TPR

Summary

TPR (translocated promoter region, nuclear basket protein, HGNC:12017) is a protein-coding gene on chromosome 1q31.1, encoding Nucleoprotein TPR (P12270). Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope. It is a common-essential gene (DepMap: required in 98.7% of cancer cell lines).

This gene encodes a large coiled-coil protein that forms intranuclear filaments attached to the inner surface of nuclear pore complexes (NPCs). The protein directly interacts with several components of the NPC. It is required for the nuclear export of mRNAs and some proteins. Oncogenic fusions of the 5’ end of this gene with several different kinase genes occur in some neoplasias.

Source: NCBI Gene 7175 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual developmental disorder, autosomal recessive 79 (Limited, GenCC)
• Clinical variants (ClinVar): 223 total
• Phenotypes (HPO): 25
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• Cancer dependency (DepMap): dependent in 98.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_003292

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12017
Approved symbol	TPR
Name	translocated promoter region, nuclear basket protein
Location	1q31.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000047410
Ensembl biotype	protein_coding
OMIM	189940
Entrez	7175

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 4 retained_intron, 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000367478, ENST00000451586, ENST00000467810, ENST00000469463, ENST00000474852, ENST00000481347, ENST00000491783, ENST00000492973, ENST00000613151

RefSeq mRNA: 1 — MANE Select: NM_003292 NM_003292

CCDS: CCDS41446

Canonical transcript exons

ENST00000367478 — 51 exons

Exon	Start	End
ENSE00000790824	186317482	186317600
ENSE00000790825	186318447	186318603
ENSE00000790829	186322518	186322586
ENSE00000790830	186323686	186323870
ENSE00000790831	186325764	186325854
ENSE00000823022	186314629	186314724
ENSE00001030867	186346135	186346287
ENSE00001030868	186351330	186351470
ENSE00001030871	186350223	186350388
ENSE00001030886	186333122	186333394
ENSE00001030889	186335338	186335543
ENSE00001030892	186337013	186337156
ENSE00001030900	186332195	186332343
ENSE00001030902	186334325	186334533
ENSE00001030903	186336496	186336694
ENSE00001030908	186326104	186326235
ENSE00001030911	186347292	186347458
ENSE00001030922	186335068	186335129
ENSE00001030927	186331498	186331581
ENSE00001030928	186338033	186338243
ENSE00001068221	186344375	186344578
ENSE00001068222	186341252	186341389
ENSE00001068225	186345580	186345696
ENSE00001265722	186343326	186343473
ENSE00001444646	186311652	186314026
ENSE00001444649	186327460	186327660
ENSE00003477153	186359799	186359996
ENSE00003487734	186373359	186373463
ENSE00003490606	186362288	186362380
ENSE00003507780	186322318	186322412
ENSE00003514225	186361622	186361709
ENSE00003522190	186363342	186363445
ENSE00003525673	186320312	186320418
ENSE00003529386	186343906	186344090
ENSE00003535023	186360765	186360905
ENSE00003577455	186362837	186363001
ENSE00003582311	186355635	186355768
ENSE00003582315	186351976	186352110
ENSE00003587929	186370970	186371043
ENSE00003604606	186361789	186361869
ENSE00003608274	186357397	186357623
ENSE00003610313	186355410	186355558
ENSE00003615941	186339642	186339772
ENSE00003623500	186341028	186341159
ENSE00003645437	186358543	186358650
ENSE00003662167	186367886	186367982
ENSE00003670368	186353688	186353850
ENSE00003685897	186356286	186356449
ENSE00003689727	186360273	186360364
ENSE00003691190	186318733	186318828
ENSE00003843206	186374878	186375253

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 52.5047 / max 727.5935, expressed in 1820 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16344	26.2489	1795
16343	15.9210	1772
16347	7.3484	1703
16342	2.0896	907
16345	0.4717	194
16346	0.4251	175

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	98.51	gold quality
endometrium epithelium	UBERON:0004811	98.02	gold quality
cranial nerve II	UBERON:0000941	97.97	gold quality
tendon	UBERON:0000043	97.84	gold quality
pylorus	UBERON:0001166	97.68	gold quality
calcaneal tendon	UBERON:0003701	97.60	gold quality
tongue squamous epithelium	UBERON:0006919	97.54	gold quality
mammary duct	UBERON:0001765	97.46	gold quality
superficial temporal artery	UBERON:0001614	97.23	gold quality
renal medulla	UBERON:0000362	97.22	gold quality
ventricular zone	UBERON:0003053	97.20	gold quality
epithelium of mammary gland	UBERON:0003244	96.93	gold quality
pericardium	UBERON:0002407	96.92	gold quality
medial globus pallidus	UBERON:0002477	96.91	gold quality
superior surface of tongue	UBERON:0007371	96.65	gold quality
urethra	UBERON:0000057	96.52	gold quality
vena cava	UBERON:0004087	96.50	gold quality
adrenal tissue	UBERON:0018303	96.49	gold quality
cauda epididymis	UBERON:0004360	96.48	gold quality
globus pallidus	UBERON:0001875	96.45	gold quality
trabecular bone tissue	UBERON:0002483	96.45	gold quality
caput epididymis	UBERON:0004358	96.27	gold quality
trigeminal ganglion	UBERON:0001675	96.23	gold quality
cardia of stomach	UBERON:0001162	96.13	gold quality
left testis	UBERON:0004533	96.11	gold quality
inferior vagus X ganglion	UBERON:0005363	96.04	gold quality
corpus epididymis	UBERON:0004359	96.03	gold quality
right testis	UBERON:0004534	95.91	gold quality
testis	UBERON:0000473	95.89	gold quality
ganglionic eminence	UBERON:0004023	95.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

174 targeting TPR, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-5696	99.98	72.36	4487
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-4775	99.98	75.00	6394
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 29)

• results indicate that Tpr plays a critical role in the intranuclear dynamics of RNA pol II transcripts, including the processing, intranuclear transport and targeting, as well as their translocation through the NPC in mammalian cells (PMID:11952838)
• model in which Tpr constitutes the central architectural element that forms the scaffold of the nuclear basket (PMID:15229283)
• HSP mRNA export escapes stress inhibition via HSF1-mediated recruitment of the nuclear pore-associating protein TPR to HSP genes, functionally connecting the first and last nuclear steps of the gene expression (PMID:17897941)
• candidate target gene TPR within 1q and 22q that are potentially important in the pathogenesis of intracranial pediatric ependymomas. (PMID:18663750)
• Tpr regulates Mad1-Mad2 proteins are regulated during the cell cycle and mitotic spindle checkpoint signaling. (PMID:18981471)
• Tpr has a role as a determinant of perinuclear organization, with a direct role in forming a morphologically distinct nuclear sub-compartment and delimiting heterochromatin distribution (PMID:20407419)
• Tpr plays an important role in quality control of mRNA trafficked on the Nxf1 pathway. (PMID:21613532)
• Depletion of Tpr by RNA interference triggers G0-G1 arrest and ultimately induces a senescent-like phenotype dependent on the presence of p53. (PMID:21811608)
• Perinuclear localization of Tpr at the nucleopore complex is crucial for regulating intron containing mRNA export. (PMID:22253824)
• Exon 23 of the translocated promoter region gene was fused to exon 13 of FGFR1 resulting in 8p11 myeloproliferative syndrome. (PMID:22619110)
• Tpr depletion increased p53 nuclear accumulation and facilitated autophagy. (PMID:23170199)
• Tpr import is mediated by the most abundant import receptor, KPNA2, which binds the bipartite NLS in Tpr with nanomolar affinity (PMID:23649804)
• Tpr is a kinetochore-independent, rate-limiting factor required to mount and sustain a robust SAC response. (PMID:24344181)
• analysis of interactions between CRM1 and the nuclear pore protein Tpr and snurportin (PMID:24722547)
• Protein kinase A phosphorylates the S2094 residue and that the site is hyperphosphorylated during mitosis. (PMID:24938596)
• Tpr maintains a chromatin environment favourable for HIV replication. (PMID:25744187)
• Report mutual regulation between Tpr and Aurora A and further confirm the importance of nucleoporin function in spindle pole organization, bipolar spindle assembly, and mitosis. (PMID:25789545)
• SLK interacts with Tpr and alpha-actinin-4 in cells, and these protein-protein interactions may control the subcellular localization and the biological activity of SLK. (PMID:26094769)
• Using a BioID proximity-based proteomic screen, we identify the nuclear pore complex protein TPR as a novel AKAP95 binding partner. We show interaction between AKAP95 and TPR in mitosis, and an AKAP95-dependent enrichment of TPR in the spindle microtubule area in metaphase, then later in the spindle midzone area. (PMID:28379780)
• Fusion of TPR(2-142) protein to the MET intracellular domain strongly and selectively stabilizes the alphaG helix of the MET kinase domain.TPR has an ability to induce dimerization and activation of fusion kinases. (PMID:28528776)
• TPR is necessary for both formation and maintenance of senescence-associated heterochromatin foci (PMID:30692205)
• TPR contributes to the organization of the nuclear lamina and in cooperation with lamin B1 and lamin A-C guards the interphase assembly of nuclear pore complexes. (PMID:30762072)
• Nucleoporin TPR (translocated promoter region, nuclear basket protein) upregulation alters MTOR-HSF1 trails and suppresses autophagy induction in ependymoma. (PMID:32207633)
• TPR is required for the efficient nuclear export of mRNAs and lncRNAs from short and intron-poor genes. (PMID:33091126)
• Cancer-related SRCAP and TPR mutations in colon cancers. (PMID:33307343)
• The human nucleoporin Tpr protects cells from RNA-mediated replication stress. (PMID:34168151)
• ZC3HC1 Is a Novel Inherent Component of the Nuclear Basket, Resident in a State of Reciprocal Dependence with TPR. (PMID:34440706)
• Nucleoporin TPR promotes tRNA nuclear export and protein synthesis in lung cancer cells. (PMID:34793452)
• Identification of MKI67, TPR , and TCHH Mutations as Prognostic Biomarkers for Patients With Defective Mismatch Repair Colon Cancer Stage II/III. (PMID:37643197)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tprb	ENSDARG00000016630
danio_rerio	tpra	ENSDARG00000103004
mus_musculus	Tpr	ENSMUSG00000006005
rattus_norvegicus	Tpr	ENSRNOG00000002394
drosophila_melanogaster	Mgtor	FBGN0013756

Protein

Protein identifiers

Nucleoprotein TPR — P12270 (reviewed: P12270)

Alternative names: Megator, NPC-associated intranuclear protein, Translocated promoter region protein

All UniProt accessions (2): P12270, Q5SWX9

UniProt curated annotations — full annotation on UniProt →

Function. Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope. Functions as a scaffolding element in the nuclear phase of the NPC essential for normal nucleocytoplasmic transport of proteins and mRNAs, plays a role in the establishment of nuclear-peripheral chromatin compartmentalization in interphase, and in the mitotic spindle checkpoint signaling during mitosis. Involved in the quality control and retention of unspliced mRNAs in the nucleus; in association with NUP153, regulates the nuclear export of unspliced mRNA species bearing constitutive transport element (CTE) in a NXF1- and KHDRBS1-independent manner. Negatively regulates both the association of CTE-containing mRNA with large polyribosomes and translation initiation. Does not play any role in Rev response element (RRE)-mediated export of unspliced mRNAs. Implicated in nuclear export of mRNAs transcribed from heat shock gene promoters; associates both with chromatin in the HSP70 promoter and with mRNAs transcribed from this promoter under stress-induced conditions. Modulates the nucleocytoplasmic transport of activated MAPK1/ERK2 and huntingtin/HTT and may serve as a docking site for the XPO1/CRM1-mediated nuclear export complex. According to some authors, plays a limited role in the regulation of nuclear protein export. Also plays a role as a structural and functional element of the perinuclear chromatin distribution; involved in the formation and/or maintenance of NPC-associated perinuclear heterochromatin exclusion zones (HEZs). Finally, acts as a spatial regulator of the spindle-assembly checkpoint (SAC) response ensuring a timely and effective recruitment of spindle checkpoint proteins like MAD1L1 and MAD2L1 to unattached kinetochore during the metaphase-anaphase transition before chromosome congression. Its N-terminus is involved in activation of oncogenic kinases.

Subunit / interactions. Interacts with IFI204 (via C-terminal region). Interacts with IFI203. Homodimer. Part of the nuclear pore complex (NPC). Associates with the XPO1/CRM1-mediated nuclear export complex, the Importin alpha/Importin beta receptor and the dynein 1 complex. Interacts (via C-terminal domain) with the KPNB1; the interaction occurs in a RanGTP-dependent manner. Interacts (via C-terminal regionand phosphorylated form) with MAPK1/ERK2 (via phosphorylated form); the interaction requires dimerization of MAPK1/ERK2 and increases following EGF stimulation. Interacts with MAPK3/ERK1; the interaction increases following EGF stimulation. Interacts (via coiled coil region) with NUP153; the interaction is direct. Interacts with HSF1; the interaction increases in a stress-responsive manner and stimulates export of stress-induced HSP70 mRNA. Interacts with huntingtin/HTT; the interaction is inhibited by aggregated huntingtin/HTT forms with expanded polyglutamine stretch. Interacts with MAD1L1 (via N-terminal region), MAD2L1, and TTK; the interactions occurs in a microtubule-independent manner. Interacts (via middle region) with DYNLL1. Interacts with DCTN1, dynein, NUP153 and tubulin. Interacts with MTA1. Interacts with ZC3HC1; this interaction mediates ZC3HC1 nuclear envelopes (NE)-association but also required for proper positioning of a substantial amount of TPR at the nuclear basket (NB).

Subcellular location. Nucleus. Nucleus membrane. Nucleus envelope. Nuclear pore complex. Cytoplasm. Cytoskeleton. Spindle. Chromosome. Centromere. Kinetochore.

Tissue specificity. Expressed in esophagus, ovary, liver, skin, smooth muscles, cerebrum and fetal cerebellum (at protein level). Highest in testis, lung, thymus, spleen and brain, lower levels in heart, liver and kidney.

Post-translational modifications. Phosphorylated. Phosphorylation occurs on serine and threonine residues (comprised in the C-terminal region) by MAPK1/ERK2 and stabilizes the interaction between these two proteins. Proteolytically degraded after poliovirus (PV) infection; degradation is restricted to its unfolded C-terminal tail domain whereas its coiled-coil domain containing NCP- and NUP153-binding domains withstand degradation.

Disease relevance. A chromosomal aberration involving TPR has been found in papillary thyroid carcinomas (PTCs). Intrachromosomal rearrangement that links the 5’-end of the TPR gene to the protein kinase domain of NTRK1 forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the carboxy terminus of the NTRK1 protein. Involved in tumorigenic rearrangements with the MET. Intellectual developmental disorder, autosomal recessive 79 (MRT79) [MIM:620393] An autosomal recessive neurodevelopmental disorder apparent from infancy and characterized by global developmental delay, severe intellectual disability, poor or absent speech, ataxia, and postnatal microcephaly. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal domain mediates intranuclear attachment to the nuclear pore complex. The C-terminal domain mediates its nuclear import.

Similarity. Belongs to the TPR family.

Isoforms (2)

UniProt ID	Names	Canonical?
P12270-1	1	yes
P12270-2	2

RefSeq proteins (1): NP_003283* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012929	Nucleoprot-TPR/MLP1-2_dom	Domain
IPR057577	Nucleoprot-TPR/MLP1_dom	Domain
IPR057974	NUA/TPR/MLP1-2-like_dom	Domain

Pfam: PF07926, PF25481, PF25785

UniProt features (84 total): modified residue 33, compositionally biased region 18, region of interest 10, sequence conflict 5, coiled-coil region 4, sequence variant 4, helix 3, splice variant 2, mutagenesis site 2, initiator methionine 1, chain 1, site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5TO5	X-RAY DIFFRACTION	2.5
5TO7	X-RAY DIFFRACTION	2.6
5TO6	X-RAY DIFFRACTION	2.7
5TVB	X-RAY DIFFRACTION	2.75

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P12270-F1	61.60	0.01

Functional residue map

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

Catalytic / active sites (1): 191 (breakpoint for translocation to form trk-t1)

Post-translational modifications (33): 2, 252, 312, 345, 379, 428, 457, 477, 522, 523, 632, 713, 723, 748, 755, 1185, 1690, 1692, 1893, 2034 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
458	diminishes association to npc but not homodimerization. inhibits association to npc, interaction with nup153 and nuclear
489	diminishes association to npc but not homodimerization. inhibits association to npc, interaction with nup153 and nuclear

Function

Pathways and Gene Ontology

Reactome pathways

32 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-159227	Transport of the SLBP independent Mature mRNA
R-HSA-159230	Transport of the SLBP Dependant Mature mRNA
R-HSA-159231	Transport of Mature mRNA Derived from an Intronless Transcript
R-HSA-159236	Transport of Mature mRNA derived from an Intron-Containing Transcript
R-HSA-165054	Rev-mediated nuclear export of HIV RNA
R-HSA-168271	Transport of Ribonucleoproteins into the Host Nucleus
R-HSA-168276	NS1 Mediated Effects on Host Pathways
R-HSA-168325	Viral Messenger RNA Synthesis
R-HSA-168333	NEP/NS2 Interacts with the Cellular Export Machinery
R-HSA-170822	Regulation of Glucokinase by Glucokinase Regulatory Protein
R-HSA-180746	Nuclear import of Rev protein
R-HSA-180910	Vpr-mediated nuclear import of PICs
R-HSA-1855170	IPs transport between nucleus and cytosol
R-HSA-1855196	IP3 and IP4 transport between cytosol and nucleus
R-HSA-1855229	IP6 and IP7 transport between cytosol and nucleus
R-HSA-191859	snRNP Assembly
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins
R-HSA-3232142	SUMOylation of ubiquitinylation proteins
R-HSA-3301854	Nuclear Pore Complex (NPC) Disassembly
R-HSA-3371453	Regulation of HSF1-mediated heat shock response
R-HSA-4085377	SUMOylation of SUMOylation proteins
R-HSA-4551638	SUMOylation of chromatin organization proteins
R-HSA-4570464	SUMOylation of RNA binding proteins
R-HSA-4615885	SUMOylation of DNA replication proteins
R-HSA-5619107	Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)
R-HSA-6784531	tRNA processing in the nucleus
R-HSA-9609690	HCMV Early Events
R-HSA-9610379	HCMV Late Events
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses

MSigDB gene sets: 567 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_INTERACTIONS_OF_VPR_WITH_HOST_CELLULAR_PROTEINS, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, PAX4_01, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_VIRAL_MESSENGER_RNA_SYNTHESIS, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, MORF_ATRX

GO Biological Process (28): negative regulation of transcription by RNA polymerase II (GO:0000122), RNA import into nucleus (GO:0006404), RNA export from nucleus (GO:0006405), mRNA export from nucleus (GO:0006406), protein import into nucleus (GO:0006606), nucleocytoplasmic transport (GO:0006913), nuclear pore organization (GO:0006999), mitotic spindle assembly checkpoint signaling (GO:0007094), regulation of mitotic sister chromatid separation (GO:0010965), positive regulation of heterochromatin formation (GO:0031453), mRNA export from nucleus in response to heat stress (GO:0031990), regulation of protein localization (GO:0032880), cellular response to heat (GO:0034605), cellular response to interferon-alpha (GO:0035457), positive regulation of protein import into nucleus (GO:0042307), negative regulation of translational initiation (GO:0045947), positive regulation of protein export from nucleus (GO:0046827), negative regulation of RNA export from nucleus (GO:0046832), cell division (GO:0051301), response to epidermal growth factor (GO:0070849), positive regulation of mitotic cell cycle spindle assembly checkpoint (GO:0090267), positive regulation of intracellular protein transport (GO:0090316), regulation of mitotic spindle assembly (GO:1901673), intracellular protein transport (GO:0006886), protein transport (GO:0015031), positive regulation of nucleocytoplasmic transport (GO:0046824), mRNA transport (GO:0051028), nuclear export (GO:0051168)

GO Molecular Function (10): chromatin binding (GO:0003682), RNA binding (GO:0003723), mRNA binding (GO:0003729), tubulin binding (GO:0015631), structural constituent of nuclear pore (GO:0017056), heat shock protein binding (GO:0031072), protein homodimerization activity (GO:0042803), mitogen-activated protein kinase binding (GO:0051019), dynein complex binding (GO:0070840), protein binding (GO:0005515)

GO Cellular Component (17): kinetochore (GO:0000776), nucleus (GO:0005634), nuclear envelope (GO:0005635), nuclear pore (GO:0005643), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytoplasmic dynein complex (GO:0005868), nuclear membrane (GO:0031965), nuclear periphery (GO:0034399), nuclear inclusion body (GO:0042405), nuclear pore nuclear basket (GO:0044615), mitotic spindle (GO:0072686), chromosome, centromeric region (GO:0000775), chromosome (GO:0005694), spindle (GO:0005819), cytoskeleton (GO:0005856), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Transport of Mature mRNAs Derived from Intronless Transcripts	3
Inositol phosphate metabolism	3
Interactions of Rev with host cellular proteins	2
Influenza Infection	2
SUMO E3 ligases SUMOylate target proteins	2
Antimicrobial mechanism of IFN-stimulated genes	1
Transport of Mature Transcript to Cytoplasm	1
Late Phase of HIV Life Cycle	1
Influenza Viral RNA Transcription and Replication	1
Export of Viral Ribonucleoproteins from Nucleus	1
Glycolysis	1
Interactions of Vpr with host cellular proteins	1
Metabolism of non-coding RNA	1
Nuclear Envelope Breakdown	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membraneless organelle	4
cellular anatomical structure	4
nucleus	3
RNA transport	2
import into nucleus	2
RNA export from nucleus	2
positive regulation of nucleocytoplasmic transport	2
positive regulation of intracellular protein transport	2
binding	2
nuclear pore	2
nuclear envelope	2
nuclear protein-containing complex	2
nuclear lumen	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
nuclear export	1
gene expression	1
mRNA transport	1
intracellular protein transport	1
protein localization to nucleus	1
establishment of protein localization to organelle	1
nuclear transport	1
nucleus organization	1
protein-containing complex organization	1
mitotic cell cycle	1
negative regulation of mitotic metaphase/anaphase transition	1
spindle assembly checkpoint signaling	1
mitotic spindle checkpoint signaling	1
mitotic sister chromatid separation	1
regulation of chromosome separation	1
regulation of heterochromatin formation	1
heterochromatin formation	1
positive regulation of cellular component biogenesis	1
positive regulation of heterochromatin organization	1
mRNA export from nucleus	1
cellular response to heat	1
response to nitrogen compound	1
intracellular protein localization	1
regulation of localization	1

Protein interactions and networks

STRING

2530 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TPR	NUP153	P49790	975
TPR	NUP50	Q9UKX7	895
TPR	RANBP2	P49792	886
TPR	RGPD1	P0C839	821
TPR	NUP88	Q99567	795
TPR	NUP98	P52948	794
TPR	NUP62	P37198	774
TPR	SEH1L	Q96EE3	769
TPR	NUP107	P57740	744
TPR	AHCTF1	Q8WYP5	730
TPR	NUP85	Q9BW27	728
TPR	NUP133	Q8WUM0	713
TPR	NUP214	P35658	688
TPR	AAAS	Q9NRG9	681
TPR	RAE1	P78406	671

IntAct

141 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
ZC3HC1	TPR	psi-mi:“MI:0914”(association)	0.640
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
CHEK2	PPM1G	psi-mi:“MI:0914”(association)	0.560
Mad2l1	BUB1B	psi-mi:“MI:0915”(physical association)	0.560
LRRK2	DFFA	psi-mi:“MI:0914”(association)	0.530
MAD1L1	TPR	psi-mi:“MI:0915”(physical association)	0.520
TPR	MAD1L1	psi-mi:“MI:0915”(physical association)	0.520
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
TGOLN2	PGRMC1	psi-mi:“MI:0914”(association)	0.420
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
MAP9	TPR	psi-mi:“MI:0915”(physical association)	0.400
TOP1	TPR	psi-mi:“MI:0915”(physical association)	0.400
MNT	TPR	psi-mi:“MI:0915”(physical association)	0.400
NFXL1	TPR	psi-mi:“MI:0915”(physical association)	0.400
NDUFB7	TPR	psi-mi:“MI:0915”(physical association)	0.400
PHIP	TPR	psi-mi:“MI:0915”(physical association)	0.400
ADCY10	TPR	psi-mi:“MI:0915”(physical association)	0.400
ZNF721	TPR	psi-mi:“MI:0915”(physical association)	0.400
PCCB	TPR	psi-mi:“MI:0915”(physical association)	0.400
ABCC12	TPR	psi-mi:“MI:0915”(physical association)	0.400
NPY2R	TPR	psi-mi:“MI:0915”(physical association)	0.400
Tpr		psi-mi:“MI:0915”(physical association)	0.400
Kifc1	TPR	psi-mi:“MI:0915”(physical association)	0.400
PIK3CB	TPR	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (347): TPR (Affinity Capture-MS), TPR (Affinity Capture-MS), TPR (Affinity Capture-MS), TPR (Affinity Capture-MS), TPR (Reconstituted Complex), ATL3 (Co-fractionation), EEF1D (Co-fractionation), GLRX (Co-fractionation), NUP107 (Co-fractionation), RRP12 (Co-fractionation), SRSF11 (Co-fractionation), STIP1 (Co-fractionation), TPR (Co-fractionation), TPR (Co-fractionation), TPR (Affinity Capture-MS)

ESM2 similar proteins: A1Z8P9, A2ZAC2, B0WPU9, B3DLE8, B3MNR6, B3NL60, B4G831, B4I5P7, B4JAL5, B4KE73, B4N1C2, B4PAF2, B4Q9E6, F1MA98, F6ZDS4, O15078, O15083, O61308, O61493, O74424, P12270, P16568, P34537, P34562, P40457, P85001, Q02455, Q11102, Q17AF4, Q1PE49, Q24185, Q29N92, Q336R3, Q5EE04, Q5ZKK5, Q60YN5, Q66GS9, Q6A078, Q6PH08, Q7PWT9

Diamond homologs: F1MA98, F6ZDS4, P12270, Q5EE04, G0SA56, Q02455

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
MAPK1	up-regulates	TPR	phosphorylation
TPR	up-regulates	MAD1L1	binding
TPR	up-regulates	MAD2L1	binding
TPR	“form complex”	NPC	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
Nuclear import of Rev protein	5	14.2×	6e-03
Vpr-mediated nuclear import of PICs	5	14.2×	6e-03
mRNA Splicing - Major Pathway	11	5.1×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitotic spindle assembly checkpoint signaling	5	19.6×	6e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — HCC, MBL.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	193
Likely benign	13
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

6336 predictions. Top by Δscore:

Variant	Effect	Δscore
1:186312151:ATGT:A	acceptor_gain	1.0000
1:186312152:T:G	acceptor_gain	1.0000
1:186312163:A:AG	acceptor_gain	1.0000
1:186312369:AAAG:A	donor_loss	1.0000
1:186312370:AAGG:A	donor_loss	1.0000
1:186312371:AGGTA:A	donor_loss	1.0000
1:186312373:GTA:G	donor_loss	1.0000
1:186312374:T:A	donor_loss	1.0000
1:186312754:ACAT:A	acceptor_gain	1.0000
1:186312756:A:AG	acceptor_gain	1.0000
1:186312756:AT:A	acceptor_gain	1.0000
1:186312757:T:G	acceptor_gain	1.0000
1:186312764:TACA:T	acceptor_loss	1.0000
1:186312766:CAGG:C	acceptor_loss	1.0000
1:186312767:A:G	acceptor_loss	1.0000
1:186312891:AAAG:A	donor_loss	1.0000
1:186312892:AAG:A	donor_loss	1.0000
1:186312893:AGG:A	donor_loss	1.0000
1:186312895:GT:G	donor_loss	1.0000
1:186312896:T:G	donor_loss	1.0000
1:186313676:TTTA:T	acceptor_loss	1.0000
1:186313679:A:AG	acceptor_gain	1.0000
1:186313680:G:GA	acceptor_gain	1.0000
1:186313680:GATC:G	acceptor_gain	1.0000
1:186313680:GATCA:G	acceptor_gain	1.0000
1:186317476:ACTC:A	donor_loss	1.0000
1:186317477:CTCA:C	donor_loss	1.0000
1:186317480:A:AC	donor_gain	1.0000
1:186317481:C:A	donor_loss	1.0000
1:186317481:C:CC	donor_gain	1.0000

AlphaMissense

15564 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:186320388:G:C	F2164L	1.000
1:186320388:G:T	F2164L	1.000
1:186320390:A:G	F2164L	1.000
1:186322332:A:C	F2149L	1.000
1:186322332:A:T	F2149L	1.000
1:186322334:A:G	F2149L	1.000
1:186322371:A:C	S2136R	1.000
1:186322371:A:T	S2136R	1.000
1:186322373:T:G	S2136R	1.000
1:186334415:G:T	R1698S	1.000
1:186334417:A:C	I1697S	1.000
1:186334417:A:G	I1697T	1.000
1:186334417:A:T	I1697N	1.000
1:186334419:A:C	S1696R	1.000
1:186334419:A:T	S1696R	1.000
1:186334421:T:G	S1696R	1.000
1:186334423:G:T	A1695D	1.000
1:186334507:G:T	A1667D	1.000
1:186338079:C:G	R1439P	1.000
1:186344524:C:G	A1090P	1.000
1:186344560:C:G	A1078P	1.000
1:186356342:C:G	R611P	1.000
1:186357484:A:G	L546P	1.000
1:186320382:A:C	F2166L	0.999
1:186320382:A:T	F2166L	0.999
1:186320384:A:G	F2166L	0.999
1:186320389:A:C	F2164C	0.999
1:186320389:A:G	F2164S	0.999
1:186322333:A:C	F2149C	0.999
1:186322333:A:G	F2149S	0.999

dbSNP variants (sampled 300 via entrez): RS1000043183 (1:186323541 T>C), RS1000104318 (1:186333001 T>C), RS1000141358 (1:186357288 T>C,G), RS1000166888 (1:186371214 T>C,G), RS1000169648 (1:186374028 G>A), RS1000183629 (1:186332038 T>C), RS1000188041 (1:186341963 A>C), RS1000381630 (1:186335819 T>A,C), RS1000391892 (1:186376550 C>A), RS1000408497 (1:186338767 C>A,G,T), RS1000510330 (1:186333568 A>G), RS1000531331 (1:186315389 G>A), RS1000544883 (1:186369573 A>G), RS1000579541 (1:186328638 A>G), RS1000605133 (1:186374401 T>C)

Disease associations

OMIM: gene MIM:189940 | disease phenotypes: MIM:620393

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder, autosomal recessive 79	Limited	Autosomal recessive

Mondo (2): intellectual developmental disorder, autosomal recessive 79 (MONDO:0957288), intellectual disability (MONDO:0001071)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000219	Thin upper lip vermilion
HP:0000319	Smooth philtrum
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000490	Deeply set eye
HP:0000876	Oligomenorrhea
HP:0000964	Eczematoid dermatitis
HP:0001238	Slender finger
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001629	Ventricular septal defect
HP:0001763	Pes planus
HP:0002066	Gait ataxia
HP:0002080	Intention tremor
HP:0002136	Broad-based gait
HP:0002188	Delayed CNS myelination
HP:0002311	Incoordination
HP:0003593	Infantile onset
HP:0004209	Clinodactyly of the 5th finger
HP:0010109	Short hallux
HP:0010864	Severe intellectual disability
HP:0011968	Feeding difficulties
HP:0100703	Tongue thrusting
HP:0100807	Long fingers

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725061 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.11	Kd	7760	nM	CHEMBL5653589
5.11	ED50	7760	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 10 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149647: Binding affinity to human TPR incubated for 45 mins by Kinobead based pull down assay	kd	7.7600	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	3
Valproic Acid	decreases expression, decreases methylation	3
methylmercuric chloride	decreases expression, increases expression	2
Doxorubicin	decreases expression, decreases phosphorylation, affects reaction, increases phosphorylation	2
Hydrogen Peroxide	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
FR900359	affects phosphorylation	1
TAK-243	affects sumoylation	1
geldanamycin	increases expression	1
testosterone enanthate	affects expression	1
oxybenzone	increases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects localization, increases expression, affects cotreatment	1
sodium arsenite	decreases expression	1
16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione	decreases expression	1
tetrabromobisphenol A	increases expression	1
coumarin	affects phosphorylation	1
beta-methylcholine	affects expression	1
homosalate	increases reaction, increases expression	1
tamibarotene	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
penconazole	increases expression	1
poly(propyleneimine)	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
pyrimidifen	decreases expression	1
torcetrapib	increases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652689	Binding	Binding affinity to human TPR incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders