TBL1X

Summary

TBL1X (transducin beta like 1 X-linked, HGNC:11585) is a protein-coding gene on chromosome Xp22.31-p22.2, encoding F-box-like/WD repeat-containing protein TBL1X (O60907). F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units.

The protein encoded by this gene has sequence similarity with members of the WD40 repeat-containing protein family. The WD40 group is a large family of proteins, which appear to have a regulatory function. It is believed that the WD40 repeats mediate protein-protein interactions and members of the family are involved in signal transduction, RNA processing, gene regulation, vesicular trafficking, cytoskeletal assembly and may play a role in the control of cytotypic differentiation. This encoded protein is found as a subunit in corepressor SMRT (silencing mediator for retinoid and thyroid receptors) complex along with histone deacetylase 3 protein. This gene is located adjacent to the ocular albinism gene and it is thought to be involved in the pathogenesis of the ocular albinism with late-onset sensorineural deafness phenotype. Four transcript variants encoding two different isoforms have been found for this gene. This gene is highly similar to the Y chromosome TBL1Y gene.

Source: NCBI Gene 6907 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypothyroidism, congenital, nongoitrous, 8 (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 219 total — 1 likely-pathogenic
• Phenotypes (HPO): 11
• Druggable target: yes
• MANE Select transcript: NM_005647

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11585
Approved symbol	TBL1X
Name	transducin beta like 1 X-linked
Location	Xp22.31-p22.2
Locus type	gene with protein product
Status	Approved
Aliases	EBI
Ensembl gene	ENSG00000101849
Ensembl biotype	protein_coding
OMIM	300196
Entrez	6907

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 25 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000380961, ENST00000407597, ENST00000415293, ENST00000422314, ENST00000424279, ENST00000452824, ENST00000497555, ENST00000645353, ENST00000645686, ENST00000646640, ENST00000647060, ENST00000647172, ENST00000683056, ENST00000684110, ENST00000869543, ENST00000869544, ENST00000869545, ENST00000869546, ENST00000869547, ENST00000869548, ENST00000869549, ENST00000869550, ENST00000970081, ENST00000970082, ENST00000970083, ENST00000970084, ENST00000970085, ENST00000970086

RefSeq mRNA: 4 — MANE Select: NM_005647 NM_001139466, NM_001139467, NM_001139468, NM_005647

CCDS: CCDS14133, CCDS48078

Canonical transcript exons

ENST00000645353 — 18 exons

Exon	Start	End
ENSE00000664786	9692113	9692254
ENSE00000664787	9693149	9693212
ENSE00001228660	9716220	9719740
ENSE00001312796	9688017	9688275
ENSE00001367838	9501780	9501849
ENSE00001386060	9640273	9640360
ENSE00001599442	9714902	9715003
ENSE00001681232	9709633	9709760
ENSE00001685357	9697369	9697429
ENSE00001690279	9711611	9711776
ENSE00001719220	9684043	9684188
ENSE00001737467	9709248	9709322
ENSE00001748276	9693322	9693419
ENSE00001777264	9691579	9691711
ENSE00001786231	9704993	9705114
ENSE00003504298	9653545	9653689
ENSE00003655089	9654215	9654322
ENSE00003815963	9465058	9465447

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 97.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.4349 / max 249.2237, expressed in 1733 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195443	5.2782	1570
195445	2.9425	1205
195442	1.3111	552
195446	1.0458	635
195444	0.6377	347
195447	0.1109	66
195448	0.0728	29
195449	0.0359	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cauda epididymis	UBERON:0004360	97.65	gold quality
seminal vesicle	UBERON:0000998	97.36	gold quality
corpus epididymis	UBERON:0004359	96.06	gold quality
renal medulla	UBERON:0000362	95.18	gold quality
caput epididymis	UBERON:0004358	95.09	gold quality
buccal mucosa cell	CL:0002336	95.07	gold quality
cranial nerve II	UBERON:0000941	94.71	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	94.45	gold quality
endometrium epithelium	UBERON:0004811	94.41	gold quality
inferior olivary complex	UBERON:0002127	93.61	gold quality
secondary oocyte	CL:0000655	93.18	gold quality
myometrium	UBERON:0001296	92.98	gold quality
body of uterus	UBERON:0009853	92.57	gold quality
saphenous vein	UBERON:0007318	92.54	gold quality
urethra	UBERON:0000057	92.37	gold quality
placenta	UBERON:0001987	92.27	gold quality
blood	UBERON:0000178	92.02	gold quality
adult organism	UBERON:0007023	91.95	gold quality
esophagus squamous epithelium	UBERON:0006920	91.77	gold quality
stromal cell of endometrium	CL:0002255	91.45	gold quality
metanephric glomerulus	UBERON:0004736	91.34	gold quality
renal glomerulus	UBERON:0000074	91.31	gold quality
cervix squamous epithelium	UBERON:0006922	91.19	gold quality
uterus	UBERON:0000995	91.07	gold quality
mucosa of urinary bladder	UBERON:0001259	91.06	gold quality
kidney epithelium	UBERON:0004819	90.82	gold quality
bronchial epithelial cell	CL:0002328	90.74	gold quality
palpebral conjunctiva	UBERON:0001812	90.65	gold quality
blood vessel layer	UBERON:0004797	90.59	gold quality
squamous epithelium	UBERON:0006914	90.58	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.76
E-MTAB-10290	no	77.75

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
MYC	Unknown

Upstream regulators (CollecTRI, top): NCOR1, NCOR2

miRNA regulators (miRDB)

116 targeting TBL1X, 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-6873-3P	100.00	71.42	2626
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872

Literature-anchored findings (GeneRIF, showing 15)

• TBL1 and TBLR1 are functionally redundant and essential for transcriptional repression by unliganded thyroid hormone receptors (TR) but not essential for transcriptional activation by liganded TR (PMID:15601853)
• Mutations within the LisH (LIS1 homology)motif of TBL 1X are likely to result in pathogenic consequences in genes associated with genetic diseases. (PMID:16258276)
• Wnt signalling induced the interaction between beta-catenin and TBL1-TBLR1, as well as their binding to Wnt target genes. Importantly, the recruitment of TBL1-TBLR1 and beta-catenin to Wnt target-gene promoters was mutually dependent on each other. (PMID:18193033)
• We localized proteins encoded by the top two regulated genes, TBL1X and USH1C, using immunohistochemistry to placental stem and anchoring villi associated with active contractile function. (PMID:23665419)
• TBL1 is required to protect GPS2 from degradation, with methylation of GPS2 by arginine methyltransferase PRMT6 regulating the interaction with TBL1 and inhibiting proteasome-dependent degradation. (PMID:26070566)
• Here, the authors show that transcriptional co-factor Transducin beta-like (TBL) 1 was over-expressed in both human and murine pancreatic ductal adenocarcinoma and TBL1 deficiency both prevented and reversed pancreatic tumor growth. (PMID:26070712)
• Targeted SUMOylation of TBL1 and TBLR1 may be a useful strategy for therapeutic treatment of androgen-independent prostate cancer. (PMID:27129164)
• TBL1X mutations are associated with central hypothyroidism and hearing loss. (PMID:27603907)
• missense mutations in the gene for TBLR1 that are associated with intellectual disability also prevent MeCP2 binding (PMID:28348241)
• TBL1X deletion is associated with Ocular albinism with infertility and late-onset sensorineural hearing loss. (PMID:30160833)
• TBL1X mRNA and protein expression were significantly increased in the gestational diabetes mellitus placenta. TBL1X is a potential target of miR-138-5p contributed to the abnormal growth of the placenta by enhancing the proliferation of trophoblasts. (PMID:30463081)
• Transducin beta-like protein 1 controls multiple oncogenic networks in diffuse large B-cell lymphoma. (PMID:33054136)
• TBL1X: At the crossroads of transcriptional and posttranscriptional regulation. (PMID:36206873)
• Further Delineation of Central Congenital Hypothyroidism due to Variants in TBL1X and IRS4. (PMID:36860195)
• Long noncoding RNA MIAT regulates TP53 ubiquitination and expedites prostate adenocarcinoma progression by recruiting TBL1X. (PMID:37356458)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbl1x	ENSDARG00000060438
mus_musculus	Tbl1x	ENSMUSG00000025246
rattus_norvegicus	Tbl1xr1	ENSRNOG00000003686
drosophila_melanogaster	ebi	FBGN0263933

Paralogs (2): TBL1Y (ENSG00000092377), TBL1XR1 (ENSG00000177565)

Protein

Protein identifiers

F-box-like/WD repeat-containing protein TBL1X — O60907 (reviewed: O60907)

Alternative names: SMAP55, Transducin beta-like protein 1X, Transducin-beta-like protein 1, X-linked

All UniProt accessions (6): O60907, A0A2R8Y757, A0A2R8YFW3, A0A804HJZ5, C9J5F9, C9JCW3

UniProt curated annotations — full annotation on UniProt →

Function. F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units. Plays an essential role in transcription activation mediated by nuclear receptors. Probably acts as integral component of corepressor complexes that mediates the recruitment of the 19S proteasome complex, leading to the subsequent proteasomal degradation of transcription repressor complexes, thereby allowing cofactor exchange.

Subunit / interactions. Homotetramer; dimer of dimers. Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2. Interacts with GPS2 (when sumoylated); leading to protect GPS2 against degradation by the proteasome. Component of a E3 ubiquitin ligase complex containing UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X. Probably part of other corepressor complexes, that do not contain NCOR1 and NCOR2. Interacts with histones H2B, H3a and H4. Interacts with MECP2; recruits TBL1X to the heterochromatin foci. Interacts with USP44.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitous.

Disease relevance. Hypothyroidism, congenital, non-goitrous, 8 (CHNG8) [MIM:301033] A form of central hypothyroidism, a disorder characterized by sub-optimal thyroid hormone secretion, due to insufficient stimulation by the thyroid stimulating hormone of an otherwise normal thyroid gland. It may be caused by congenital or acquired disorders of the pituitary gland or hypothalamus. CHNG8 is a congenital, X-linked, relatively mild form which may be accompanied by hearing loss in some patients. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The F-box-like domain is related to the F-box domain, and apparently displays the same function as component of ubiquitin E3 ligase complexes.

Similarity. Belongs to the WD repeat EBI family.

Isoforms (2)

UniProt ID	Names	Canonical?
O60907-1	1	yes
O60907-2	2

RefSeq proteins (4): NP_001132938, NP_001132939, NP_001132940, NP_005638* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR006594	LisH	Conserved_site
IPR011047	Quinoprotein_ADH-like_sf	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR019775	WD40_repeat_CS	Conserved_site
IPR020472	WD40_PAC1	Repeat
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR045183	Ebi-like	Family

Pfam: PF00400, PF08513

UniProt features (36 total): repeat 8, mutagenesis site 7, sequence variant 6, helix 5, domain 2, modified residue 2, sequence conflict 2, chain 1, region of interest 1, cross-link 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2XTC	X-RAY DIFFRACTION	2.22
2XTD	X-RAY DIFFRACTION	3.2
2XTE	X-RAY DIFFRACTION	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60907-F1	82.78	0.64

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 (3): 153, 183, 340

Mutagenesis-validated functional residues (7):

Position	Phenotype
77	abolished homotetramerization, leading to a homodimer.
90	reduced interaction with ncor2 and gps2.
94	does not affect interaction with ncor2 and gps2.
96	does not affect interaction with ncor2 and gps2.
108	reduced interaction with ncor2 and gps2.
111	reduced interaction with ncor2 and gps2. abolished ability to repress transcription.
117	does not affect interaction with ncor2 and gps2.

Function

Pathways and Gene Ontology

Reactome pathways

61 pathways

ID	Pathway
R-HSA-1368108	BMAL1:CLOCK,NPAS2 activates circadian expression
R-HSA-1989781	PPARA activates gene expression
R-HSA-2122947	NOTCH1 Intracellular Domain Regulates Transcription
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-2426168	Activation of gene expression by SREBF (SREBP)
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-3214815	HDACs deacetylate histones
R-HSA-350054	Notch-HLH transcription pathway
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-400206	Regulation of lipid metabolism by PPARalpha
R-HSA-9022537	Loss of MECP2 binding ability to the NCoR/SMRT complex
R-HSA-9022692	Regulation of MECP2 expression and activity
R-HSA-9029569	NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux
R-HSA-9609690	HCMV Early Events
R-HSA-9707564	Cytoprotection by HMOX1
R-HSA-9707616	Heme signaling
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis
R-HSA-9931509	Expression of BMAL (ARNTL), CLOCK, and NPAS2
R-HSA-9933387	RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)
R-HSA-1266738	Developmental Biology
R-HSA-1368082
R-HSA-1430728	Metabolism
R-HSA-157118	Signaling by NOTCH
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-1655829	Regulation of cholesterol biosynthesis by SREBP (SREBF)
R-HSA-1852241	Organelle biogenesis and maintenance

MSigDB gene sets: 434 (showing top): REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, REACTOME_SIGNALING_BY_NOTCH, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, NKX25_02, TGCACTT_MIR519C_MIR519B_MIR519A, GCANCTGNY_MYOD_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, MITSIADES_RESPONSE_TO_APLIDIN_DN, RACCACAR_AML_Q6, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, CEBPB_01, ATGTTAA_MIR302C

GO Biological Process (10): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), proteolysis (GO:0006508), sensory perception of sound (GO:0007605), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), protein stabilization (GO:0050821), positive regulation of canonical Wnt signaling pathway (GO:0090263), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (5): transcription cis-regulatory region binding (GO:0000976), transcription corepressor activity (GO:0003714), histone binding (GO:0042393), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (5): histone deacetylase complex (GO:0000118), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription repressor complex (GO:0017053), mitotic spindle (GO:0072686)

Reactome top-level categories

Rollup of top-18 pathways:

Category	Pathways
Circadian clock	3
Regulation of lipid metabolism by PPARalpha	1
Signaling by NOTCH1	1
Mitochondrial biogenesis	1
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Chromatin modifying enzymes	1
Generic Transcription Pathway	1
Adipogenesis	1
Metabolism of lipids	1
Loss of function of MECP2 in Rett syndrome	1
Transcriptional Regulation by MECP2	1
NR1H2 and NR1H3-mediated signaling	1
HCMV Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	3
regulation of DNA-templated transcription	3
regulation of transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
DNA-templated transcription	2
protein binding	2
protein metabolic process	1
sensory perception of mechanical stimulus	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
regulation of protein stability	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
negative regulation of RNA biosynthetic process	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
transcription coregulator activity	1
binding	1
nucleoplasm	1
nuclear protein-containing complex	1
catalytic complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
transcription regulator complex	1
spindle	1

Protein interactions and networks

STRING

6057 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBL1X	GPS2	Q13227	997
TBL1X	NCOR1	O75376	996
TBL1X	HDAC3	O15379	994
TBL1X	TBL1XR1	Q9BZK7	987
TBL1X	NCOR2	Q9Y618	984
TBL1X	CTNNB1	P35222	953
TBL1X	TPO	P07202	914
TBL1X	P0DN79	P0DN79	786
TBL1X	H7C2H4	H7C2H4	786
TBL1X	OFD1	O75665	715
TBL1X	MKLN1	Q9UL63	711
TBL1X	TCOF1	Q13428	702
TBL1X	NOLC1	Q14978	663
TBL1X	BARX2	Q9UMQ3	635
TBL1X	TAB2	Q9NYJ8	620

IntAct

92 interactions, top by confidence:

A	B	Type	Score
GPS2	HDAC3	psi-mi:“MI:0914”(association)	0.900
HDAC3	TBL1X	psi-mi:“MI:0914”(association)	0.760
NFIC	NFIB	psi-mi:“MI:2364”(proximity)	0.690
HDAC3	AKAP8	psi-mi:“MI:0914”(association)	0.650
HDAC3	KDM1A	psi-mi:“MI:0914”(association)	0.650
TBL1XR1	HDAC3	psi-mi:“MI:0914”(association)	0.640
TBL1X	ARL3	psi-mi:“MI:0915”(physical association)	0.560
FHL2	CNOT1	psi-mi:“MI:0914”(association)	0.530
GPS2	DCTN6	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
WDR59	EPB41L2	psi-mi:“MI:0914”(association)	0.530
ERF	TBL1X	psi-mi:“MI:0914”(association)	0.530
SPATA46	MDM4	psi-mi:“MI:0914”(association)	0.530
TBL1X	TINF2	psi-mi:“MI:0915”(physical association)	0.510
EN1	NFIB	psi-mi:“MI:2364”(proximity)	0.470
TBL1X	TERF1	psi-mi:“MI:0915”(physical association)	0.370
TBL1X	HR	psi-mi:“MI:0915”(physical association)	0.370
TBL1X	DLX3	psi-mi:“MI:0915”(physical association)	0.370
HP	TBL1X	psi-mi:“MI:0915”(physical association)	0.370
TBL1X	KHDRBS1	psi-mi:“MI:0915”(physical association)	0.370
DNAJB4	TBL1X	psi-mi:“MI:0915”(physical association)	0.370
FOXK2	PHF20L1	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
EGLN3	FAM168B	psi-mi:“MI:0914”(association)	0.350
SSRP1	DDX39A	psi-mi:“MI:0914”(association)	0.350

BioGRID (244): TBL1X (Affinity Capture-MS), TBL1X (Affinity Capture-MS), TBL1X (Affinity Capture-MS), SMARCD2 (Co-fractionation), TBL1X (Co-fractionation), TBL1X (Co-fractionation), TBL1X (Co-fractionation), TBL1X (Co-purification), GPS2 (Reconstituted Complex), GPS2 (Affinity Capture-Western), TBL1X (Affinity Capture-MS), TBL1X (Co-localization), CTNNB1 (Co-localization), TBL1X (Affinity Capture-MS), TBL1X (Biochemical Activity)

ESM2 similar proteins: A0A2R8QFQ6, A0A2R8RWN9, D3Z7P3, E9PV86, G3MWR8, O54865, O60907, O89050, O94925, P13264, P16068, P20595, P58058, Q02153, Q08211, Q12800, Q13042, Q14722, Q28141, Q28D01, Q3MHJ2, Q3ULA2, Q4R8H1, Q4ZHR9, Q5R874, Q5RB35, Q5SP67, Q5SRY7, Q5ZHN3, Q6DN14, Q7RTP6, Q7T2U9, Q7Z6J6, Q8BTG7, Q8C6G8, Q8CJ19, Q8K4Q0, Q8N122, Q8N2K0, Q8R349

Diamond homologs: A2QHM1, A2QPW4, A3LNW3, A3LVM1, A5E2R6, A7EZJ5, A7RWD2, A7TLU2, A7YY75, A8IZG4, A8PWQ8, A9VDW7, B0XAF3, B3MC74, B3NQR5, B3RNR8, B4GDM7, B4GMG4, B4HRQ6, B4JW81, B4KTK4, B4LJT7, B4MY77, B4P7Q3, B4QFZ8, B5X212, B5X9P2, B7QKS1, B9WHJ2, G0SA60, O13923, O14186, O22607, O60907, O76071, O80990, O94319, P0CS50, P0CS51, P53011

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
TBL1X	“form complex”	SCF(TBL1)	binding
TBL1X	“up-regulates activity”	CTNNB1	binding
hsa-miR-610	“down-regulates quantity by repression”	TBL1X	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 102 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
Deactivation of the beta-catenin transactivating complex	6	21.2×	1e-04
Regulation of PTEN gene transcription	5	13.5×	2e-03
TCF dependent signaling in response to WNT	7	12.5×	3e-04
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	5	11.1×	4e-03
Signaling by WNT	5	8.5×	8e-03
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	6	7.5×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
cell fate commitment	7	22.2×	5e-06
cartilage development	6	16.2×	2e-04
positive regulation of miRNA transcription	5	15.6×	1e-03
anatomical structure morphogenesis	8	12.0×	5e-05
transcription by RNA polymerase II	15	11.4×	9e-10
DNA replication	5	8.9×	9e-03
gene expression	8	6.9×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	85
Likely benign	8
Benign	16

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
691491	NM_005647.4(TBL1X):c.1015C>T (p.Arg339Ter)	Likely pathogenic

SpliceAI

5334 predictions. Top by Δscore:

Variant	Effect	Δscore
X:9501778:A:AG	acceptor_gain	1.0000
X:9501779:G:GG	acceptor_gain	1.0000
X:9640269:CTA:C	acceptor_loss	1.0000
X:9640270:TAG:T	acceptor_loss	1.0000
X:9640271:A:AG	acceptor_gain	1.0000
X:9640271:A:T	acceptor_loss	1.0000
X:9640271:AGGCT:A	acceptor_gain	1.0000
X:9640272:G:GG	acceptor_gain	1.0000
X:9640272:G:GT	acceptor_loss	1.0000
X:9640272:GGCT:G	acceptor_gain	1.0000
X:9640272:GGCTG:G	acceptor_gain	1.0000
X:9640357:TAAGG:T	donor_loss	1.0000
X:9640361:G:GA	donor_loss	1.0000
X:9640361:G:GG	donor_gain	1.0000
X:9640362:T:A	donor_loss	1.0000
X:9684037:CCACA:C	acceptor_loss	1.0000
X:9684038:CACAG:C	acceptor_loss	1.0000
X:9684040:CAGGT:C	acceptor_loss	1.0000
X:9684041:A:T	acceptor_loss	1.0000
X:9684186:GAG:G	donor_gain	1.0000
X:9684189:G:GC	donor_loss	1.0000
X:9684189:G:GG	donor_gain	1.0000
X:9684190:T:A	donor_loss	1.0000
X:9688012:CCCA:C	acceptor_loss	1.0000
X:9688013:CCA:C	acceptor_loss	1.0000
X:9688014:CAGG:C	acceptor_loss	1.0000
X:9688015:A:AC	acceptor_loss	1.0000
X:9688015:A:AG	acceptor_gain	1.0000
X:9688015:AG:A	acceptor_gain	1.0000
X:9688015:AGGAT:A	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000014045 (X:9651797 A>G), RS1000017839 (X:9609576 T>C), RS1000078296 (X:9595989 A>G), RS1000079523 (X:9469713 G>C), RS1000098091 (X:9597863 C>T), RS1000104315 (X:9465311 G>A), RS1000128481 (X:9477222 A>C), RS1000145886 (X:9469883 G>A), RS1000146027 (X:9629648 C>G), RS1000154183 (X:9573487 T>C), RS1000159490 (X:9682733 C>T), RS1000161078 (X:9571698 A>G,T), RS1000172567 (X:9660371 G>T), RS1000174169 (X:9622188 A>G), RS1000174715 (X:9492338 A>C)

Disease associations

OMIM: gene MIM:300196 | disease phenotypes: MIM:301033

GenCC curated gene-disease

Disease	Classification	Inheritance
hypothyroidism, congenital, nongoitrous, 8	Strong	X-linked

Mondo (2): hypothyroidism, congenital, nongoitrous, 8 (MONDO:0026731), congenital hypothyroidism (MONDO:0018612)

Orphanet (1): Congenital hypothyroidism (Orphanet:442)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000256	Macrocephaly
HP:0000869	Secondary amenorrhea
HP:0001417	X-linked inheritance
HP:0002019	Constipation
HP:0003124	Hypercholesterolemia
HP:0003593	Infantile onset
HP:0007018	Attention deficit hyperactivity disorder
HP:0011787	Central hypothyroidism
HP:0031987	Diminished ability to concentrate
HP:0033075	Inappropriately normal thyroid-stimulating hormone level
HP:0033078	Decreased circulating free T4 concentration

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001942_23	Prostate cancer	2.000000e-10
GCST010002_85	Refractive error	2.000000e-18

MeSH disease descriptors (1)

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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6195564 (PROTEIN-PROTEIN INTERACTION)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	6
Valproic Acid	decreases expression, increases methylation	4
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	3
trichostatin A	decreases expression, affects cotreatment	2
Acetaminophen	decreases expression, increases expression	2
Cisplatin	decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
Tretinoin	decreases expression	2
Aflatoxin B1	affects expression, affects methylation	2
Cadmium Chloride	increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
methylselenic acid	increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	decreases expression	1
aflatoxin B2	increases methylation	1
Am 580	decreases expression	1
perfluoro-n-nonanoic acid	increases expression	1
AM 251	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
ON 01910	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Bortezomib	increases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL6073631	Binding	PROTAC activity at CRBN/TBL1X in human Ri-1 cells assessed as fold decrease in TBL1X level at 0.008 uM incubated for 6 hrs by Western blotting analysis (Rvb = 1 No_unit)	Design, Synthesis, and Biological Evaluation of Selective TBL1X Degraders. — ACS Med Chem Lett

Cellosaurus cell lines

2 cell lines: 1 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B2I9	Abcam HeLa TBL1X KO	Cancer cell line	Female
CVCL_C0H7	LZUi002-A	Induced pluripotent 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