OTUD4

Summary

OTUD4 (OTU deubiquitinase 4, HGNC:24949) is a protein-coding gene on chromosome 4q31.21, encoding OTU domain-containing protein 4 (Q01804). Deubiquitinase which hydrolyzes the isopeptide bond between the ubiquitin C-terminus and the lysine epsilon-amino group of the target protein.

Alternatively spliced transcript variants have been found for this gene. The smaller protein isoform encoded by the shorter transcript variant is found only in HIV-1 infected cells.

Source: NCBI Gene 54726 — RefSeq curated summary.

At a glance

• GWAS associations: 36
• Clinical variants (ClinVar): 158 total
• Phenotypes (HPO): 1
• MANE Select transcript: NM_001366057

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24949
Approved symbol	OTUD4
Name	OTU deubiquitinase 4
Location	4q31.21
Locus type	gene with protein product
Status	Approved
Aliases	HSHIN1, KIAA1046, DUBA6
Ensembl gene	ENSG00000164164
Ensembl biotype	protein_coding
OMIM	611744
Entrez	54726

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 14 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000447906, ENST00000454497, ENST00000455611, ENST00000504331, ENST00000504501, ENST00000505976, ENST00000509517, ENST00000509620, ENST00000509985, ENST00000514973, ENST00000906677, ENST00000906678, ENST00000924605, ENST00000924606, ENST00000924607, ENST00000924608, ENST00000924609, ENST00000924610, ENST00000924611

RefSeq mRNA: 4 — MANE Select: NM_001366057 NM_001102653, NM_001366057, NM_001366058, NM_017493

CCDS: CCDS3764, CCDS47139, CCDS93644

Canonical transcript exons

ENST00000447906 — 21 exons

Exon	Start	End
ENSE00001789351	145133650	145138650
ENSE00002042731	145179815	145180589
ENSE00003486676	145139951	145139991
ENSE00003497277	145150513	145150699
ENSE00003507727	145152541	145152635
ENSE00003514194	145142196	145142334
ENSE00003543219	145159503	145159635
ENSE00003553407	145144311	145144434
ENSE00003555395	145143365	145143445
ENSE00003558044	145162640	145162721
ENSE00003571635	145155411	145155475
ENSE00003574214	145174661	145174744
ENSE00003587501	145171670	145171720
ENSE00003595230	145164154	145164226
ENSE00003597863	145143946	145144001
ENSE00003604321	145155569	145155686
ENSE00003645620	145165151	145165197
ENSE00003660103	145155936	145155996
ENSE00003675533	145141379	145141639
ENSE00003683772	145150802	145150905
ENSE00003691613	145146267	145146429

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.3158 / max 137.5056, expressed in 1788 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
54228	9.0554	1768
54226	1.0197	300
54227	0.7466	315
54229	0.4839	289
54224	0.0102	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle frontal gyrus	UBERON:0002702	99.14	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.16	gold quality
paraflocculus	UBERON:0005351	98.11	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.99	gold quality
frontal pole	UBERON:0002795	97.51	gold quality
diaphragm	UBERON:0001103	96.71	gold quality
body of tongue	UBERON:0011876	96.53	gold quality
biceps brachii	UBERON:0001507	96.31	gold quality
cerebellar vermis	UBERON:0004720	96.17	gold quality
epithelium of nasopharynx	UBERON:0001951	96.03	gold quality
lateral globus pallidus	UBERON:0002476	95.67	gold quality
vena cava	UBERON:0004087	95.66	gold quality
tongue	UBERON:0001723	95.58	gold quality
endometrium epithelium	UBERON:0004811	95.52	gold quality
heart right ventricle	UBERON:0002080	95.50	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.40	gold quality
tongue squamous epithelium	UBERON:0006919	95.19	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.01	gold quality
secondary oocyte	CL:0000655	94.97	gold quality
superficial temporal artery	UBERON:0001614	94.90	gold quality
renal medulla	UBERON:0000362	94.88	gold quality
pharyngeal mucosa	UBERON:0000355	94.46	gold quality
thymus	UBERON:0002370	94.41	gold quality
superior surface of tongue	UBERON:0007371	94.41	gold quality
CA1 field of hippocampus	UBERON:0003881	94.01	gold quality
pylorus	UBERON:0001166	93.93	gold quality
urethra	UBERON:0000057	93.87	gold quality
cardia of stomach	UBERON:0001162	93.67	gold quality
gluteal muscle	UBERON:0002000	93.43	gold quality
synovial joint	UBERON:0002217	93.39	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.29

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting OTUD4, 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-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-7849-3P	99.47	68.17	1224
HSA-MIR-4999-5P	99.35	69.15	926
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-1273H-3P	99.29	67.55	980
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-4777-3P	99.15	68.92	626
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-4724-5P	98.87	67.75	1324
HSA-MIR-6512-5P	98.76	69.29	1195
HSA-MIR-6730-5P	98.03	68.12	1299
HSA-MIR-4678	97.59	68.31	902
HSA-MIR-6509-5P	97.39	68.27	969
HSA-MIR-875-5P	96.74	66.48	579
HSA-MIR-331-5P	96.59	67.94	705
HSA-MIR-4485-3P	93.21	62.11	61

Literature-anchored findings (GeneRIF, showing 12)

• The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4 (PMID:23656588)
• OTUD4 is a positive regulator of ALKBH2 and ALKBH3, two DNA demethylases critical for alkylation repair. (PMID:25944111)
• There is an evolutionary loss of activity in de-ubiquitylating enzymes of the OTU family, OTUD4, otu, and CG3251. (PMID:26588485)
• Authors demonstrate that the deubiquitinase OTUD4, which nominally encodes a K48-specific deubiquitinase, is phosphorylated near its catalytic domain, activating a latent K63-specific deubiquitinase. Besides phosphorylation, this latter activity requires an adjacent ubiquitin-interacting motif, which increases the affinity of OTUD4 for K63-linked chains. (PMID:29395066)
• Knockdown of OTUD4 in HeLa cells resulted in defects in stress granule formation and led to apoptotic cell death (PMID:31138677)
• OTUD4 enhances TGFbeta signalling through regulation of the TGFbeta receptor complex. (PMID:32973272)
• Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes. (PMID:37149835)
• OTUD4 regulates metastasis and chemoresistance in melanoma by stabilizing Snail1. (PMID:37642406)
• Deubiquitinating enzyme OTUD4 regulates metastasis in triple-negative breast cancer by stabilizing Snail1. (PMID:38040050)
• OTUD4 promotes the progression of glioblastoma by deubiquitinating CDK1 and activating MAPK signaling pathway. (PMID:38429268)
• NRF2 regulates EGF stability through OTUD4 in lung adenocarcinoma. (PMID:38518721)
• Deubiquitinating enzyme OTUD4 stabilizes RBM47 to induce ATF3 transcription: a novel mechanism underlying the restrained malignant properties of ccRCC cells. (PMID:38553613)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	otud4	ENSDARG00000077810
mus_musculus	Otud4	ENSMUSG00000036990
rattus_norvegicus	Otud4	ENSRNOG00000018477
drosophila_melanogaster	otu	FBGN0003023
drosophila_melanogaster	CG7857	FBGN0026738
drosophila_melanogaster	CG3251	FBGN0031622
caenorhabditis_elegans		WBGENE00009007

Paralogs (5): OTUD5 (ENSG00000068308), OTUD6B (ENSG00000155100), OTUD1 (ENSG00000165312), OTUD3 (ENSG00000169914), OTUD6A (ENSG00000189401)

Protein

Protein identifiers

OTU domain-containing protein 4 — Q01804 (reviewed: Q01804)

Alternative names: HIV-1-induced protein HIN-1

All UniProt accessions (3): D6RA27, D6RI06, Q01804

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinase which hydrolyzes the isopeptide bond between the ubiquitin C-terminus and the lysine epsilon-amino group of the target protein. May negatively regulate inflammatory and pathogen recognition signaling in innate immune response. Upon phosphorylation at Ser-202 and Ser-204 residues, via IL-1 receptor and Toll-like receptor signaling pathway, specifically deubiquitinates ‘Lys-63’-polyubiquitinated MYD88 adapter protein triggering down-regulation of NF-kappa-B-dependent transcription of inflammatory mediators. Independently of the catalytic activity, acts as a scaffold for alternative deubiquitinases to assemble specific deubiquitinase-substrate complexes. Associates with USP7 and USP9X deubiquitinases to stabilize alkylation repair enzyme ALKBH3, thereby promoting the repair of alkylated DNA lesions.

Subunit / interactions. Interacts with MYD88; the interaction is direct. Interacts with ALKBH3; the interaction is direct. Interacts with USP7; the interaction is direct. Interacts with USP9X; the interaction is direct. Interacts with MYCBP.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylated on Ser-202 and Ser-204 likely by CSNK2A1-CSNK2A2 serine/threonine-protein kinase complex. Activates ‘Lys-63’-specific deubiquitinase activity.

Activity regulation. Phosphorylation on Ser-202 and Ser-204 induces ‘Lys-63’-specific deubiquitinase activity.

Induction. By HIV-1 insertion.

Miscellaneous. Predicted from a chimeric transcript isolated from HIV-1-infected cells. The premature stop may be due to intron retention.

Isoforms (4)

UniProt ID	Names	Canonical?
Q01804-1	1	yes
Q01804-5	2
Q01804-3	3
Q01804-4	4

RefSeq proteins (4): NP_001096123, NP_001352986, NP_001352987, NP_059963 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003323	OTU_dom	Domain
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050704	Peptidase_C85-like	Family

Pfam: PF02338

UniProt features (59 total): modified residue 22, compositionally biased region 10, region of interest 7, mutagenesis site 7, active site 3, splice variant 3, sequence variant 3, sequence conflict 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q01804-F1	49.68	0.16

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): 42; 45 (nucleophile); 148

Post-translational modifications (22): 1, 120, 126, 128, 131, 166, 199, 202, 204, 341, 439, 443, 460, 546, 893, 900, 1006, 1011, 1014, 1023 …

Mutagenesis-validated functional residues (7):

Position	Phenotype
45	abolishes ’lys-48’- and ’lys-63’-specific deubiquitinase activity. impairs ’lys-63’-specific deubiquitinase activity tow
45	abolishes ’lys-48’- and ’lys-63’-specific deubiquitinase activity.
181–550	abolishes interaction with usp7 and usp9x deubiquitinases.
202	decreases ’lys-63’-specific deubiquitinase activity. loss of ’lys-63’-specific deubiquitinase activity; when associated
204	loss of ’lys-63’-specific deubiquitinase activity; when associated with a-204.
273–275	abolishes ’lys-63’-specific deubiquitinase activity by impairing the affinity for ’lys-63’-linked ubiquitin chain substr
279	abolishes ’lys-63’-specific deubiquitinase activity by impairing the affinity for ’lys-63’-linked ubiquitin chain substr

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 317 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_PEPTIDE, GOBP_NEGATIVE_REGULATION_OF_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY, CTATGCA_MIR153, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_REGULATION_OF_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY, GOBP_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, GTGTTGA_MIR505

GO Biological Process (13): DNA alkylation repair (GO:0006307), proteolysis (GO:0006508), negative regulation of toll-like receptor signaling pathway (GO:0034122), protein K11-linked deubiquitination (GO:0035871), protein K63-linked deubiquitination (GO:0070536), protein K48-linked deubiquitination (GO:0071108), antiviral innate immune response (GO:0140374), regulation of protein K48-linked deubiquitination (GO:1903093), negative regulation of interleukin-1-mediated signaling pathway (GO:2000660), immune system process (GO:0002376), protein deubiquitination (GO:0016579), protein K27-linked ubiquitination (GO:0044314), innate immune response (GO:0045087)

GO Molecular Function (8): RNA binding (GO:0003723), cysteine-type deubiquitinase activity (GO:0004843), molecular adaptor activity (GO:0060090), K63-linked deubiquitinase activity (GO:0061578), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein deubiquitination	3
deubiquitinase activity	2
binding	2
cellular anatomical structure	2
DNA repair	1
protein metabolic process	1
toll-like receptor signaling pathway	1
negative regulation of immune system process	1
negative regulation of signal transduction	1
regulation of toll-like receptor signaling pathway	1
innate immune response	1
defense response to virus	1
protein K48-linked deubiquitination	1
regulation of protein deubiquitination	1
negative regulation of cytokine-mediated signaling pathway	1
interleukin-1-mediated signaling pathway	1
regulation of interleukin-1-mediated signaling pathway	1
biological_process	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
protein polyubiquitination	1
immune response	1
defense response to symbiont	1
nucleic acid binding	1
cysteine-type peptidase activity	1
molecular_function	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

1438 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OTUD4	RNF216	Q9NWF9	692
OTUD4	USP7	Q93009	656
OTUD4	USP9X	Q93008	643
OTUD4	SLC35F6	Q8N357	639
OTUD4	OTUD5	Q96G74	621
OTUD4	OTUD3	Q5T2D3	615
OTUD4	OTUD6B	Q8N6M0	613
OTUD4	OTUD6A	Q7L8S5	613
OTUD4	YOD1	Q5VVQ6	608
OTUD4	OTUD1	Q5VV17	598
OTUD4	FAF2	Q96CS3	594
OTUD4	OTUB2	Q96DC9	591
OTUD4	FBXO6	Q9NRD1	591
OTUD4	OTUB1	Q96FW1	590
OTUD4	OTUD7B	Q6GQQ9	576

IntAct

126 interactions, top by confidence:

A	B	Type	Score
PRMT8	SYNCRIP	psi-mi:“MI:0914”(association)	0.830
EXOSC8	OTUD4	psi-mi:“MI:0915”(physical association)	0.720
OTUD4	EXOSC8	psi-mi:“MI:0915”(physical association)	0.720
MAPK7	PFDN6	psi-mi:“MI:0914”(association)	0.640
DUSP10	CASK	psi-mi:“MI:0914”(association)	0.590
OTUD4	TCF4	psi-mi:“MI:0915”(physical association)	0.560
STAT1	OTUD4	psi-mi:“MI:0915”(physical association)	0.560
OTUD4	REL	psi-mi:“MI:0915”(physical association)	0.560
TCF4	OTUD4	psi-mi:“MI:0915”(physical association)	0.560
OTUD4	STAT1	psi-mi:“MI:0915”(physical association)	0.560
OTUD4	VDR	psi-mi:“MI:0915”(physical association)	0.560
VDR	OTUD4	psi-mi:“MI:0915”(physical association)	0.560
OTUD4	ZNF655	psi-mi:“MI:0915”(physical association)	0.560
MYCBP	AKAP8	psi-mi:“MI:0914”(association)	0.550
PCGF1	CBX4	psi-mi:“MI:0914”(association)	0.530
ODAPH	TCAF2	psi-mi:“MI:0914”(association)	0.530
TSPYL6	NME4	psi-mi:“MI:0914”(association)	0.530
WBP2NL	OTUD4	psi-mi:“MI:0914”(association)	0.530
VTN	HAT1	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
CLEC11A	VWA8	psi-mi:“MI:0914”(association)	0.530
OTUD4	ENTREP1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (773): OTUD4 (Two-hybrid), OTUD4 (Two-hybrid), OTUD4 (Two-hybrid), OTUD4 (Two-hybrid), OTUD4 (Affinity Capture-MS), OTUD4 (Affinity Capture-MS), OTUD4 (Affinity Capture-MS), OTUD4 (Affinity Capture-MS), OTUD4 (Affinity Capture-MS), OTUD4 (Affinity Capture-MS), OTUD4 (Affinity Capture-MS), OTUD4 (Affinity Capture-MS), OTUD4 (Affinity Capture-MS), OTUD4 (Affinity Capture-MS), OTUD4 (Affinity Capture-Western)

ESM2 similar proteins: A0A1D5NVS8, A0AVK6, A2A891, A5GFT6, A5PLL1, A5X7A0, A7XYH5, A7XYJ6, B7ZS37, D3ZGB1, D4A4D7, D4A666, E1B7L7, E1BE02, E1BKK0, E1BLP6, E7F888, F1LMN3, F1QZ88, F6YVB9, F7EA39, O35914, O54916, P0C6C1, Q01804, Q14B70, Q3U1C4, Q3UUF8, Q566I1, Q58FA4, Q5RIX9, Q5ZJ69, Q68FE9, Q69ZF8, Q6A098, Q6S7F2, Q6ZSZ6, Q6ZU65, Q76L83, Q80WC1

Diamond homologs: B2RRE7, F4K3M6, P10383, Q01804, Q08BW0, Q2YDU3, Q3U2S4, Q5T2D3, Q640H3, Q6GL44, Q7ZX21, Q96G74, Q9D8C3, Q9NP73, Q9XIP2, B1AZ99, Q0V869, Q5ZIP6, Q6IE21, Q7L8S5, Q8LBW2, Q5VV17, Q9CUB6, Q9LZF7, Q9VR20, Q9SGA5, O14190, P0CN88, P0CN89, P53178, Q4WQN1, Q5ABE5, Q5I0K7, Q6BST1, Q6C3P1, Q6CXY0, Q6FVR6, Q748D6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	121
Likely benign	9
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

4653 predictions. Top by Δscore:

Variant	Effect	Δscore
4:145111060:GATAT:G	donor_gain	1.0000
4:145111061:A:G	donor_gain	1.0000
4:145111065:G:GG	donor_gain	1.0000
4:145112235:A:AG	acceptor_gain	1.0000
4:145112236:T:G	acceptor_gain	1.0000
4:145112237:A:AG	acceptor_gain	1.0000
4:145112237:AGT:A	acceptor_loss	1.0000
4:145112238:G:GA	acceptor_gain	1.0000
4:145112238:GT:G	acceptor_gain	1.0000
4:145112238:GTT:G	acceptor_gain	1.0000
4:145112238:GTTT:G	acceptor_gain	1.0000
4:145112238:GTTTC:G	acceptor_gain	1.0000
4:145112324:GATAG:G	donor_gain	1.0000
4:145112326:TAGGT:T	donor_loss	1.0000
4:145112327:AGGT:A	donor_loss	1.0000
4:145112329:GTA:G	donor_loss	1.0000
4:145112330:T:A	donor_loss	1.0000
4:145117287:TTTCA:T	acceptor_loss	1.0000
4:145117288:TTCAG:T	acceptor_loss	1.0000
4:145117289:TCAG:T	acceptor_loss	1.0000
4:145117290:CA:C	acceptor_loss	1.0000
4:145117291:A:AG	acceptor_gain	1.0000
4:145117291:A:G	acceptor_loss	1.0000
4:145117292:G:GC	acceptor_loss	1.0000
4:145117292:G:GG	acceptor_gain	1.0000
4:145117292:GAT:G	acceptor_gain	1.0000
4:145117292:GATA:G	acceptor_gain	1.0000
4:145117292:GATAT:G	acceptor_gain	1.0000
4:145117403:GT:G	donor_gain	1.0000
4:145117410:AGAAG:A	donor_loss	1.0000

AlphaMissense

7266 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:145165166:A:G	L109P	1.000
4:145165169:G:T	A108D	1.000
4:145174689:A:G	L72P	1.000
4:145174710:C:G	R65T	1.000
4:145179833:G:C	F47L	1.000
4:145179833:G:T	F47L	1.000
4:145179834:A:G	F47S	1.000
4:145179835:A:G	F47L	1.000
4:145179850:C:G	D42H	1.000
4:145139958:C:T	G706D	0.999
4:145139959:C:G	G706R	0.999
4:145139961:A:G	L705P	0.999
4:145141387:A:G	L692P	0.999
4:145162714:A:G	L141P	0.999
4:145164218:A:G	F117S	0.999
4:145165166:A:T	L109H	0.999
4:145165188:C:G	G102R	0.999
4:145165188:C:T	G102R	0.999
4:145165194:A:G	W100R	0.999
4:145165194:A:T	W100R	0.999
4:145174667:A:C	F79L	0.999
4:145174667:A:T	F79L	0.999
4:145174669:A:G	F79L	0.999
4:145174700:A:C	C68W	0.999
4:145174702:A:G	C68R	0.999
4:145174709:T:A	R65S	0.999
4:145174709:T:G	R65S	0.999
4:145174710:C:A	R65I	0.999
4:145179823:C:G	A51P	0.999
4:145179829:C:G	A49P	0.999

dbSNP variants (sampled 300 via entrez): RS1000040729 (4:145173252 G>A,T), RS1000076974 (4:145140855 G>A,C), RS1000221480 (4:145170900 A>G,T), RS1000233933 (4:145164355 A>G), RS1000255155 (4:145147000 G>A), RS1000267979 (4:145153564 T>G), RS1000285153 (4:145159606 C>T), RS1000333193 (4:145170335 C>G), RS1000369514 (4:145176108 G>A,C), RS1000430515 (4:145176626 G>T), RS1000486905 (4:145153429 C>G), RS1000534537 (4:145141148 GAC>G), RS1000622559 (4:145158287 C>G), RS1000704903 (4:145170617 T>C), RS1000817377 (4:145154807 T>A,C)

Disease associations

OMIM: gene MIM:611744 | disease phenotypes: MIM:617452

GenCC curated gene-disease

Mondo (2): amenorrhea (MONDO:0001836), intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies (MONDO:0044319)

Orphanet (1): Early-onset seizures-distal limb anomalies-facial dysmorphism-global developmental delay syndrome (Orphanet:505237)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000141	Amenorrhea

GWAS associations

36 associations (top):

Study	Trait	p-value
GCST004029_21	Angiotensin-converting enzyme inhibitor intolerance	6.000000e-07
GCST004067_128	Hip circumference adjusted for BMI	4.000000e-06
GCST004067_16	Hip circumference adjusted for BMI	5.000000e-13
GCST004067_210	Hip circumference adjusted for BMI	8.000000e-10
GCST004619_106	Reticulocyte fraction of red cells	5.000000e-13
GCST004622_169	Reticulocyte count	5.000000e-16
GCST006288_210	Heel bone mineral density	1.000000e-06
GCST006288_316	Heel bone mineral density	4.000000e-10
GCST006288_528	Heel bone mineral density	3.000000e-17
GCST006481_16	Lung function (FEV1)	2.000000e-08
GCST006481_40	Lung function (FEV1)	2.000000e-07
GCST006979_755	Heel bone mineral density	7.000000e-38
GCST008163_300	Height	8.000000e-13
GCST008163_574	Height	4.000000e-08
GCST009698_118	Metabolite levels	3.000000e-08
GCST010002_17	Refractive error	5.000000e-09
GCST010701_94	Cortical surface area (MOSTest)	2.000000e-13
GCST010702_38	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_203	Brain morphology (MOSTest)	1.000000e-11
GCST010725_4	Malaria	4.000000e-10
GCST010725_84	Malaria	7.000000e-11
GCST010725_89	Malaria	7.000000e-11
GCST012227_1322	Hip circumference adjusted for BMI	2.000000e-09
GCST012227_1323	Hip circumference adjusted for BMI	3.000000e-25
GCST012227_1326	Hip circumference adjusted for BMI	1.000000e-28
GCST012227_1328	Hip circumference adjusted for BMI	2.000000e-17
GCST012227_1329	Hip circumference adjusted for BMI	1.000000e-10
GCST90002391_23	Mean corpuscular hemoglobin concentration	2.000000e-19
GCST90002392_670	Mean corpuscular volume	2.000000e-23
GCST90002396_241	Mean reticulocyte volume	5.000000e-81

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0005325	response to angiotensin-converting enzyme inhibitor
EFO:0008039	BMI-adjusted hip circumference
EFO:0007986	reticulocyte count
EFO:0009270	heel bone mineral density
EFO:0004314	forced expiratory volume
EFO:0004346	neuroimaging measurement
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0010701	mean reticulocyte volume
EFO:0004305	erythrocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
geldanamycin	increases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
cupric oxide	decreases expression	1
pentanal	decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
torcetrapib	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Coal	decreases expression, increases abundance	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	increases expression	1
Folic Acid	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Ribonucleotides	affects binding	1
Smoke	decreases expression, increases abundance	1
Thimerosal	decreases expression	1

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_B1ZL	Abcam HeLa OTUD4 KO	Cancer cell line	Female
CVCL_E4Q7	KOLF2.1J OTUD4 30.9kbdel DEL/WT	Induced pluripotent stem cell	Male
CVCL_TB74	HAP1 OTUD4 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01103518	PHASE4	UNKNOWN	Ethinyl Estradiol and Cyproterone Acetate in Irregular Menstruation
NCT01206153	PHASE4	COMPLETED	Metformin for Treatment Antipsychotic Induced Amenorrhea in Female Schizophrenic Patients
NCT02393482	PHASE4	UNKNOWN	Psychological Impact of Amenorrhea in Women With Endometriosis
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
NCT00130117	PHASE2	COMPLETED	Study of Leptin for the Treatment of Hypothalamic Amenorrhea
NCT00152282	PHASE2	COMPLETED	A Study to Evaluate the Safety and Effectiveness of Asoprisnil and Estrogen Administration to Postmenopausal Women
NCT00196391	PHASE2	COMPLETED	A Trial to Evaluate DR-2021 in Women With Secondary Amenorrhea
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT00881608	PHASE1	TERMINATED	Study to Evaluate Menses Induction in Women Administered Proellex
NCT07152730	PHASE1	WITHDRAWN	A Study to Measure Pharmacokinetic (PK) Concentrations of Gonadotropin-Releasing Hormone Delivered by the OmniPod Pump
NCT03916978	PHASE2/PHASE3	RECRUITING	Autologous PRP Intra Ovarian Infusion to Restore Ovarian Function in Menopausal Women
NCT00556400	PHASE1/PHASE2	TERMINATED	Treatment of Menorrhagia in Women With Thrombocytopenia Using Platelets or Platelets and Hormones
NCT01187043	PHASE1/PHASE2	COMPLETED	Determination of the Lowest, Safe and Effective Dose of Proellex
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00011388	Not specified	COMPLETED	Reproductive Effects of Pesticide, PCB and Mercury Exposure in Laotian Immigrants
NCT00243607	Not specified	COMPLETED	Hydrotherapy Against Menopausal Symptoms in Breast Cancer Survivors
NCT00260286	Not specified	COMPLETED	Effects of Gynecological Age on LH Sensitivity to Energy Availability
NCT00456274	Not specified	UNKNOWN	Baselines in Reproductive Disorders
NCT00589654	Not specified	ACTIVE_NOT_RECRUITING	Menstrual Cycle Maintenance and Quality of Life: A Prospective Study
NCT01423487	Not specified	WITHDRAWN	Efficacy and Safety of Metformin in Preventing Patients With Risperidone From Weight Gain and Amenorrhea
NCT01500447	Not specified	RECRUITING	Inherited Reproductive Disorders
NCT01511588	Not specified	COMPLETED	Hormonal Regulation of Puberty and Fertility
NCT01785719	Not specified	COMPLETED	Evaluation of Ovarian Morphology and Function in Overweight Women During Weight Loss
NCT01927432	Not specified	COMPLETED	Ultrasound Characterization of Ovarian Follicle Dynamics in Women With Amenorrhea
NCT02224976	Not specified	COMPLETED	Effect of Intense Training on Ovarian Function and Bone Turnover
NCT04135729	Not specified	COMPLETED	Mental Health in Fitness Instructors
NCT04424576	Not specified	RECRUITING	Ovarian Morphology in Girls
NCT04938622	Not specified	COMPLETED	Bioenergetics of Exercise-Induced Menstrual Disturbances
NCT06280807	Not specified	RECRUITING	Observation of Environment and Reproductive-Endocrine Effects
NCT06800170	Not specified	RECRUITING	Treatment of Menstrual Cycle Alterations in Adolescents
NCT07015476	Not specified	RECRUITING	Retrospective Observational Evaluation of the Bone Mineral Density Outcome in Young Women With Amenorrhea
NCT07164248	Not specified	COMPLETED	Evaluation of Bone Mineral Density Indications and Outcomes in Female Adolescents: Implications for Early Detection of Osteopenia/Osteoporosis and Gynecologic Practice
NCT07612735	Not specified	NOT_YET_RECRUITING	Effects of Resistance Training on Women With Functional Hypothalamic Amenorrhea