSG00000129514), FOXJ1 (ENSG00000129654), FOXK2 (ENSG00000141568), FOXO1 (ENSG00000150907), FOXH1 (ENSG00000160973), FOXQ1 (ENSG00000164379), FOXK1 (ENSG00000164916), FOXD4 (ENSG00000170122), FOXA3 (ENSG00000170608), FOXB1 (ENSG00000171956), FOXR1 (ENSG00000176302), FOXL1 (ENSG00000176678), FOXC2 (ENSG00000176692), FOXS1 (ENSG00000179772), FOXL2 (ENSG00000183770), FOXO4 (ENSG00000184481), FOXD4L1 (ENSG00000184492), FOXD4L4 (ENSG00000184659), FOXD2 (ENSG00000186564), FOXI2 (ENSG00000186766), FOXE3 (ENSG00000186790), FOXD3 (ENSG00000187140), FOXD4L3 (ENSG00000187559), FOXR2 (ENSG00000189299), FOXJ3 (ENSG00000198815), FOXO6 (ENSG00000204060), FOXB2 (ENSG00000204612), FOXD4L5 (ENSG00000204779), FOXI3 (ENSG00000214336), FOXL3 (ENSG00000248767), FOXD1 (ENSG00000251493)

Protein

Protein identifiers

Forkhead box protein E1 — O00358 (reviewed: O00358)

Alternative names: Forkhead box protein E2, Forkhead-related protein FKHL15, HFKH4, HNF-3/fork head-like protein 5, Thyroid transcription factor 2

All UniProt accessions (1): O00358

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that binds consensus sites on a variety of gene promoters and activate their transcription. Involved in proper palate formation, most probably through the expression of MSX1 and TGFB3 genes which are direct targets of this transcription factor. Also implicated in thyroid gland morphogenesis. May indirectly play a role in cell growth and migration through the regulation of WNT5A expression.

Subcellular location. Nucleus.

Tissue specificity. Detected in adult brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, heart, colon, small intestine testis and thymus. Expression was strongest in heart and pancreas.

Post-translational modifications. Phosphorylated.

Disease relevance. Bamforth-Lazarus syndrome (BAMLAZ) [MIM:241850] An autosomal recessive disease characterized by congenital hypothyroidism due to thyroid agenesis or thyroid hypoplasia, cleft palate, spiky hair, with or without choanal atresia, and bifid epiglottis. The disease is caused by variants affecting the gene represented in this entry. Thyroid cancer, non-medullary, 4 (NMTC4) [MIM:616534] A form of non-medullary thyroid cancer (NMTC), a cancer characterized by tumors originating from the thyroid follicular cells. NMTCs represent approximately 95% of all cases of thyroid cancer and are classified into papillary, follicular, Hurthle cell, and anaplastic neoplasms. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Polymorphism. An alanine stretch that varies from 12 to 19 residues is present. This polymorphisms can be used as a marker to study the role of FOXE1 in other cases of thyroid dysgenesis, especially in familial cases.

RefSeq proteins (1): NP_004464* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR018122	TF_fork_head_CS_1	Conserved_site
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR050211	FOX_domain-containing	Family

Pfam: PF00250

UniProt features (12 total): sequence variant 8, chain 1, DNA-binding region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00358-F1	62.02	0.21

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 250 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_EPIDERMIS_MORPHOGENESIS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_THYMUS_DEVELOPMENT, SCHLESINGER_METHYLATED_DE_NOVO_IN_CANCER, GOBP_THYROID_HORMONE_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GOBP_DIGESTIVE_SYSTEM_DEVELOPMENT, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS

GO Biological Process (21): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), thyroid hormone generation (GO:0006590), anatomical structure morphogenesis (GO:0009653), cell migration (GO:0016477), cell differentiation (GO:0030154), thyroid gland development (GO:0030878), hair follicle morphogenesis (GO:0031069), cellular response to insulin stimulus (GO:0032869), positive regulation of DNA-templated transcription (GO:0045893), thymus development (GO:0048538), embryonic organ morphogenesis (GO:0048562), hard palate development (GO:0060022), soft palate development (GO:0060023), chordate pharynx development (GO:0160093), cranial skeletal system development (GO:1904888), regulation of DNA-templated transcription (GO:0006355), negative regulation of DNA-templated transcription (GO:0045892), animal organ development (GO:0048513), system development (GO:0048731), roof of mouth development (GO:0060021)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	6
regulation of DNA-templated transcription	4
DNA-templated transcription	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
gland development	2
secondary palate development	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
negative regulation of DNA-templated transcription	1
thyroid hormone metabolic process	1
developmental process	1
cell motility	1
cellular developmental process	1
endocrine system development	1
hair follicle development	1
anatomical structure morphogenesis	1
hair cycle process	1
epidermis morphogenesis	1
response to insulin	1
cellular response to peptide hormone stimulus	1
positive regulation of RNA biosynthetic process	1
hematopoietic or lymphoid organ development	1
animal organ morphogenesis	1
embryonic organ development	1
embryonic morphogenesis	1
pharynx development	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
negative regulation of RNA biosynthetic process	1
multicellular organism development	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1

Protein interactions and networks

STRING

1500 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXE1	NKX2-1	P43699	948
FOXE1	PAX8	Q06710	940
FOXE1	TSHR	P16473	889
FOXE1	TG	P01266	857
FOXE1	SLC5A5	Q92911	836
FOXE1	TRMO	Q9BU70	753
FOXE1	SLC26A4	O43511	730
FOXE1	TPO	P07202	710
FOXE1	IYD	Q6PHW0	708
FOXE1	TBX10	O75333	659
FOXE1	HHEX	Q03014	641
FOXE1	IRF6	O14896	635
FOXE1	DUOXA2	Q1HG44	625
FOXE1	MSX1	P28360	620
FOXE1	HEMGN	Q9BXL5	617

IntAct

27 interactions, top by confidence:

A	B	Type	Score
FOXE1	ELK1	psi-mi:“MI:0915”(physical association)	0.630
ELK1	FOXE1	psi-mi:“MI:0915”(physical association)	0.630
FOXE1	REL	psi-mi:“MI:0915”(physical association)	0.400
FOXE1	TERT	psi-mi:“MI:0915”(physical association)	0.400
	FOXE1	psi-mi:“MI:0915”(physical association)	0.400
FOXE1	TPO	psi-mi:“MI:0915”(physical association)	0.400
FOXE1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXE1	FOXE1	psi-mi:“MI:0914”(association)	0.350
	FOXE1	psi-mi:“MI:0914”(association)	0.350
FOXE1	IDE	psi-mi:“MI:0914”(association)	0.350
AGGF1	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
DGCR8	VWA8	psi-mi:“MI:2364”(proximity)	0.270
FASTKD2	MED19	psi-mi:“MI:2364”(proximity)	0.270
GNL3	VWA8	psi-mi:“MI:2364”(proximity)	0.270
HNRNPC	SBNO1	psi-mi:“MI:2364”(proximity)	0.270
RBM15	ILVBL	psi-mi:“MI:2364”(proximity)	0.270
RPS3	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
SF3B4	MED19	psi-mi:“MI:2364”(proximity)	0.270
SUPV3L1	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (79): RECQL (Affinity Capture-MS), CHD4 (Affinity Capture-MS), CUX1 (Affinity Capture-MS), H2AFY (Affinity Capture-MS), POLE (Affinity Capture-MS), SMARCA5 (Affinity Capture-MS), DLX5 (Affinity Capture-MS), HOXD13 (Affinity Capture-MS), ORC2 (Affinity Capture-MS), PSIP1 (Affinity Capture-MS), RALY (Affinity Capture-MS), SATB2 (Affinity Capture-MS), ZFR (Affinity Capture-MS), ALX4 (Affinity Capture-MS), HEATR1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8V0YY16, A2T7H5, A7MB54, A8MTJ6, B5DFK3, B5RHS5, D3Z120, O00358, O09029, O35392, O54743, O88470, P23813, P28356, P28357, P31260, P31277, P31310, P32183, P46153, P47902, P50548, P55318, P58012, P78415, P79772, P81067, Q00939, Q12947, Q12948, Q12952, Q14774, Q3I5G5, Q3Y598, Q4VUF1, Q61345, Q61572, Q61850, Q63244, Q63246

Diamond homologs: A0A078BQN7, A0A1W2PRP0, A0A8V0YY16, A1L1S5, A3KNJ3, A8MTJ6, A8XJN7, B5RHS5, D3Z120, F1R8Z9, O00358, O17617, O43638, O54743, O60129, O88470, P32027, P32028, P32030, P32315, P42128, P55316, P56260, P58012, P79772, P85037, P91278, Q00939, Q01167, Q02360, Q12946, Q12947, Q12948, Q12950, Q12951, Q12952, Q13461, Q19802, Q1A1A1, Q1A1A2

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
FOXE1	“up-regulates quantity by expression”	TPO	“transcriptional regulation”
FOXE1	“up-regulates quantity by expression”	MSX1	“transcriptional regulation”
FOXE1	“up-regulates quantity by expression”	TGFB3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

116 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	72
Likely benign	13
Benign	23

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
2443729	NM_004473.4(FOXE1):c.145dup (p.Leu49fs)	Pathogenic
6986	NM_004473.4(FOXE1):c.194C>T (p.Ala65Val)	Pathogenic
6987	NM_004473.4(FOXE1):c.170G>A (p.Ser57Asn)	Pathogenic
6988	NM_004473.4(FOXE1):c.304C>T (p.Arg102Cys)	Pathogenic
3343971	NM_004473.4(FOXE1):c.326A>T (p.Asp109Val)	Likely pathogenic
3362432	NM_004473.4(FOXE1):c.346C>A (p.Arg116Ser)	Likely pathogenic

SpliceAI

6 predictions. Top by Δscore:

Variant	Effect	Δscore
9:97856561:T:TA	acceptor_gain	0.8000
9:97856562:G:A	acceptor_gain	0.7800
9:97853311:T:TA	donor_gain	0.5000
9:97853972:G:GT	donor_gain	0.3100
9:97855081:C:G	acceptor_gain	0.2800
9:97855091:A:AG	acceptor_gain	0.2000

AlphaMissense

2361 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:97854071:A:G	K53E	1.000
9:97854073:G:C	K53N	1.000
9:97854073:G:T	K53N	1.000
9:97854074:C:T	P54S	1.000
9:97854075:C:A	P54Q	1.000
9:97854080:T:G	Y56D	1.000
9:97854083:A:C	S57R	1.000
9:97854084:G:A	S57N	1.000
9:97854084:G:T	S57I	1.000
9:97854085:C:A	S57R	1.000
9:97854085:C:G	S57R	1.000
9:97854086:T:C	Y58H	1.000
9:97854087:A:G	Y58C	1.000
9:97854090:T:A	I59N	1.000
9:97854096:T:A	L61H	1.000
9:97854096:T:C	L61P	1.000
9:97854099:T:A	I62N	1.000
9:97854099:T:G	I62S	1.000
9:97854102:C:A	A63D	1.000
9:97854106:G:A	M64I	1.000
9:97854106:G:C	M64I	1.000
9:97854106:G:T	M64I	1.000
9:97854107:G:C	A65P	1.000
9:97854108:C:A	A65D	1.000
9:97854111:T:A	I66N	1.000
9:97854111:T:G	I66S	1.000
9:97854135:T:C	L74P	1.000
9:97854141:T:A	L76Q	1.000
9:97854141:T:C	L76P	1.000
9:97854150:T:A	I79N	1.000

dbSNP variants (sampled 300 via entrez): RS1000516777 (9:97855507 G>A,C), RS1000797539 (9:97851387 C>T), RS1000912332 (9:97851551 C>T), RS1000974612 (9:97851658 G>A,C), RS1001124807 (9:97857082 G>A), RS1001409320 (9:97856763 T>C), RS1001864896 (9:97852591 G>A), RS1001929490 (9:97853853 C>A,G,T), RS1002081447 (9:97853964 C>A,T), RS1002380825 (9:97852801 C>T), RS1003048488 (9:97855900 C>A,T), RS10046805 (9:97851674 G>A,C), RS1004933822 (9:97853813 C>G,T), RS1005749867 (9:97851972 G>C), RS1005763003 (9:97857180 A>C)

Disease associations

OMIM: gene MIM:602617 | disease phenotypes: MIM:241850, MIM:616534

GenCC curated gene-disease

Disease	Classification	Inheritance
Bamforth-Lazarus syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Bamforth-Lazarus syndrome	Definitive	AR

Mondo (3): Bamforth-Lazarus syndrome (MONDO:0009437), thyroid cancer, nonmedullary, 4 (MONDO:0014681), congenital hypothyroidism (MONDO:0018612)

Orphanet (2): Bamforth-Lazarus syndrome (Orphanet:1226), Congenital hypothyroidism (Orphanet:442)

HPO phenotypes

63 total (30 of 63 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000158	Macroglossia
HP:0000175	Cleft palate
HP:0000239	Large fontanelles
HP:0000271	Abnormality of the face
HP:0000278	Retrognathia
HP:0000280	Coarse facial features
HP:0000282	Facial edema
HP:0000316	Hypertelorism
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000453	Choanal atresia
HP:0000821	Hypothyroidism
HP:0000851	Congenital hypothyroidism
HP:0000853	Goiter
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001262	Excessive daytime somnolence
HP:0001263	Global developmental delay
HP:0001324	Muscle weakness
HP:0001510	Growth delay
HP:0001537	Umbilical hernia
HP:0001561	Polyhydramnios
HP:0001615	Hoarse cry
HP:0002019	Constipation
HP:0002176	Spinal cord compression
HP:0002653	Bone pain
HP:0002671	Basal cell carcinoma

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST000335_1	Thyroid cancer	2.000000e-27
GCST000640_1	Thyroid cancer (Papillary, radiation-related)	5.000000e-12
GCST001265_1	Hypothyroidism	4.000000e-09
GCST001474_18	Hypothyroidism	2.000000e-19
GCST001762_338	Obesity-related traits	1.000000e-09
GCST001856_16	Thyroid hormone levels	3.000000e-06
GCST001856_17	Thyroid hormone levels	5.000000e-07
GCST001856_45	Thyroid hormone levels	2.000000e-11
GCST002102_1	Thyroid cancer	3.000000e-10
GCST002371_3	Parent of origin effect on language impairment (paternal)	5.000000e-06
GCST002458_3	Serum thyroid-stimulating hormone levels	1.000000e-13
GCST002707_2	Serum thyroid-stimulating hormone levels	1.000000e-06
GCST002873_1	Thyroid cancer	1.000000e-17
GCST002873_2	Thyroid cancer	1.000000e-17
GCST003427_184	Alzheimer disease and age of onset	2.000000e-07
GCST003988_4	Hypothyroidism	1.000000e-89
GCST004276_2	Plasma thyroid-stimulating hormone levels	2.000000e-20
GCST004753_9	Papillary thyroid cancer	5.000000e-07
GCST004798_10	Differentiated thyroid cancer	8.000000e-06
GCST004866_3	Alopecia areata	9.000000e-07
GCST006897_8	Hyperthyroidism	1.000000e-08
GCST006898_7	Hypothyroidism	6.000000e-20
GCST006988_24	Blond vs. brown/black hair color	3.000000e-19
GCST008165_10	Thyroid stimulating hormone levels	6.000000e-20
GCST010571_90	Autoimmune thyroid disease	9.000000e-110

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004730	hormone measurement
EFO:0004847	age at onset
EFO:0003924	hair color

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003409	Congenital Hypothyroidism	C05.116.099.343.347; C05.116.132.256; C16.320.240.625; C19.297.155; C19.874.482.281
C537901	Bamforth syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	1
sodium arsenite	increases expression	1
zinc chromate	decreases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
pentabromodiphenyl ether	decreases expression	1
Resveratrol	increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Estradiol	affects cotreatment, increases expression	1
Formaldehyde	decreases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Vitamin E	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Lactic Acid	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A1Z1	SEES3-1V human FOXE1, clone1	Embryonic stem cell	Male
CVCL_A1Z2	SEES3-1V human FOXE1, clone2	Embryonic stem cell	Male
CVCL_A1Z3	SEES3-1V human FOXE1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

24 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05228184	PHASE4	TERMINATED	Use of Tirosint®-SOL or Tablet Formulations of Levothyroxine in Pediatric Patients With Congenital Hypothyroidism (CH)
NCT05371262	PHASE4	COMPLETED	Influence of Initial Levothyroxine Dose on Neurodevelopmental and Growth Outcomes in Congenital Hypothyroidism
NCT00403390	Not specified	COMPLETED	Generic vs. Name-Brand Levothyroxine
NCT00493103	Not specified	COMPLETED	TG Gene Mutations and Congenital Hypothyroidism
NCT00497575	Not specified	COMPLETED	Diagnosis and Follow-up of Patients With Subclinical Hypothyroidism
NCT00505479	Not specified	UNKNOWN	Iodine Status in Pregnant Women and Their Newborns: is Congenital Hypothyroidism Related to Iodine Deficiency in Pregnancy?
NCT01223638	Not specified	WITHDRAWN	The Prevalence of Hearing Loss Among Children With Congenital Hypothyroidism
NCT01349634	Not specified	COMPLETED	The Effects of Iodized Salt on Cognitive Development in Ethiopia
NCT01488721	Not specified	COMPLETED	Clinical Evaluation of NeoPlex4 Assay and NeoPlex System
NCT01916018	Not specified	COMPLETED	Clinical and Genetic Analysis in Congenital Hypothyroidism Due to Thyroid Dysgenesis.
NCT02307175	Not specified	COMPLETED	A Study of 99m Tc Pertechnetate Produced in High Energy Cyclotron in Patients With Thyroid Scan Indication
NCT02374593	Not specified	COMPLETED	Targeted Levothyroxine Dosing in Infants With Congenital Hypothyroidism
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04712760	Not specified	UNKNOWN	Congenital Hypothyroidism in Children With Eutopic Gland or Thyroid Hemiagenesis: Predictive Factors for Transient vs Permanent Hypothyroidism.
NCT04734457	Not specified	UNKNOWN	Final Height in Patients With CH Diagnosed by the Screening
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06724224	Not specified	RECRUITING	Comparison of Levothyroxine Formulations in the Treatment of Congenital Hypothyroidism
NCT06728735	Not specified	RECRUITING	Role of Next Generation Sequencing in the Etiological Diagnosis of Permanent Congenital Hypothyroidism With in Situ Thyroid
NCT06864039	Not specified	ENROLLING_BY_INVITATION	Quality of Life and Long-term Outcome of Adequately Treated Congenital Hypothyroidism
NCT06864351	Not specified	RECRUITING	Prospective Evaluation of OptiThyDose
NCT07126353	Not specified	NOT_YET_RECRUITING	Metabolic Risk Assessment in Prepubertal Children With Congenital Hypothyroidism
NCT07280104	Not specified	RECRUITING	Infants With Primary Congenital Hypothyroidism and Development
NCT07425028	Not specified	NOT_YET_RECRUITING	Evaluation of an Intensified Systematic Screening for Congenital Hypothyroidism in Premature Newborns
NCT07579988	Not specified	NOT_YET_RECRUITING	Ultrasound Measurement of Thyroid Volume in Term Newborns