USP25

Summary

USP25 (ubiquitin specific peptidase 25, HGNC:12624) is a protein-coding gene on chromosome 21q21.1, encoding Ubiquitin carboxyl-terminal hydrolase 25 (Q9UHP3). Deubiquitinating enzyme that hydrolyzes ubiquitin moieties conjugated to substrates and thus, functions in various biological processes including inflammation and immune response.

Ubiquitin (MIM 191339) is a highly conserved 76-amino acid protein involved in regulation of intracellular protein breakdown, cell cycle regulation, and stress response. Ubiquitin is released from degraded proteins by disassembly of the polyubiquitin chains, which is mediated by ubiquitin-specific proteases (USPs), such as USP25 (Valero et al., 1999 [PubMed 10644437]).

Source: NCBI Gene 29761 — RefSeq curated summary.

At a glance

• Gene–disease (curated): epilepsy, idiopathic generalized, susceptibility to, 19 (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 9
• Clinical variants (ClinVar): 245 total
• Druggable target: yes
• MANE Select transcript: NM_001283041

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12624
Approved symbol	USP25
Name	ubiquitin specific peptidase 25
Location	21q21.1
Locus type	gene with protein product
Status	Approved
Aliases	USP21
Ensembl gene	ENSG00000155313
Ensembl biotype	protein_coding
OMIM	604736
Entrez	29761

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 18 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000285679, ENST00000285681, ENST00000351097, ENST00000400183, ENST00000449491, ENST00000453553, ENST00000464435, ENST00000478932, ENST00000547201, ENST00000549362, ENST00000926090, ENST00000926091, ENST00000926092, ENST00000926093, ENST00000941966, ENST00000941967, ENST00000941968, ENST00000941969, ENST00000941970, ENST00000941971, ENST00000941972, ENST00000941973

RefSeq mRNA: 9 — MANE Select: NM_001283041 NM_001283041, NM_001283042, NM_001352560, NM_001352561, NM_001388299, NM_001388300, NM_001388301, NM_001388302, NM_013396

CCDS: CCDS33515, CCDS63336, CCDS63337

Canonical transcript exons

ENST00000400183 — 26 exons

Exon	Start	End
ENSE00001020263	15877796	15877991
ENSE00001020266	15842398	15842540
ENSE00001020279	15818698	15818846
ENSE00001020284	15866266	15866344
ENSE00001020305	15765997	15766141
ENSE00001020310	15824039	15824166
ENSE00001020314	15831401	15831629
ENSE00001020318	15849777	15849872
ENSE00001020323	15864268	15864446
ENSE00001020326	15830531	15830601
ENSE00001020331	15874403	15874526
ENSE00001020332	15870068	15870147
ENSE00001020334	15824966	15825061
ENSE00001020335	15833348	15833548
ENSE00001183063	15826204	15826365
ENSE00001183092	15826977	15827203
ENSE00001382509	15762891	15762968
ENSE00001736182	15847663	15847776
ENSE00003471173	15799757	15799843
ENSE00003513801	15777904	15778027
ENSE00003563904	15805121	15805258
ENSE00003612782	15791502	15791664
ENSE00003615186	15808809	15808885
ENSE00003654731	15811137	15811210
ENSE00003745204	15878303	15880064
ENSE00003921014	15729982	15730438

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 99.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.2039 / max 212.9012, expressed in 1807 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
188507	11.1908	1772
188508	6.8572	1699
188511	0.1559	53

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	99.91	gold quality
male germ cell	CL:0000015	98.36	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.71	gold quality
gluteal muscle	UBERON:0002000	97.09	gold quality
amniotic fluid	UBERON:0000173	96.95	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.46	gold quality
biceps brachii	UBERON:0001507	96.44	gold quality
calcaneal tendon	UBERON:0003701	96.33	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.18	gold quality
muscle of leg	UBERON:0001383	96.17	gold quality
gastrocnemius	UBERON:0001388	96.17	gold quality
skeletal muscle tissue	UBERON:0001134	96.16	gold quality
vastus lateralis	UBERON:0001379	96.16	gold quality
muscle organ	UBERON:0001630	96.16	gold quality
deltoid	UBERON:0001476	96.07	gold quality
quadriceps femoris	UBERON:0001377	96.04	gold quality
diaphragm	UBERON:0001103	95.08	gold quality
tibialis anterior	UBERON:0001385	95.06	gold quality
endothelial cell	CL:0000115	94.68	gold quality
triceps brachii	UBERON:0001509	94.24	gold quality
adrenal tissue	UBERON:0018303	93.85	gold quality
secondary oocyte	CL:0000655	93.39	gold quality
cauda epididymis	UBERON:0004360	93.09	gold quality
left testis	UBERON:0004533	92.83	gold quality
colonic epithelium	UBERON:0000397	92.70	gold quality
muscle tissue	UBERON:0002385	92.69	gold quality
right testis	UBERON:0004534	92.58	gold quality
monocyte	CL:0000576	92.50	gold quality
mononuclear cell	CL:0000842	92.47	gold quality
leukocyte	CL:0000738	92.38	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.76

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4

miRNA regulators (miRDB)

213 targeting USP25, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
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-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593

Literature-anchored findings (GeneRIF, showing 35)

• characterization of alternatively spliced products and tissue-specific isoforms (PMID:11597335)
• downregulation of USP25 gene in human lung cancer (PMID:18523997)
• Seven amino acids in the SIM of USP25 are sufficient for SUMO2/3-specific binding and conjugation (PMID:18538659)
• Data show that USP25m is regulated through alternative conjugation of ubiquitin (activating) or SUMO (inhibiting) to the same lysine residue (K99), which may promote the interaction with distinct intramolecular regulatory domains. (PMID:19440361)
• the second SH2 domain of SYK physically interacts with a tyrosine-rich, C-terminal region of USP25 independently of tyrosine phosphorylation (PMID:19909739)
• Studies indicate that DUBs recycle ubiquitin by processing polyubiquitin chains to generate free ubiquitin, and can be regulated by ubiquitination or phosphorylation. (PMID:21480003)
• a model where USP25 counteracts ubiquitination of ERAD substrates by the ubiquitin ligase HRD1, rescuing them from degradation by the proteasome. (PMID:22590560)
• USP25 is a novel deubiquitinating enzyme negatively regulating virus-induced interferon-beta production. (PMID:24260525)
• These findings indicate that miR-200c exerts tumor-suppressive effects for NSCLC through the suppression of USP25 expression and suggests a new therapeutic application of miR-200c in the treatment of NSCLC. (PMID:24997798)
• Findings suggest that ubiquitin-specific protease 25 (USP25) as a VRK2 substrate that acts on TRiC deubiquitination. (PMID:25755282)
• REM Sleep Behavior Disorder patients with homozygous USP25 rs2823357 progressed to synucleinopathies faster than others. (PMID:25929833)
• We detected SNPs at USP25 with associations of genome-wide significance for Inflammatory Bowel Disease. (PMID:27693347)
• Results suggest inhibition of Usp25’s catalytic activity upon the non-covalent binding of SUMO2 to the Usp25 SUMO-interacting motif, and found that SUMO2 can competitively block the interaction between the Usp25 ubiquitin-binding region and its ubiquitin substrates. (PMID:28538147)
• USP25 directly interacted with tankyrases to promote their deubiquitination and stabilization and demonstrated that USP25 deficiency could promote the degradation of tankyrases and consequent stabilization of Axin to antagonize Wnt signaling (PMID:28619731)
• Smurf1 overexpression decreases USP25 protein turnover, and the E3 ligase enzymatic activity of Smurf1 is required for USP25 degradation. (PMID:29518389)
• Polymorphism of SREBF1 gene rs11868035 may increase susceptibility to Parkinson’s disease in the northeastern Chinese population, while variant of USP25 gene rs2823357 may have no association with susceptibility to Parkinson’s disease in northeastern Chinese. (PMID:30231795)
• the high stabilization of tankyrases in cultured cells by ectopic expression of a constitutive dimer of USP25 supports a biological relevance of this tetramerization/inhibition mechanism. (PMID:30478318)
• These findings indicate that USP25 promotes stability of HBO1 in bacterial infection thereby enhances HBO1-mediated inflammatory gene transcription. (PMID:30745998)
• We confirm oligomeric states of USP25 and USP28 in cells and show that modulating oligomerization affects substrate stabilization in accordance with in vitro activity data (PMID:30926242)
• Our work led to the identification of significant differences between USP25 and USP28 and provided the molecular basis for the development of new and highly specific anti-cancer drugs (PMID:30926243)
• USP25 downregulation by miR-27a-3p contributes to the epithelial-to-mesenchymal transition process, thereby inhibiting the migration and invasion of trophoblast cells, and these findings might provide potential biomarkers for recurrent miscarriage. (PMID:30953360)
• Deubiquitylase USP25 prevents degradation of BCR-ABL protein and ensures proliferation of Ph-positive leukemia cells. (PMID:32203161)
• USP28 and USP25 are downregulated by Vismodegib in vitro and in colorectal cancer cell lines. (PMID:32578360)
• USP25 Regulates EGFR Fate by Modulating EGF-Induced Ubiquitylation Dynamics. (PMID:33202887)
• The deubiquitinase USP25 supports colonic inflammation and bacterial infection and promotes colorectal cancer. (PMID:35122046)
• Deubiquitination of TNKS1 Regulates Wnt/beta-Catenin to Affect the Expression of USP25 to Promote the Progression of Glioma. (PMID:35450028)
• USP25 UPREGULATION BOOSTS GSDMD -MEDIATED PYROPTOSIS OF ACINAR CELLS IN ACUTE PANCREATITIS. (PMID:36155610)
• Downregulation of deubiquitinating enzyme USP25 promotes the development of allergic rhinitis by enhancing TSLP signaling in the nasal epithelium. (PMID:36177892)
• Regulation of USP25 by SP1 Associates with Amyloidogenesis. (PMID:36938736)
• USP25 inhibits renal fibrosis by regulating TGFbeta-SMAD signaling pathway in Ang II-induced hypertensive mice. (PMID:37059312)
• USP25 contributes to defective neurogenesis and cognitive impairments. (PMID:37171286)
• USP25 promotes hepatocellular carcinoma progression by interacting with TRIM21 via the Wnt/beta-catenin signaling pathway. (PMID:37439386)
• Usp25-Erlin1/2 activity limits cholesterol flux to restrict virus infection. (PMID:37683630)
• Expression of USP25 associates with fibrosis, inflammation and metabolism changes in IgG4-related disease. (PMID:38521787)
• Heterozygous variants in USP25 cause genetic generalized epilepsy. (PMID:38875478)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	usp25	ENSDARG00000012314
mus_musculus	Usp25	ENSMUSG00000022867
rattus_norvegicus	Usp25	ENSRNOG00000001573

Paralogs (71): USP2 (ENSG00000036672), USP28 (ENSG00000048028), USP36 (ENSG00000055483), USP13 (ENSG00000058056), USP33 (ENSG00000077254), USP40 (ENSG00000085982), USP48 (ENSG00000090686), USP14 (ENSG00000101557), USP11 (ENSG00000102226), USP10 (ENSG00000103194), USP31 (ENSG00000103404), USP42 (ENSG00000106346), USP5 (ENSG00000111667), USP4 (ENSG00000114316), USP9Y (ENSG00000114374), USP34 (ENSG00000115464), USP35 (ENSG00000118369), USP45 (ENSG00000123552), USP22 (ENSG00000124422), USP9X (ENSG00000124486), USP6 (ENSG00000129204), USP29 (ENSG00000131864), USP26 (ENSG00000134588), USP30 (ENSG00000135093), USP15 (ENSG00000135655), USP37 (ENSG00000135913), USP44 (ENSG00000136014), USP20 (ENSG00000136878), USP8 (ENSG00000138592), USP3 (ENSG00000140455), USP21 (ENSG00000143258), USP43 (ENSG00000154914), USP16 (ENSG00000156256), USP24 (ENSG00000162402), USP1 (ENSG00000162607), USP49 (ENSG00000164663), USP38 (ENSG00000170185), USP50 (ENSG00000170236), USP47 (ENSG00000170242), USP32 (ENSG00000170832)

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase 25 — Q9UHP3 (reviewed: Q9UHP3)

Alternative names: Deubiquitinating enzyme 25, USP on chromosome 21, Ubiquitin thioesterase 25, Ubiquitin-specific-processing protease 25

All UniProt accessions (4): Q9UHP3, H7C1T8, H7C253, Q96B65

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinating enzyme that hydrolyzes ubiquitin moieties conjugated to substrates and thus, functions in various biological processes including inflammation and immune response. Modulates the Wnt/beta-catenin pathway by deubiquitinating and stabilizing tankyrases TNKS1 and TNKS2. Regulates KEAP1-NRF2 axis in the defense against oxidative assaults by deubiquitinating KEAP1 and protecting it from degradation leading to degradation of the NRF2 transcription factor that is responsible for mounting an anti-oxidation gene expression program. Positively regulates RNA virus-induced innate signaling by interacting with and deubiquitinating ERLIN1 and ERLIN2. In turn, restricts virus production by regulating cholesterol biosynthetic flux. Acts as a negative regulator of interleukin-17-mediated signaling and inflammation through the removal of ‘Lys-63’-linked ubiquitination of TRAF5 and TRAF6. Prevents the ubiquitination and degradation of TRAF3 to reduce the phosphorylation levels of JNK and P38, the secretion of IL-1B and to induce endotoxin tolerance. The muscle-specific isoform (USP25m) may have a role in the regulation of muscular differentiation and function.

Subunit / interactions. Homotetramer, inhibited form. Homodimer, active form. Interacts with ACTA1 (via its C-terminus); the interaction occurs for all isoforms but is strongest for isoform USP25m in muscle differentiating cells. Interacts (isoform USP25m only) with MYBPC1; the interaction prevents proteasomal degradation of MYBPC1. Interacts (isoform USP25m only) with FLNC (via filament repeats 17-18, 20-21 and 24). Interacts with GAPDH. Interacts with SUMO3; the interaction sumoylates efficiently USP25. Interacts with SUMO2; the interaction sumoylates efficiently USP25. Interacts with SUMO1; the interaction only weakly sumoylates USP25. Interacts with SYK; phosphorylates USP25 and regulates USP25 intracellular levels.

Subcellular location. Cytoplasm Cytoplasm. Nucleus.

Tissue specificity. Isoform USP25a is found in most adult and fetal tissues; expression is moderately high in testis, pancreas, kidney, skeletal muscle, liver, lung, placenta, heart, but very low in peripheral blood, colon, small intestine, ovary, prostate, thymus and spleen. Expressed in the brain, with high levels in the cerebral cortex. Isoform USP25b is found in all tissues except heart and skeletal muscle. Isoform USP25m is heart and skeletal muscle specific.

Post-translational modifications. Acetylated. Sumoylation impairs binding to and hydrolysis of ubiquitin chains. Sumoylated preferentially with SUMO2 or SUMO3. Desumoylated by SENP1. Polyubiquitinated by SMURF1 by promoting the ‘Lys-48’-linkage leading to proteasomal degradation. Preferentially monoubiquitinated but can also be polyubiquitinated. Autodeubiquitinated. Ubiquitination activates the enzymatic activity either by preventing sumoylation or by allowing novel interactions. Phosphorylation in the C-terminal by SYK regulates USP25 cellular levels.

Disease relevance. Epilepsy, idiopathic generalized 19 (EIG19) [MIM:621064] An autosomal dominant form of idiopathic generalized epilepsy, a disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures. EIG19 is characterized by onset of variable types of seizures in the first two decades of life. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Induction. The muscle-specific isoform (USP25m) is up-regulated during myocyte differentiation. Levels increase up to 100-fold towards completion of differentiation.

Similarity. Belongs to the peptidase C19 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UHP3-2	USP25a	yes
Q9UHP3-1	USP25b
Q9UHP3-3	USP25m, Muscle-specific isoform

RefSeq proteins (9): NP_001269970, NP_001269971, NP_001339489, NP_001339490, NP_001375228, NP_001375229, NP_001375230, NP_001375231, NP_037528 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001394	Peptidase_C19_UCH	Domain
IPR003903	UIM_dom	Conserved_site
IPR009060	UBA-like_sf	Homologous_superfamily
IPR018200	USP_CS	Conserved_site
IPR028889	USP	Domain
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050164	Peptidase_C19	Family
IPR054108	USP25/28_UIM	Conserved_site
IPR054109	UBA_8	Domain

Pfam: PF00443, PF21909, PF22566

UniProt features (106 total): helix 39, strand 22, turn 9, mutagenesis site 8, sequence variant 5, domain 4, active site 3, region of interest 3, compositionally biased region 2, modified residue 2, cross-link 2, splice variant 2, coiled-coil region 2, chain 1, short sequence motif 1, sequence conflict 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5GP7	X-RAY DIFFRACTION	1.5
6HEM	X-RAY DIFFRACTION	1.72
6H4K	X-RAY DIFFRACTION	2.05
6HEL	X-RAY DIFFRACTION	2.94
6H4J	X-RAY DIFFRACTION	3.07
5O71	X-RAY DIFFRACTION	3.28
2MUX	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UHP3-F1	78.12	0.38

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 (3): 178; 599; 607

Post-translational modifications (4): 85, 740, 99, 99

Mutagenesis-validated functional residues (8):

Position	Phenotype
91	no interaction with sumo3; when associated with a-92.
92	no interaction with sumo3; when associated with a-91.
99	abolishes sumoylation. decreased enzymatic activity.
178	abrogates deubiquitinating activity. no effect on homo- or oligomerization.
740	no effect on interaction with syk.
878	no effect on interaction with syk.
880	no effect on interaction with syk.
883	no effect on interaction with syk.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5689880	Ub-specific processing proteases

MSigDB gene sets: 434 (showing top): WENDT_COHESIN_TARGETS_UP, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, MODULE_97, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_PEPTIDE, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_MATURE_CELL, HUMMERICH_BENIGN_SKIN_TUMOR_UP, MODULE_182

GO Biological Process (13): proteolysis (GO:0006508), protein deubiquitination (GO:0016579), regulation of protein stability (GO:0031647), protein modification process (GO:0036211), protein K63-linked deubiquitination (GO:0070536), protein K48-linked deubiquitination (GO:0071108), negative regulation of response to oxidative stress (GO:1902883), negative regulation of interleukin-17-mediated signaling pathway (GO:1903882), negative regulation of ERAD pathway (GO:1904293), cellular response to oxidative stress (GO:0034599), interleukin-17A-mediated signaling pathway (GO:0038173), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), protein K48-linked ubiquitination (GO:0070936)

GO Molecular Function (11): cysteine-type deubiquitinase activity (GO:0004843), peptidase activity (GO:0008233), ubiquitin-like protein peptidase activity (GO:0019783), ubiquitin protein ligase binding (GO:0031625), SUMO binding (GO:0032183), ubiquitin binding (GO:0043130), ATPase binding (GO:0051117), deubiquitinase activity (GO:0101005), protein binding (GO:0005515), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	2
protein deubiquitination	2
response to oxidative stress	2
peptidase activity	2
ubiquitin-like protein binding	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
cytoplasm	2
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
regulation of biological quality	1
macromolecule modification	1
negative regulation of response to stimulus	1
regulation of response to oxidative stress	1
negative regulation of cytokine-mediated signaling pathway	1
interleukin-17-mediated signaling pathway	1
regulation of interleukin-17-mediated signaling pathway	1
ERAD pathway	1
negative regulation of proteasomal protein catabolic process	1
negative regulation of response to endoplasmic reticulum stress	1
regulation of ERAD pathway	1
cellular response to chemical stress	1
cytokine-mediated signaling pathway	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
protein polyubiquitination	1
cysteine-type peptidase activity	1
deubiquitinase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
ubiquitin-like protein ligase binding	1
enzyme binding	1
ubiquitin-like protein peptidase activity	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
endomembrane system	1

Protein interactions and networks

STRING

1864 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP25	USP13	Q92995	775
USP25	SUMO1	P55856	728
USP25	USP5	P45974	722
USP25	USP2	O75604	686
USP25	USP8	P40818	682
USP25	YOD1	Q5VVQ6	681
USP25	ZUP1	Q96AP4	677
USP25	USP1	O94782	671
USP25	USP7	Q93009	668
USP25	ATXN3	P54252	665
USP25	USP14	P54578	647
USP25	SUMO2	P55855	639
USP25	USP39	Q53GS9	632
USP25	USP15	Q9Y4E8	626
USP25	USP4	Q13107	624

IntAct

112 interactions, top by confidence:

A	B	Type	Score
RAD23A	USP25	psi-mi:“MI:0915”(physical association)	0.890
USP25	RAD23A	psi-mi:“MI:0915”(physical association)	0.890
RAD23B	USP25	psi-mi:“MI:0915”(physical association)	0.850
SYK	USP25	psi-mi:“MI:0915”(physical association)	0.830
USP25	SYK	psi-mi:“MI:0915”(physical association)	0.830
GDI1	RAB4A	psi-mi:“MI:0914”(association)	0.820
rep	USP25	psi-mi:“MI:0915”(physical association)	0.760
rep	USP25	psi-mi:“MI:2364”(proximity)	0.760
USP25	SUMO2	psi-mi:“MI:0915”(physical association)	0.720
SUMO2	USP25	psi-mi:“MI:0915”(physical association)	0.720
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
TNKS2	USP25	psi-mi:“MI:0407”(direct interaction)	0.590
MAGEB4	USP25	psi-mi:“MI:0915”(physical association)	0.560
USP25	ZNF426	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (227): USP25 (Reconstituted Complex), USP25 (Biochemical Activity), UBC (Biochemical Activity), UBC (Reconstituted Complex), USP25 (Two-hybrid), USP25 (Two-hybrid), USP25 (Two-hybrid), USP25 (Two-hybrid), ZNF426 (Two-hybrid), USP25 (Affinity Capture-MS), APP (Affinity Capture-Western), SYK (Two-hybrid), USP25 (Affinity Capture-MS), KCTD13 (Affinity Capture-MS), TNFAIP1 (Affinity Capture-MS)

ESM2 similar proteins: A1CHL6, A1CIL1, A1CW53, A1CX69, A2Q9N1, A2QIL5, A6RYB8, A6S9E2, A7EWF5, A7F0W2, A7KAL2, B0Y4P5, B8NSV5, C4B4E5, G2X3G1, I1RNG8, I1S8Q3, J4W0G2, M2T5U2, O14019, P0CAQ1, P0CO28, P0CO29, P0CQ10, P0CQ11, P43638, P57080, Q0CLX3, Q0CT11, Q0UY20, Q1DN93, Q2H6X2, Q2H9Y1, Q2UGZ7, Q2UUG8, Q3ZDQ4, Q4PBL3, Q4WHB7, Q4WPF2, Q4WQI1

Diamond homologs: A2BGT0, A4QNN3, D3ZPG5, Q3UN04, Q70CQ3, Q7JKC3, Q9UHP3, A0JM59, A5PMR2, B1AY13, B1WBD7, F8VPZ3, P57080, P70398, Q5ZM45, Q84WU2, Q8BW70, Q8NFA0, Q93008, Q9FPT1, Q9UPU5, Q9UTT1, A0A0R4IB93, A6QNM7, D3ZJ96, Q28CN3, Q5I043, Q5REG5, Q5ZID5, Q86UV5, Q8BWR4, Q8NB14, Q8R5K2, Q8TEY7, Q96RU2, Q9P3U0, Q9WTV6, Q9P2H5, A5PN09, A7Z056

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
VRK2	“down-regulates activity”	USP25	phosphorylation
USP25	“up-regulates quantity by stabilization”	TRiC	deubiquitination
SYK	“down-regulates quantity”	USP25	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 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
Formation of Incision Complex in GG-NER	6	28.2×	3e-05
Neddylation	8	7.0×	3e-03
Ub-specific processing proteases	7	6.9×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein autoubiquitination	5	17.0×	2e-03
protein polyubiquitination	8	13.4×	1e-04
proteasome-mediated ubiquitin-dependent protein catabolic process	8	6.0×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	190
Likely benign	9
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

5457 predictions. Top by Δscore:

Variant	Effect	Δscore
21:15730436:AAGGT:A	donor_loss	1.0000
21:15730437:AGGT:A	donor_loss	1.0000
21:15730438:GGTG:G	donor_loss	1.0000
21:15762886:TCTA:T	acceptor_loss	1.0000
21:15762887:CTA:C	acceptor_loss	1.0000
21:15762888:TA:T	acceptor_loss	1.0000
21:15762889:A:AG	acceptor_gain	1.0000
21:15762889:AG:A	acceptor_loss	1.0000
21:15762890:G:GT	acceptor_gain	1.0000
21:15762890:GC:G	acceptor_gain	1.0000
21:15762890:GCA:G	acceptor_gain	1.0000
21:15762890:GCACC:G	acceptor_gain	1.0000
21:15762964:TGAAG:T	donor_loss	1.0000
21:15762965:GAAGG:G	donor_loss	1.0000
21:15762967:AGGT:A	donor_loss	1.0000
21:15762970:T:G	donor_loss	1.0000
21:15765985:T:TA	acceptor_gain	1.0000
21:15765989:A:AG	acceptor_gain	1.0000
21:15765989:ATTT:A	acceptor_gain	1.0000
21:15765992:T:TA	acceptor_gain	1.0000
21:15765992:TGAA:T	acceptor_loss	1.0000
21:15765993:GAA:G	acceptor_loss	1.0000
21:15765995:A:AG	acceptor_gain	1.0000
21:15765995:A:T	acceptor_loss	1.0000
21:15765996:G:GC	acceptor_gain	1.0000
21:15765996:GGATA:G	acceptor_gain	1.0000
21:15766137:TACAA:T	donor_gain	1.0000
21:15766138:ACAA:A	donor_gain	1.0000
21:15766139:CAA:C	donor_gain	1.0000
21:15766140:AA:A	donor_gain	1.0000

AlphaMissense

7441 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:15777952:T:A	I106N	1.000
21:15777952:T:G	I106S	1.000
21:15791628:T:A	N173K	1.000
21:15791628:T:G	N173K	1.000
21:15791641:T:C	C178R	1.000
21:15791642:G:A	C178Y	1.000
21:15791643:T:G	C178W	1.000
21:15791644:T:A	W179R	1.000
21:15791644:T:C	W179R	1.000
21:15791646:G:C	W179C	1.000
21:15791646:G:T	W179C	1.000
21:15791647:T:C	F180L	1.000
21:15791648:T:C	F180S	1.000
21:15791649:T:A	F180L	1.000
21:15791649:T:G	F180L	1.000
21:15791650:A:C	S181R	1.000
21:15791652:T:A	S181R	1.000
21:15791652:T:G	S181R	1.000
21:15791654:C:A	A182D	1.000
21:15799779:T:C	F193S	1.000
21:15799791:T:A	V197D	1.000
21:15805152:T:C	L225P	1.000
21:15805203:C:A	P242Q	1.000
21:15805224:T:C	L249P	1.000
21:15808812:G:C	D262H	1.000
21:15808813:A:C	D262A	1.000
21:15808813:A:T	D262V	1.000
21:15808818:A:C	S264R	1.000
21:15808820:T:A	S264R	1.000
21:15808820:T:G	S264R	1.000

dbSNP variants (sampled 300 via entrez): RS1000019297 (21:15739723 C>A), RS1000032276 (21:15867192 T>G), RS1000042006 (21:15825718 T>C), RS1000046758 (21:15784496 C>T), RS1000057539 (21:15866945 T>C), RS1000073859 (21:15787846 A>G), RS1000076181 (21:15750122 A>T), RS1000083671 (21:15744478 A>C,G), RS1000088094 (21:15809291 G>A), RS1000090532 (21:15873336 G>T), RS1000100946 (21:15831485 G>A), RS1000121605 (21:15873594 C>G,T), RS1000122395 (21:15729864 G>A), RS1000139754 (21:15858547 ACT>A), RS1000158678 (21:15766826 T>C)

Disease associations

OMIM: gene MIM:604736 | disease phenotypes: MIM:621064, MIM:600669

GenCC curated gene-disease

Disease	Classification	Inheritance
epilepsy, idiopathic generalized, susceptibility to, 19	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
epilepsy	Disputed	AD

Mondo (2): epilepsy, idiopathic generalized, susceptibility to, 19 (MONDO:0976128), idiopathic generalized epilepsy (MONDO:0005579)

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000320_11	Panic disorder	9.000000e-06
GCST001126_11	Parkinson’s disease	6.000000e-07
GCST003872_17	QRS complex (12-leadsum)	4.000000e-09
GCST006291_42	Spherical equivalent or myopia (age of diagnosis)	5.000000e-12
GCST008485_6	Crohn’s disease	2.000000e-07
GCST009066_31	Mosaic loss of chromosome Y (Y chromosome dosage)	1.000000e-08
GCST009391_2007	Metabolite levels	8.000000e-06
GCST90011900_14	Serum alkaline phosphatase levels	5.000000e-09
GCST90026412_2	Severe autoimmune type 2 diabetes	1.000000e-06

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005054	QRS complex
EFO:0007742	QRS amplitude
EFO:0004847	age at onset
EFO:0007783	mosaic loss of chromosome Y measurement
EFO:0010347	cholesteryl ester 20:3 measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562694	Epilepsy, Idiopathic Generalized (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295975 (SINGLE PROTEIN)

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

ChEMBL bioactivities

369 potent at pChembl≥5 of 383 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.70	IC50	200	nM	CHEMBL4174196
6.70	IC50	200	nM	CHEMBL4300392
6.70	IC50	200	nM	CHEMBL4443504
6.70	IC50	200	nM	CHEMBL4584152
6.70	IC50	200	nM	CHEMBL4451295
6.70	IC50	200	nM	CHEMBL4462420
6.70	IC50	200	nM	CHEMBL4459980
6.70	IC50	200	nM	CHEMBL4585832
6.70	IC50	200	nM	CHEMBL4533281
6.70	IC50	200	nM	CHEMBL4593462
6.70	IC50	200	nM	CHEMBL4590597
6.70	IC50	200	nM	CHEMBL4527267
6.70	IC50	200	nM	CHEMBL4580403
6.70	IC50	200	nM	CHEMBL4556612
6.70	IC50	200	nM	CHEMBL4590745
6.70	IC50	200	nM	CHEMBL4557308
6.70	IC50	200	nM	CHEMBL4534946
6.70	IC50	200	nM	CHEMBL4541247
6.70	IC50	200	nM	CHEMBL4521756
6.70	IC50	200	nM	CHEMBL4588664
6.70	IC50	200	nM	CHEMBL4583154
6.70	IC50	200	nM	CHEMBL4553911
6.70	IC50	200	nM	CHEMBL4530046
6.70	IC50	200	nM	CHEMBL4574201
6.70	IC50	200	nM	CHEMBL4581055
6.70	IC50	200	nM	CHEMBL4548150
6.70	IC50	200	nM	CHEMBL4552439
6.70	IC50	200	nM	CHEMBL4539489
6.70	IC50	200	nM	CHEMBL4575333
6.70	IC50	200	nM	CHEMBL4548452
6.70	IC50	200	nM	CHEMBL4574312
6.70	IC50	200	nM	CHEMBL4514285
6.70	IC50	200	nM	CHEMBL4551619
6.70	IC50	200	nM	CHEMBL4542243
6.70	IC50	200	nM	CHEMBL4575704
6.70	IC50	200	nM	CHEMBL4562757
6.70	IC50	200	nM	CHEMBL4572877
6.70	IC50	200	nM	CHEMBL4483621
6.70	IC50	200	nM	CHEMBL4535435
6.70	IC50	200	nM	CHEMBL4568633
6.70	IC50	200	nM	CHEMBL4538680
6.70	IC50	200	nM	CHEMBL4519889
6.70	IC50	200	nM	CHEMBL4537585
6.70	IC50	200	nM	CHEMBL4569303
6.70	IC50	200	nM	CHEMBL4585155
6.70	IC50	200	nM	CHEMBL4539113
6.70	IC50	200	nM	CHEMBL4556121
6.70	IC50	200	nM	CHEMBL4565666
6.70	IC50	200	nM	CHEMBL4526977
6.70	IC50	200	nM	CHEMBL4539562

PubChem BioAssay actives

7 with measured affinity, of 34 total; 7 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
7-amino-N-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2,5-difluorophenyl]ethyl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide;hydrochloride	1504900: Inhibition of recombinant human His6-tagged USP25 expressed in baculovirus infected Sf21 insect cells using Ub-Rh110 as substrate pretreated for 30 mins followed by substrate addition measured after 45 mins by fluorescence assay	ic50	0.2000	uM
7-amino-N-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl]ethyl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide;hydrochloride	1504900: Inhibition of recombinant human His6-tagged USP25 expressed in baculovirus infected Sf21 insect cells using Ub-Rh110 as substrate pretreated for 30 mins followed by substrate addition measured after 45 mins by fluorescence assay	ic50	0.2000	uM
2-[[5-bromo-2-[[4-fluoro-3-(trifluoromethyl)phenyl]methoxy]phenyl]methylamino]ethanol	1930832: Inhibition of USP25 (unknown origin) using Ub-Rho100 as substrate by calorimetric analysis	ic50	0.6200	uM
2-[[5-bromo-2-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl]methylamino]ethanol	1930832: Inhibition of USP25 (unknown origin) using Ub-Rho100 as substrate by calorimetric analysis	ic50	0.8800	uM
7-amino-N-[(2S)-2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl]propyl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide	1504900: Inhibition of recombinant human His6-tagged USP25 expressed in baculovirus infected Sf21 insect cells using Ub-Rh110 as substrate pretreated for 30 mins followed by substrate addition measured after 45 mins by fluorescence assay	ic50	2.0000	uM
7-amino-N-[(2R)-2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl]propyl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide	1504900: Inhibition of recombinant human His6-tagged USP25 expressed in baculovirus infected Sf21 insect cells using Ub-Rh110 as substrate pretreated for 30 mins followed by substrate addition measured after 45 mins by fluorescence assay	ic50	2.0000	uM
7-amino-N-[2-(2,5-difluoro-4-piperazin-1-ylphenyl)ethyl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide	1504900: Inhibition of recombinant human His6-tagged USP25 expressed in baculovirus infected Sf21 insect cells using Ub-Rh110 as substrate pretreated for 30 mins followed by substrate addition measured after 45 mins by fluorescence assay	ic50	2.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression, increases abundance	3
bisphenol A	decreases expression, decreases methylation	2
potassium chromate(VI)	decreases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
geldanamycin	increases expression	1
methylmercuric chloride	decreases expression, increases expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
jinfukang	decreases expression	1
(+)-JQ1 compound	increases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1

ChEMBL screening assays

19 unique, capped per target: 19 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4136598	Binding	Inhibition of recombinant human His6-tagged USP25 expressed in baculovirus infected Sf21 insect cells using Ub-Rh110 as substrate pretreated for 30 mins followed by substrate addition measured after 45 mins by fluorescence assay	Ubiquitin-Specific Inhibitors for the Treatment of Cancers, Autoimmune, and Infectious Diseases. — ACS Med Chem Lett

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D6BF	HyCyte HEK293 KO-hUSP25	Transformed cell line	Female
CVCL_D8Y0	Ubigene HCT 116 USP25 KO	Cancer cell line	Male
CVCL_DX67	HAP1 USP25 (-) USP28 (-) 1	Cancer cell line	Male
CVCL_DX68	HAP1 USP25 (-) USP28 (-) 2	Cancer cell line	Male
CVCL_TW79	HAP1 USP25 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03590197	PHASE4	COMPLETED	Effect of Melatonin on Seizure Outcome, Neuronal Damage and Quality of Life in Patients With Generalized Epilepsy
NCT03940326	PHASE4	COMPLETED	Levetiracetam Versus Valproate in Idiopathic Generalized Tonic-clonic Seizures
NCT00150735	PHASE3	COMPLETED	Monotherapy With Levetiracetam in Newly Diagnosed Patients Suffering From Epilepsy
NCT00150748	PHASE3	COMPLETED	Long Term Follow up Treatment With Levetiracetam in Subjects of 4 Years and Older With Generalized Epilepsy
NCT03678753	PHASE3	COMPLETED	Randomized, Double-Blind Study to Evaluate Efficacy and Safety of Cenobamate Adjunctive Therapy in PGTC Seizures
NCT05147571	PHASE3	ACTIVE_NOT_RECRUITING	RNS System NAUTILUS Study
NCT06908356	PHASE2	RECRUITING	An Open Label Trial to Evaluate the Efficacy and Safety of PRAX-628 in Adults With Focal Onset or Tonic-Clonic Seizures
NCT06425159	PHASE2/PHASE3	TERMINATED	A Study to Determine if BHV-7000 is Effective and Safe in Adults With Idiopathic Generalized Epilepsy With Generalized Tonic-clonic Seizures
NCT00001325	Not specified	COMPLETED	Metabolic Abnormalities in Children With Epilepsy
NCT00916903	Not specified	TERMINATED	Genetic Disease Gene Identification
NCT01311440	Not specified	COMPLETED	Modified Atkins Diet Treatment for Adults With Drug-resistant Epilepsy
NCT01432821	Not specified	COMPLETED	Blinking and Yawning in Epilepsy: The Role of Dopamine
NCT03368469	Not specified	WITHDRAWN	Transcranial Direct Current Stimulation (tDCS) in Children and Adolescents With Epilepsy and Depression
NCT03457961	Not specified	UNKNOWN	Post-market Study of AMPA Receptor Antagonists for Epilepsy Patients in Hong Kong
NCT03955432	Not specified	TERMINATED	Long-term Cardiac Monitoring in Epilepsy
NCT04252846	Not specified	COMPLETED	A Study to Investigate Dosage, Effectiveness, and Safety of Perampanel When Used as First Add-on Therapy in Participants >=12 Years With Partial Onset Seizures With or Without Secondary Generalization or With Primary Generalized Tonic-Clonic Seizures Associated With Idiopathic Generalized Epilepsy
NCT04965571	Not specified	COMPLETED	Clinical Features and Outcome of Wilson’s Disease With Generalized Epilepsy in Chinese Patients
NCT05374928	Not specified	ACTIVE_NOT_RECRUITING	Human Epilepsy Project 3
NCT05530109	Not specified	TERMINATED	Study of Attentional Disorders in Patients Suffering From Idiopathic Generalized Epilepsy.
NCT06388174	Not specified	RECRUITING	Idiopathic Generalized Epilepsy Syndromes
NCT06797791	Not specified	COMPLETED	Assessment of Multifocal Continuous Theta Burst Transcranial Magnetic Stimulation (cTBS) Effects in Generalized Epilepsy Patients.