TLE1

Summary

TLE1 (TLE family member 1, transcriptional corepressor, HGNC:11837) is a protein-coding gene on chromosome 9q21.32, encoding Transducin-like enhancer protein 1 (Q04724). Transcriptional corepressor that binds to a number of transcription factors.

Enables DNA-binding transcription factor binding activity; identical protein binding activity; and transcription corepressor activity. Involved in negative regulation of anoikis; negative regulation of signal transduction; and regulation of gene expression. Located in cytosol and nucleoplasm. Part of beta-catenin-TCF complex.

Source: NCBI Gene 7088 — RefSeq curated summary.

At a glance

• Gene–disease (curated): movement disorder (Limited, GenCC)
• GWAS associations: 22
• Clinical variants (ClinVar): 115 total
• MANE Select transcript: NM_005077

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11837
Approved symbol	TLE1
Name	TLE family member 1, transcriptional corepressor
Location	9q21.32
Locus type	gene with protein product
Status	Approved
Aliases	ESG1, GRG1, ESG, TLE-1
Ensembl gene	ENSG00000196781
Ensembl biotype	protein_coding
OMIM	600189
Entrez	7088

Gene structure

Transcript identifiers

Ensembl transcripts: 52 — 51 protein_coding, 1 nonsense_mediated_decay

ENST00000376463, ENST00000376484, ENST00000376499, ENST00000418319, ENST00000464999, ENST00000491534, ENST00000674113, ENST00000879079, ENST00000879080, ENST00000879081, ENST00000879082, ENST00000879083, ENST00000879084, ENST00000879085, ENST00000879086, ENST00000879087, ENST00000879088, ENST00000879089, ENST00000879090, ENST00000879091, ENST00000879092, ENST00000925488, ENST00000925489, ENST00000925490, ENST00000925491, ENST00000925492, ENST00000925493, ENST00000925494, ENST00000925495, ENST00000925496, ENST00000925497, ENST00000925498, ENST00000946426, ENST00000946427, ENST00000946428, ENST00000946429, ENST00000946430, ENST00000946431, ENST00000946432, ENST00000946433, ENST00000946434, ENST00000946435, ENST00000946436, ENST00000946437, ENST00000946438, ENST00000946439, ENST00000946440, ENST00000946441, ENST00000946442, ENST00000946443, ENST00000946444, ENST00000946445

RefSeq mRNA: 3 — MANE Select: NM_005077 NM_001303103, NM_001303104, NM_005077

CCDS: CCDS6661

Canonical transcript exons

ENST00000376499 — 20 exons

Exon	Start	End
ENSE00001607617	81585505	81585655
ENSE00001644386	81584448	81584524
ENSE00001646911	81587681	81587828
ENSE00001691307	81610220	81610296
ENSE00001694782	81593025	81593274
ENSE00001728569	81590805	81591052
ENSE00001742393	81611769	81611959
ENSE00001850808	81688217	81689547
ENSE00001927275	81583683	81584305
ENSE00003482649	81616646	81616699
ENSE00003492768	81615982	81616134
ENSE00003646932	81620441	81620557
ENSE00003720523	81634097	81634301
ENSE00003722994	81633348	81633364
ENSE00003724594	81613377	81613521
ENSE00003740059	81653974	81654036
ENSE00003740181	81687334	81687434
ENSE00003742849	81652214	81652288
ENSE00003744964	81685833	81685896
ENSE00003750123	81685676	81685720

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 97.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.6689 / max 182.1816, expressed in 1635 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101120	11.2352	1560
101119	4.2134	1224
101117	0.6178	335
205533	0.5767	381
205532	0.4727	286
101116	0.3027	141
101118	0.2504	146

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	97.79	gold quality
adrenal tissue	UBERON:0018303	96.62	gold quality
sural nerve	UBERON:0015488	95.62	gold quality
tibial nerve	UBERON:0001323	95.59	gold quality
endometrium	UBERON:0001295	95.21	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.05	gold quality
parotid gland	UBERON:0001831	94.84	gold quality
right lobe of liver	UBERON:0001114	94.69	gold quality
endocervix	UBERON:0000458	94.68	gold quality
ganglionic eminence	UBERON:0004023	94.61	gold quality
gastrocnemius	UBERON:0001388	94.50	gold quality
middle temporal gyrus	UBERON:0002771	94.27	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.26	gold quality
hair follicle	UBERON:0002073	94.16	gold quality
muscle of leg	UBERON:0001383	94.08	gold quality
cortical plate	UBERON:0005343	93.90	gold quality
left uterine tube	UBERON:0001303	93.72	gold quality
body of uterus	UBERON:0009853	93.51	gold quality
uterus	UBERON:0000995	93.24	gold quality
body of pancreas	UBERON:0001150	93.21	gold quality
amygdala	UBERON:0001876	93.14	gold quality
ectocervix	UBERON:0012249	93.04	gold quality
omental fat pad	UBERON:0010414	93.01	gold quality
peritoneum	UBERON:0002358	93.00	gold quality
ascending aorta	UBERON:0001496	92.98	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.97	gold quality
thoracic aorta	UBERON:0001515	92.94	gold quality
descending thoracic aorta	UBERON:0002345	92.72	gold quality
putamen	UBERON:0001874	92.53	gold quality
adipose tissue	UBERON:0001013	92.49	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	94.58
E-GEOD-134144	yes	28.65
E-CURD-88	yes	28.05
E-CURD-46	yes	25.44
E-CURD-122	yes	11.47
E-MTAB-8271	yes	6.58
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
BCL2	Activation

Upstream regulators (CollecTRI, top): ATF2, CTNNB1, ESR1, FOXG1, HES1, HESX1, HHEX, PROP1, SPI1

miRNA regulators (miRDB)

70 targeting TLE1, 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-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-1277-5P	100.00	73.95	5056
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AW	99.99	72.57	3559
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-4789-5P	99.98	70.76	2721
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-548M	99.70	68.87	1749

Literature-anchored findings (GeneRIF, showing 40)

• The transcription co-repressor TLE1 interacted with the intracellular region of gpl30 through its Q domain (PMID:12030375)
• 1.6 A crystal structure of a C-terminal fragment of human Groucho/TLE1, comprising part of the Ser/Pro-rich region and a seven-bladed beta propeller WD40 repeat domain, implicated in protein-protein interactions (PMID:12057191)
• Not only PNRC2 but also the corepressor TLE1 functioned as ERRgamma coactivator in a reporter gene analysis. (PMID:14651967)
• beta-catenin displaces Groucho/TLE from Tcf/Lef by binding to a previously unidentified second, low-affinity binding site on lymphoid enhancer factor 1 (PMID:15768032)
• ESG1 expression in human cells is studied. (PMID:16166252)
• TLE is a robust immunohistochemical marker for synovial sarcoma in humans. (PMID:17255769)
• interaction between Sirt1 and TLE1 is important for mediating repression of NF-kappaB activity (PMID:17680780)
• Knockdown of TLE1 or TLE4 levels increased the rate of cell division of the AML1-ETO-expressing Kasumi-1 cell line, whereas forced expression of either TLE1 or TLE4 caused apoptosis and cell death. (PMID:18258796)
• data suggest that TLE1 epigenetic inactivation contributes to the development of hematologic malignancies by disrupting critical differentiation and growth-suppressing pathways (PMID:18519670)
• Inhibition of cortical neuron differentiation by Groucho/TLE1 requires interaction with WRPW, but not Eh1, repressor peptides (PMID:18611861)
• Results demonstrate that transcriptional repression by PRH is dependent on TLE availability and suggest that subnuclear localization of TLE plays an important role in transcriptional repression by PRH. (PMID:18713067)
• TLX1 interacts with TLE1 via an Eh1-like motif. (PMID:19250647)
• TLE1 expression is by no means specific for synovial sarcoma, being present in a number of tumors, which enter its differential diagnosis. (PMID:19363472)
• Findings confirm, in a prospective diagnostic context, that TLE1 is more sensitive and specific for synovial sarcoma than any other currently available immunohistochemical stains. (PMID:19809272)
• Hyperphosphorylation induced by cofactor binding plays a positive role in the regulation of Gro/TLE1 anti-neurogenic activity. (PMID:19956621)
• Biologically, loss of TLE-dependent rRNA gene repression coincides with increased global protein synthesis and enhanced cell proliferation (PMID:20160071)
• Studies suggest that TLE1 and TLE3 might also play roles independent of HESX1 by interacting with other transcription factors like PROP1. (PMID:20181723)
• TLE1 is a critical factor for the survival of synovial sarcomas (PMID:21319215)
• TLE1, is a necessary transcriptional component of the ER complex, where it facilitates ER-chromatin interactions. (PMID:21536917)
• Epistatic and biological interactions between TLE1 and NOD2 are involved in inflammatory bowel disease pathogenesis. (PMID:21699783)
• TLE1 is selectively upregulated in invasive breast tumors relative to noninvasive ductal carcinoma in situ and normal mammary epithelial tissues. (PMID:22952044)
• highly specific biomarker for synovial sarcoma (PMID:23197007)
• Although molecular confirmation is the diagnostic gold standard for synovial sarcoma, TLE1, in view of its high sensitivity may be a useful marker within the optimal IHC panel comprising EMA, BCL2, MIC2, CD34 and CK7 (PMID:23287123)
• signaling and increases the expression of recombinant recognition sequence binding protein at the Jkappa site (RBP-J) and transducin-like enhancer of Split (TLE). (PMID:23775085)
• There was no difference in TLE-1 staining between different subtypes of synovial sarcoma (PMID:24422953)
• GrG1 is involved in pancreatic cell differentiation, establishing a monohormonal beta cell identity. Grg1 is the predominant Groucho expressed in human beta-cells but acts functionally similarly to Grg3. (PMID:24487024)
• TCF/TLE tetramer complex promotes structural transitions of chromatin to mediate repression. (PMID:24596249)
• TLE1 has a role in regulating epithelial-to-mesenchymal transition in A549 cells through its repressive effect on E-cadherin (PMID:25446087)
• Data suggest TLE1 is highly expressed in macrophages cultured in vitro, in macrophages of atherosclerotic plaques, and in macrophages of visceral adipose tissue from obese women; expression of TLE1 is up-regulated upon macrophage activation. (PMID:26763127)
• TLE1 is not a stand-alone diagnostic immunohistochemical marker for synovial sarcoma (PMID:27568668)
• studies indicate Bit1 is an inhibitor of EMT and metastasis in lung cancer and hence can serve as a molecular target in curbing lung cancer aggressiveness (PMID:27655370)
• Authors present data indicating that TLE1 is rapidly excluded from the nucleus following epidermal growth factor receptor pathway activation, an effect that likely accounts for its inability to mediate effective repression under such conditions. (PMID:28192406)
• TLE1 is a potential immunohistochemical marker for glomus tumors (PMID:28632567)
• The Utility of NKX2.2 and TLE1 Immunohistochemistry in the Differentiation of Ewing Sarcoma and Synovial Sarcoma. (PMID:28800015)
• SATB2 and TLE1 Expression in BCOR-CCNB3 (Ewing-like) Sarcoma, Mimicking Small Cell Osteosarcoma and Poorly Differentiated Synovial Sarcoma. (PMID:29084055)
• These results provide previously unavailable insight into the transcriptional programs underlying the tumour-promoting functions of FOXG1:TLE1 in glioblastoma. (PMID:29316219)
• The majority of malignant rhabdoid tumors and atypical teratoid/rhabdoid tumor cases showed some TLE1 immunoreactivity (n = 16; 89% for >/=1 + staining); 14 (78%) of total cases showed >/=2 + positivity using any of the 3 scoring systems. Over half (n = 10; 56%) of cases showed >/=2 + staining; 4 (22%) cases showed 3 + strong and diffuse TLE1 staining measured by all scoring systems in agreement. (PMID:29490565)
• Case Report: primary subcutaneous biphasic synovial sarcoma with TlE1 immunoreactivity. (PMID:29742555)
• Using trio-based exome sequencing, we identified a homozygous missense mutation in the Transducin-like enhancer of split-1 (TLE1) gene, encoding for a non DNA-binding transcriptional corepressor, highly expressed in the postnatal brain (PMID:29758293)
• Immunohistochemical analysis for TLE1 can identify basal cell adenomas and basal cell adenocarcinomas by luminal cell staining difference, especially indistinct luminal cell expression for TLE1 in invasive areas of BCAC. (PMID:30053869)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tle1	ENSMUSG00000008305
rattus_norvegicus	Tle1	ENSRNOG00000005882
caenorhabditis_elegans	unc-37	WBGENE00006773

Paralogs (6): TLE2 (ENSG00000065717), TLE6 (ENSG00000104953), TLE5 (ENSG00000104964), TLE4 (ENSG00000106829), TLE3 (ENSG00000140332), TLE7 (ENSG00000260734)

Protein

Protein identifiers

Transducin-like enhancer protein 1 — Q04724 (reviewed: Q04724)

Alternative names: E(Sp1) homolog, Enhancer of split groucho-like protein 1

All UniProt accessions (7): Q04724, A0A669KAE5, A0A669KBB1, A0A669KBK8, F6T2C8, Q5T3G2, Q5T3G3

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional corepressor that binds to a number of transcription factors. Inhibits NF-kappa-B-regulated gene expression. Inhibits the transcriptional activation mediated by FOXA2, and by CTNNB1 and TCF family members in Wnt signaling. Enhances FOXG1/BF-1- and HES1-mediated transcriptional repression. The effects of full-length TLE family members may be modulated by association with dominant-negative AES. Unusual function as coactivator for ESRRG.

Subunit / interactions. Homooligomer and heterooligomer with other family members. Binds RUNX1, RUNX3, FOXA2, KDM6A, UTY, histone H3, HESX1, ESRRG and the NF-kappa-B subunit RELA. Interacts with HES1 (via WRPW motif). Binds TCF7, LEF1, TCF7L1 and TCF7L2. Interacts with SIX3. Interacts with EFNB1. Interacts with TLE4. Interacts with FOXG1/BF-1; the interaction is inhibited by TLE6/GRG6.

Subcellular location. Nucleus.

Tissue specificity. In all tissues examined, mostly in brain, liver and muscle.

Post-translational modifications. Phosphorylated, probably by CDK1. The degree of phosphorylation varies throughout the cell cycle, and is highest at the G2/M transition. Becomes hyperphosphorylated in response to cell differentiation and interaction with HES1 or RUNX1. Ubiquitinated by XIAP/BIRC4.

Domain organisation. WD repeat Groucho/TLE family members are characterized by 5 regions, a glutamine-rich Q domain, a glycine/proline-rich GP domain, a central CcN domain, containing a nuclear localization signal, and a serine/proline-rich SP domain. The most highly conserved are the N-terminal Q domain and the C-terminal WD-repeat domain.

Similarity. Belongs to the WD repeat Groucho/TLE family.

RefSeq proteins (3): NP_001290032, NP_001290033, NP_005068* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR005617	Groucho/TLE_N	Domain
IPR009146	Groucho_enhance	Family
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR019775	WD40_repeat_CS	Conserved_site
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily

Pfam: PF00400, PF03920

UniProt features (72 total): strand 34, repeat 6, region of interest 6, compositionally biased region 6, modified residue 5, mutagenesis site 4, helix 4, turn 3, sequence conflict 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
1GXR	X-RAY DIFFRACTION	1.65
2CE8	X-RAY DIFFRACTION	2.03
5MWJ	X-RAY DIFFRACTION	2.04
2CE9	X-RAY DIFFRACTION	2.12
4OM3	X-RAY DIFFRACTION	2.85
4OM2	X-RAY DIFFRACTION	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q04724-F1	69.11	0.43

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (5): 239, 259, 263, 267, 286

Mutagenesis-validated functional residues (4):

Position	Phenotype
486	abolishes hesx1 binding.
532	abolishes hesx1 binding.
702	abolishes hesx1 binding.
715	abolishes hesx1 binding.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex
R-HSA-2122947	NOTCH1 Intracellular Domain Regulates Transcription
R-HSA-3769402	Deactivation of the beta-catenin transactivating complex
R-HSA-4641265	Repression of WNT target genes
R-HSA-9764725	Negative Regulation of CDH1 Gene Transcription

MSigDB gene sets: 305 (showing top): MYAATNNNNNNNGGC_UNKNOWN, REACTOME_SIGNALING_BY_NOTCH, HNF3ALPHA_Q6, PEREZ_TP63_TARGETS, GOZGIT_ESR1_TARGETS_DN, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, HASLINGER_B_CLL_WITH_MUTATED_VH_GENES, KYNG_DNA_DAMAGE_DN, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, SHIPP_DLBCL_CURED_VS_FATAL_DN, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, MODULE_66, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, UEDA_PERIFERAL_CLOCK

GO Biological Process (10): signal transduction (GO:0007165), animal organ morphogenesis (GO:0009887), positive regulation of gene expression (GO:0010628), Wnt signaling pathway (GO:0016055), negative regulation of Wnt signaling pathway (GO:0030178), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), negative regulation of DNA-templated transcription (GO:0045892), negative regulation of canonical Wnt signaling pathway (GO:0090090), negative regulation of anoikis (GO:2000811), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (4): transcription corepressor activity (GO:0003714), identical protein binding (GO:0042802), DNA-binding transcription factor binding (GO:0140297), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytosol (GO:0005829), beta-catenin-TCF complex (GO:1990907)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	2
Signaling by NOTCH1	1
Degradation of beta-catenin by the destruction complex	1
Regulation of CDH1 Gene Transcription	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of gene expression	2
DNA-templated transcription	2
cellular anatomical structure	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
anatomical structure morphogenesis	1
animal organ development	1
gene expression	1
positive regulation of macromolecule biosynthetic process	1
cell surface receptor signaling pathway	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
negative regulation of apoptotic process	1
anoikis	1
regulation of anoikis	1
regulation of RNA biosynthetic process	1
transcription coregulator activity	1
negative regulation of DNA-templated transcription	1
protein binding	1
transcription factor binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
protein-containing complex	1
cytoplasm	1
RNA polymerase II transcription regulator complex	1

Protein interactions and networks

STRING

1334 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TLE1	HNF4A	P41235	923
TLE1	HES6	Q96HZ4	814
TLE1	RUNX1	Q01196	804
TLE1	CTBP1	Q13363	798
TLE1	ESRRG	P62508	789
TLE1	SS18	Q15532	778
TLE1	SSX1	Q16384	778
TLE1	PNRC2	Q9NPJ4	764
TLE1	CD99	P14209	700
TLE1	CD99L2	Q8TCZ2	697
TLE1	LEF1	Q9UJU2	687
TLE1	PIK3R1	P27986	663
TLE1	BCL2	P10415	620
TLE1	FOXG1	P55315	617
TLE1	HDAC1	Q13547	610

IntAct

258 interactions, top by confidence:

A	B	Type	Score
NFIC	NFIB	psi-mi:“MI:2364”(proximity)	0.690
TLE1	DAZAP2	psi-mi:“MI:0915”(physical association)	0.670
DAZAP2	TLE1	psi-mi:“MI:0915”(physical association)	0.670
TLE2	CCT6A	psi-mi:“MI:0914”(association)	0.640
RUNX2	UBTF	psi-mi:“MI:0914”(association)	0.560
GRN	TLE1	psi-mi:“MI:0915”(physical association)	0.560
HEXB	TLE1	psi-mi:“MI:0915”(physical association)	0.560
PRKN	TLE1	psi-mi:“MI:0915”(physical association)	0.560
TLE1	ATXN10	psi-mi:“MI:0915”(physical association)	0.560
TLE1	RNF11	psi-mi:“MI:0915”(physical association)	0.560
TLE1	VENTX	psi-mi:“MI:0915”(physical association)	0.550
TLE1	HES6	psi-mi:“MI:0915”(physical association)	0.550
VENTX	TLE1	psi-mi:“MI:0914”(association)	0.550
HES6	TLE1	psi-mi:“MI:0914”(association)	0.550
rep	TBKBP1	psi-mi:“MI:0914”(association)	0.530
TLE2	TCP1	psi-mi:“MI:0914”(association)	0.530
TLE4	TLE1	psi-mi:“MI:0914”(association)	0.530
TLE3	TLE1	psi-mi:“MI:0914”(association)	0.530
SYT-SSX2	ATF2	psi-mi:“MI:0914”(association)	0.530

BioGRID (526): TLE1 (Affinity Capture-MS), TLE1 (Affinity Capture-MS), TLE1 (Affinity Capture-MS), TLE1 (Affinity Capture-MS), TLE1 (Affinity Capture-MS), TLE1 (Affinity Capture-MS), TLE1 (Affinity Capture-MS), HES6 (Two-hybrid), FOXA2 (Two-hybrid), TLE1 (Two-hybrid), TLE1 (Affinity Capture-MS), TLE1 (Affinity Capture-MS), TLE1 (Affinity Capture-MS), TLE1 (Affinity Capture-MS), TLE1 (Affinity Capture-MS)

ESM2 similar proteins: A1L1N5, A4IFD2, B0R0I6, E9Q7E2, O13166, O13168, O42469, O42478, O45962, O74365, P0CF24, P23899, P27889, P35680, P49847, P49848, P58462, P83038, Q03365, Q04724, Q04727, Q05041, Q07141, Q09441, Q1LVF3, Q26622, Q2LE08, Q498D1, Q58NQ4, Q5RER5, Q5RJH6, Q5W1J5, Q62311, Q62440, Q62441, Q63801, Q68CP9, Q6P4L9, Q7ZX03, Q8MJ98

Diamond homologs: A0A1W2PR48, O02482, O13166, O13168, O42469, O42478, P16371, Q04724, Q04725, Q04726, Q04727, Q07141, Q08122, Q62440, Q62441, Q9H808, Q9JIT3, Q9WVB2, Q9WVB3, A2RRU3, O14435, O42470, O94365, P16520, P40066, P63002, P63003, P79083, Q08117, Q10281, Q5A7Q3, Q5GIS3, Q5REE0, Q8C7V3, Q8TED0, A6ZQL5, A8XZJ9, P47025, Q06078, Q08924

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
CSNK2A1	up-regulates	TLE1	phosphorylation
PHF12	“up-regulates activity”	TLE1	binding
TLE1	“up-regulates activity”	SIX6	binding
TLE1	“up-regulates activity”	SIX3	binding
TLE1	“down-regulates activity”	LEF1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 159 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Repression of WNT target genes	5	31.9×	7e-05
Deactivation of the beta-catenin transactivating complex	10	20.8×	2e-08
Transcriptional regulation by RUNX2	6	13.6×	4e-04
MITF-M-dependent gene expression	7	11.3×	4e-04
NOTCH1 Intracellular Domain Regulates Transcription	5	10.6×	3e-03
Regulation of PTEN gene transcription	6	9.6×	1e-03
Transcriptional and post-translational regulation of MITF-M expression and activity	6	9.6×	1e-03
MITF-M-regulated melanocyte development	8	8.2×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
urogenital system development	5	32.6×	3e-05
neuron fate specification	6	27.7×	9e-06
cell fate specification	6	20.8×	3e-05
positive regulation of miRNA transcription	8	15.3×	8e-06
epithelial cell proliferation	7	14.4×	4e-05
inner ear morphogenesis	7	13.9×	5e-05
dorsal/ventral pattern formation	5	13.9×	1e-03
oligodendrocyte differentiation	5	13.9×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	84
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3177 predictions. Top by Δscore:

Variant	Effect	Δscore
9:81584185:C:CT	donor_gain	1.0000
9:81584211:T:TA	donor_gain	1.0000
9:81584259:T:C	donor_gain	1.0000
9:81584306:C:CC	acceptor_gain	1.0000
9:81584442:A:AC	donor_gain	1.0000
9:81584443:C:CC	donor_gain	1.0000
9:81584443:CT:C	donor_gain	1.0000
9:81584443:CTCA:C	donor_gain	1.0000
9:81584446:A:C	donor_loss	1.0000
9:81584520:TTTAC:T	acceptor_gain	1.0000
9:81584524:CCT:C	acceptor_loss	1.0000
9:81584525:C:T	acceptor_loss	1.0000
9:81584526:T:A	acceptor_loss	1.0000
9:81585498:AACTC:A	donor_loss	1.0000
9:81585499:ACTCA:A	donor_loss	1.0000
9:81585500:CTCAC:C	donor_loss	1.0000
9:81585501:TCA:T	donor_loss	1.0000
9:81585502:CAC:C	donor_loss	1.0000
9:81585503:A:AC	donor_gain	1.0000
9:81585504:C:CC	donor_gain	1.0000
9:81585504:CCA:C	donor_gain	1.0000
9:81585536:G:C	donor_gain	1.0000
9:81585652:AGAT:A	acceptor_gain	1.0000
9:81585656:C:CC	acceptor_gain	1.0000
9:81585657:T:G	acceptor_loss	1.0000
9:81587677:TCACC:T	donor_loss	1.0000
9:81587679:AC:A	donor_loss	1.0000
9:81587680:C:CG	donor_loss	1.0000
9:81590072:A:T	acceptor_gain	1.0000
9:81590802:CA:C	donor_loss	1.0000

AlphaMissense

5081 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:81584235:C:T	G759E	1.000
9:81584241:C:T	G757D	1.000
9:81584242:C:G	G757R	1.000
9:81584247:A:T	V755D	1.000
9:81584283:A:G	L743P	1.000
9:81584283:A:T	L743H	1.000
9:81584455:A:T	I733K	1.000
9:81584464:C:T	G730E	1.000
9:81584465:C:G	G730R	1.000
9:81584465:C:T	G730R	1.000
9:81584476:C:G	R726P	1.000
9:81584478:C:A	W725C	1.000
9:81584478:C:G	W725C	1.000
9:81584480:A:G	W725R	1.000
9:81584480:A:T	W725R	1.000
9:81584482:G:T	A724D	1.000
9:81584488:A:G	L722P	1.000
9:81584491:A:G	L721P	1.000
9:81584497:T:A	D719V	1.000
9:81584497:T:G	D719A	1.000
9:81584498:C:G	D719H	1.000
9:81584500:T:A	K718I	1.000
9:81584503:C:A	G717V	1.000
9:81584503:C:T	G717E	1.000
9:81584504:C:G	G717R	1.000
9:81584504:C:T	G717R	1.000
9:81584508:A:C	S715R	1.000
9:81584508:A:T	S715R	1.000
9:81584510:T:G	S715R	1.000
9:81584515:A:G	F713S	1.000

dbSNP variants (sampled 300 via entrez): RS1000002732 (9:81635351 T>A), RS1000005639 (9:81623528 C>G), RS1000021105 (9:81665552 C>T), RS1000039521 (9:81676527 A>G), RS1000100098 (9:81623884 G>A), RS1000110246 (9:81671671 A>C), RS1000119261 (9:81585774 CTG>C), RS1000120549 (9:81635680 G>A), RS1000141089 (9:81671482 T>C), RS1000153744 (9:81618215 G>A,T), RS1000191550 (9:81689809 T>C), RS1000212277 (9:81658547 G>C), RS1000232570 (9:81690271 C>G,T), RS1000257163 (9:81654362 A>G), RS1000258802 (9:81650823 C>T)

Disease associations

OMIM: gene MIM:600189 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
movement disorder	Limited	Autosomal recessive

Mondo (1): movement disorder (MONDO:0005395)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST001523_18	Visceral adipose tissue adjusted for BMI	9.000000e-06
GCST001525_15	Visceral fat	3.000000e-06
GCST001530_9	Hippocampal atrophy	1.000000e-06
GCST002352_56	Type 2 diabetes	2.000000e-06
GCST002539_2	Schizophrenia	4.000000e-09
GCST003400_46	Type 2 diabetes	3.000000e-06
GCST004744_68	Lung adenocarcinoma	6.000000e-06
GCST004894_149	Type 2 diabetes	2.000000e-14
GCST004894_71	Type 2 diabetes	8.000000e-10
GCST005047_10	Type 2 diabetes	5.000000e-09
GCST005047_102	Type 2 diabetes	5.000000e-09
GCST006106_5	Forehead morphology	7.000000e-06
GCST006867_106	Type 2 diabetes	2.000000e-22
GCST006867_112	Type 2 diabetes	3.000000e-12
GCST007843_16	Rheumatoid arthritis	1.000000e-09
GCST007847_20	Type 2 diabetes	3.000000e-19
GCST008179_11	Moderate-to-late spontaneous preterm birth	4.000000e-06
GCST009379_89	Type 2 diabetes	4.000000e-24
GCST010118_174	Type 2 diabetes	1.000000e-28
GCST90000025_471	Appendicular lean mass	2.000000e-10
GCST90002390_388	Mean corpuscular hemoglobin	1.000000e-11
GCST90002392_536	Mean corpuscular volume	7.000000e-12

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0005039	hippocampal atrophy
EFO:0006917	spontaneous preterm birth
EFO:0004980	appendicular lean mass
EFO:0004527	mean corpuscular hemoglobin

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009069	Movement Disorders	C10.228.662

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

47 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation, decreases expression	4
Tetrachlorodibenzodioxin	affects expression, increases expression	3
Acetaminophen	increases expression	2
Doxorubicin	decreases expression, increases expression	2
Estradiol	affects expression, decreases expression	2
Nickel	decreases expression	2
Tobacco Smoke Pollution	decreases methylation, increases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases methylation, increases expression, increases methylation	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	increases methylation	1
geraniol	increases expression	1
trichostatin A	decreases expression	1
cobaltous chloride	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1

Cellosaurus cell lines

8 cell lines: 5 cancer cell line, 2 transformed cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4PC	TLE1-464-G04	Embryonic stem cell	Male
CVCL_B0ZZ	Abcam MCF-7 TLE1 KO	Cancer cell line	Female
CVCL_B2IM	Abcam HeLa TLE1 KO	Cancer cell line	Female
CVCL_B3JC	Abcam HEK293T TLE1 KO	Transformed cell line	Female
CVCL_D8CI	Ubigene A-549 TLE1 KO	Cancer cell line	Male
CVCL_D9UB	Ubigene HEK293 TLE1 KO	Transformed cell line	Female
CVCL_TS48	HAP1 TLE1 (-) 1	Cancer cell line	Male
CVCL_TS49	HAP1 TLE1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT06710574	PHASE4	RECRUITING	Multimodal Image Technologies Investigate the Role and Mechanism of Probiotics in Improving RBD with Parkinson’s Disease
NCT01838278	PHASE3	UNKNOWN	Effectiveness of Vojta Therapy in Motor Development of Preterm Children
NCT00001929	PHASE2	COMPLETED	Treatment of Parkinson’s Disease With Eliprodil
NCT00331669	PHASE2	UNKNOWN	Efficacy and Safety of Deep Brain Stimulation (DBS) of the Pallidal (GPi) in Patients With Tardive Dystonia
NCT00406029	PHASE2	COMPLETED	Dyskinesia in Parkinson’s Disease (Study P04501)
NCT00537017	PHASE2	COMPLETED	Follow Up Safety Study of SCH 420814 in Subjects With Parkinson’s Disease (P05175)
NCT00693472	PHASE2	TERMINATED	Study of Preladenant for the Treatment of Neuroleptic Induced Akathisia (Study P05145)
NCT01385592	PHASE2	COMPLETED	Evaluation of the Efficacy and Safety of AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT01491529	PHASE2	COMPLETED	Evaluation of the Efficacy and Safety of Modified Release AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT01491932	PHASE2	COMPLETED	Open-label, Long-term Safety Extension Study of AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT04536987	PHASE2	COMPLETED	Robot Therapy for Rehabilitation of Hand Movement After Stroke
NCT04912115	PHASE2	SUSPENDED	Randomized, Double-Blind, Active Placebo-Controlled Study of Ketamine to Treat Levodopa-Induced Dyskinesia
NCT05636852	PHASE2	TERMINATED	Altropane Dose for Imaging Patients With Suspected Parkinson’s Disease
NCT00001663	PHASE1	COMPLETED	Treatment of Cortical Myoclonus With Repetitive Transcranial Magnetic Stimulation
NCT02589340	PHASE1	TERMINATED	Buspirone, in Combination With Amantadine, for the Treatment of Levodopa-induced Dyskinesia
NCT03065192	PHASE1	COMPLETED	Safety and Efficacy Study of VY-AADC01 for Advanced Parkinson’s Disease
NCT07232147	PHASE1	NOT_YET_RECRUITING	Clinical Research on Stem Cell Therapy for Parkinson’s Disease
NCT00036296	PHASE1/PHASE2	COMPLETED	Effects of Talampanel on Patients With Advanced Parkinson’s Disease
NCT00037167	PHASE1/PHASE2	COMPLETED	Effects of Exercise Poles on Older Adults During Exercise Walking
NCT03295786	PHASE1/PHASE2	COMPLETED	Clinical Study to Test the Safety of CDNF by Brain Infusion in Patients With Parkinson’s Disease
NCT03775538	PHASE1/PHASE2	COMPLETED	Safety of CDNF by Brain Infusion in Patients With Parkinson’s Disease. Extension to HP-CD-CL-2002 Clinical Study
NCT04228653	PHASE1/PHASE2	UNKNOWN	Long-Term Follow-up Safety After DDS Implantation With/Without CDNF Infusions
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT00500994	EARLY_PHASE1	COMPLETED	Neurobiology of Functional Movement Disorder and Non-Epileptic Seizures
NCT00001208	Not specified	RECRUITING	Botulinum Toxin for the Treatment of Involuntary Movement Disorders
NCT00001252	Not specified	RECRUITING	Human Movement Database
NCT00001324	Not specified	COMPLETED	PET Scan to Study Brain Control of Human Movement
NCT00001361	Not specified	COMPLETED	Magnetic Resonance Imaging Studies of Motor and Thought Processes
NCT00001549	Not specified	COMPLETED	Diagnosis and Natural History Study of Patients With Neurological Conditions
NCT00001665	Not specified	COMPLETED	Transcranial Magnetic Stimulation for the Treatment of Parkinson’s Disease
NCT00001667	Not specified	COMPLETED	Genotype/Phenotype Correlation of Movement Disorders and Other Neurological Diseases
NCT00001780	Not specified	COMPLETED	Magnetic Stimulation of the Human Nervous System
NCT00017966	Not specified	COMPLETED	Brain Excitability During Self-Paced Voluntary Movements
NCT00017979	Not specified	COMPLETED	Study of Brain Control of Movement
NCT00018889	Not specified	RECRUITING	Phenotype/Genotype Correlations in Movement Disorders
NCT00042120	Not specified	COMPLETED	Farming and Movement Evaluation Study (FAME)
NCT00056888	Not specified	COMPLETED	Neurophysiological Studies in Patients With Paroxysmal Hyperkinetic Movement Disorders