HUWE1

Summary

HUWE1 (HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1, HGNC:30892) is a protein-coding gene on chromosome Xp11.22, encoding E3 ubiquitin-protein ligase HUWE1 (Q7Z6Z7). E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins. It is a selective cancer dependency (DepMap: 88.4% of cell lines).

This gene encodes a protein containing a C-terminal HECT (E6AP type E3 ubiquitin protein ligase) domain that functions as an E3 ubiquitin ligase. The encoded protein is required for the ubiquitination and subsequent degradation of the anti-apoptotic protein Mcl1 (myeloid cell leukemia sequence 1 (BCL2-related)). This protein also ubiquitinates the p53 tumor suppressor, core histones, and DNA polymerase beta. Mutations in this gene are associated with Turner type X-linked syndromic cognitive disability.

Source: NCBI Gene 10075 — RefSeq curated summary.

At a glance

• Gene–disease (curated): non-syndromic X-linked intellectual disability (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 2,544 total — 12 pathogenic, 62 likely-pathogenic
• Phenotypes (HPO): 79
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 88.4% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_031407

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30892
Approved symbol	HUWE1
Name	HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1
Location	Xp11.22
Locus type	gene with protein product
Status	Approved
Aliases	Ib772, KIAA0312, UREB1
Ensembl gene	ENSG00000086758
Ensembl biotype	protein_coding
OMIM	300697
Entrez	10075

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 11 protein_coding, 7 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000218328, ENST00000262854, ENST00000342160, ENST00000426907, ENST00000446750, ENST00000463852, ENST00000468322, ENST00000471676, ENST00000474288, ENST00000474971, ENST00000480438, ENST00000488459, ENST00000489876, ENST00000612484, ENST00000622887, ENST00000704099, ENST00000704100, ENST00000704101, ENST00000704102, ENST00000913493, ENST00000913494

RefSeq mRNA: 1 — MANE Select: NM_031407 NM_031407

CCDS: CCDS35301

Canonical transcript exons

ENST00000262854 — 84 exons

Exon	Start	End
ENSE00000671230	53632487	53632564
ENSE00000671232	53631567	53631614
ENSE00000671235	53631414	53631482
ENSE00000671241	53630935	53631034
ENSE00000671243	53629516	53629616
ENSE00000671251	53628752	53628902
ENSE00001285569	53680049	53680186
ENSE00001285573	53686270	53686368
ENSE00001419232	53627739	53627879
ENSE00001466555	53625157	53625258
ENSE00001466559	53627410	53627515
ENSE00001466573	53648212	53648310
ENSE00001524788	53654063	53654131
ENSE00001591614	53586782	53586909
ENSE00001599207	53592398	53592628
ENSE00001639988	53628493	53628620
ENSE00001646324	53595187	53595403
ENSE00001646922	53607523	53607699
ENSE00001653792	53614534	53614745
ENSE00001680416	53594499	53594621
ENSE00001704338	53585012	53585188
ENSE00001706984	53602564	53602658
ENSE00001710782	53589547	53589816
ENSE00001729240	53608852	53608909
ENSE00001733171	53593364	53593601
ENSE00001755346	53604589	53604834
ENSE00001765217	53634236	53634298
ENSE00001765958	53603368	53603501
ENSE00001769795	53600118	53600309
ENSE00001771272	53591000	53591122
ENSE00001778794	53586490	53586571
ENSE00001790282	53615744	53615835
ENSE00001800182	53588382	53588534
ENSE00001801248	53590404	53590499
ENSE00001803888	53645311	53645463
ENSE00002281916	53647368	53647574
ENSE00003094334	53686588	53686719
ENSE00003494711	53542443	53542539
ENSE00003499859	53617340	53617446
ENSE00003519057	53546704	53546825
ENSE00003521191	53544560	53544762
ENSE00003528519	53616970	53617147
ENSE00003545167	53624595	53624675
ENSE00003590109	53539657	53539812
ENSE00003607783	53546436	53546592
ENSE00003616272	53545029	53545161
ENSE00003889494	53536380	53536667
ENSE00003889578	53568692	53568874
ENSE00003889604	53563746	53563821
ENSE00003889732	53576900	53577067
ENSE00003889834	53583558	53583916
ENSE00003889976	53573750	53573964
ENSE00003890176	53562831	53562929
ENSE00003890324	53547673	53548273
ENSE00003890608	53537556	53537696
ENSE00003890658	53561756	53561924
ENSE00003890845	53538337	53538454
ENSE00003890915	53534007	53534197
ENSE00003890918	53558971	53559060
ENSE00003890941	53535384	53535501
ENSE00003890944	53552638	53552893
ENSE00003891132	53550901	53551189
ENSE00003891190	53559354	53559532
ENSE00003891756	53538835	53539080
ENSE00003891886	53564574	53564722
ENSE00003892228	53560188	53560416
ENSE00003892292	53551266	53551480
ENSE00003892594	53536147	53536252
ENSE00003892664	53558655	53558809
ENSE00003892735	53584186	53584345
ENSE00003893660	53575155	53575221
ENSE00003893805	53562111	53562244
ENSE00003894500	53548959	53549505
ENSE00003894577	53554633	53554920
ENSE00003894683	53569616	53569827
ENSE00003894711	53552311	53552441
ENSE00003895072	53543841	53543968
ENSE00003895094	53580831	53581026
ENSE00003895462	53565067	53565239
ENSE00003895494	53575643	53575788
ENSE00003895530	53550666	53550768
ENSE00003895622	53532096	53533411
ENSE00003895683	53557382	53557427
ENSE00003895866	53534516	53534697

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 97.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.3697 / max 315.7795, expressed in 1822 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199362	14.6088	1799
199366	9.1446	1698
199367	6.9356	1729
199351	1.2200	840
199358	0.4608	220

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	97.64	gold quality
skin of abdomen	UBERON:0001416	97.52	gold quality
right lobe of thyroid gland	UBERON:0001119	97.22	gold quality
adenohypophysis	UBERON:0002196	97.17	gold quality
right ovary	UBERON:0002118	97.15	gold quality
left lobe of thyroid gland	UBERON:0001120	97.12	gold quality
left ovary	UBERON:0002119	97.08	gold quality
pituitary gland	UBERON:0000007	97.02	gold quality
adrenal tissue	UBERON:0018303	96.90	gold quality
ganglionic eminence	UBERON:0004023	96.88	gold quality
cortical plate	UBERON:0005343	96.85	gold quality
endometrium epithelium	UBERON:0004811	96.81	gold quality
metanephros cortex	UBERON:0010533	96.78	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.70	gold quality
ectocervix	UBERON:0012249	96.62	gold quality
body of uterus	UBERON:0009853	96.58	gold quality
stromal cell of endometrium	CL:0002255	96.56	gold quality
right adrenal gland cortex	UBERON:0035827	96.55	gold quality
tibial nerve	UBERON:0001323	96.53	gold quality
ventricular zone	UBERON:0003053	96.53	gold quality
minor salivary gland	UBERON:0001830	96.51	gold quality
cerebellar hemisphere	UBERON:0002245	96.49	gold quality
thyroid gland	UBERON:0002046	96.48	gold quality
cerebellar cortex	UBERON:0002129	96.46	gold quality
right testis	UBERON:0004534	96.46	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.46	gold quality
right adrenal gland	UBERON:0001233	96.44	gold quality
right uterine tube	UBERON:0001302	96.44	gold quality
zone of skin	UBERON:0000014	96.40	gold quality
lower esophagus mucosa	UBERON:0035834	96.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.33
E-MTAB-6678	yes	4.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

67 targeting HUWE1, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-548AC	99.84	70.77	4351

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 88.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Ubiquitin ligase activity of ARF-BP1 (HUWE1) is inhibited by Arf. (PMID:15989956)
• study modifies the current view of ARF-mediated p53 activation and reveals that ARF-BP1 is a critical mediator of both the p53-independent and p53-dependent tumor suppressor functions of ARF (PMID:15989956)
• Mule (HUWE1) poly-ubiquitinates anti-apoptotic gene Mcl-1. (PMID:15989957)
• Mule is both required and sufficient for the polyubiquitination of Mcl-1; Mule is a unique BH3-containing E3 ubiquitin ligase apical to Bcl-2 family proteins during DNA damage-induced apoptosis (PMID:15989957)
• LASU1 is an E3 ligase that ubiquitinates Mcl-1 in vitro and is required for its proteasome-dependent degradation, the BH3 domain of LASU1 interactes with Mcl-1. (PMID:16213503)
• HectH9-mediated ubiquitination of Myc is required for transactivation of multiple target genes. (PMID:16269333)
• These findings demonstrate an important and conserved role for Huwe1 in regulating Cdc6 abundance after DNA damage. (PMID:17567951)
• An increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of X-Linked Mental Retardation and suggest that point mutations in HUWE1 are associated with this disease too. (PMID:18252223)
• Huwe1 links destruction of N-Myc to the quiescent state that complements differentiation in the neural tissue (PMID:18488021)
• Heat shock caused the dissociation of Noxa from Mcl-1, which allowed binding of the BH3-containing ubiquitin ligase Mule followed by Mcl-1 ubiquitination and degradation. (PMID:19148187)
• Data show that the cellular levels of Pol beta and its ubiquitylated derivative are modulated by Mule and ARF and siRNA knockdown of Mule leads to accumulation of Pol beta and increased DNA repair. (PMID:19713937)
• A structural element within the HUWE1 HECT domain modulates self-ubiquitination and substrate ubiquitination activities. (PMID:20007713)
• Arf-bp1 and Pam are novel regulators of circadian gene expression that target Rev-erb alpha for degradation (PMID:20534529)
• Huwe1 interacted with HIV-1 Gag-Pol precursor protein through an IN domain (PMID:21167302)
• Mitochondrion-dependent N-terminal processing of outer membrane Mcl-1 protein removes an essential Mule/Lasu1 protein-binding site. (PMID:21613222)
• Studies indicate that ARF is induced in response to DNA damage and inhibits, by direct interaction, the E3 ubiquitin ligase Mule. (PMID:21726556)
• findings suggest that reduced Mule/Mcl-1 complex has a significant role in increasing the stability of Mcl-1 in breast cancer cells and increased resistance to apoptosis (PMID:21730980)
• The present study reveals a novel regulation of RASSF1C and the potentially important role of RASSF1C in DNA damage responses via SCFbeta-TrCP and Mule. (PMID:21910689)
• a critical regulatory mechanism of HDAC2 by Mule and suggest this pathway determines the cellular response to HDACs and DNA damage (PMID:22016339)
• The E3 ligase Mule mediates the degradation of Pol lambda and the control of Pol lambda levels by Mule has functional consequences for the ability of mammalian cells to deal with 8-oxo-G lesions. (PMID:22203964)
• the involvement of HUWE1 in the ubiquitination and proteasomal degradation of MyoD was described. (PMID:22277673)
• In PE, MULE preferentially targeted p53 for degradation, allowing accumulation of pro-apoptotic Mcl-1 isoforms. In IUGR, however, MULE targeted pro-survival Mcl-1, allowing p53 to accumulate and exert its apoptotic function. (PMID:22552282)
• Results show that ARF-BP1 was expressed at high levels in B-cell lymphoma cell lines and by regulating MYC and p53 transcriptional activity, ARF-BP1 is a critical determinant of the proliferation of B cell lymphomas. (PMID:22754359)
• Increased dosage of HUWE1 causes nonsyndromic intellectual disability. (PMID:22840365)
• HUWE1 and TRIP12 collaborate in degradation of ubiquitin-fusion proteins and misframed ubiquitin. (PMID:23209776)
• Findings indicate p53-independent roles for MDM2 and HUWE1 in apoptosis and suggest the potential for therapy directed against MDM2 to overcome lapatinib resistance. (PMID:23652204)
• Ubiquitin ligase HUWE1 regulates axon branching through the Wnt/beta-catenin pathway in a Drosophila model for intellectual disability. (PMID:24303071)
• data indicate that HUWE1 is a critical negative regulator of BRCA1 and suggest a new molecular mechanism for breast cancer pathogenesis (PMID:24342616)
• this study shows that MutYH is ubiquitinated in vitro and in vivo by the E3 ligase Mule between amino acids 475 and 535. (PMID:24443563)
• HUWE1 promotes BRCA1 ubiquitination. (PMID:24472556)
• Low Huwe1 expression is associated with medulloblastoma. (PMID:24960692)
• Results demonstrate that HUWE1 is a novel player involved in regulating ERK1/2 signal transmission through the Shoc2 scaffold complex. (PMID:25022756)
• analysis of ubiquitin-mediated proteolysis of DNA damage-inducible transcript 4 (DDIT4) by the E3 ligase HUWE1 (PMID:25147182)
• Inhibition of HUWE1 stabilizes MIZ1 and induces global accumulation of MIZ1 on MYC-bound target genes. (PMID:25253726)
• we show that HUWE1 stimulates human lung cancer cell invasion through regulating TIAM1 stability. Finally, we demonstrate that HUWE1 and TIAM1 protein levels are inversely correlated in human lung carcinomas (PMID:25543140)
• Our findings highlight the importance of microduplications at Xp11.22 to ID, even in sporadic cases, and reveal new clinical and molecular insight into HUWE1 copy number gains. (PMID:25652354)
• TNF activates Mule by inducing the dissociation of Mule from its inhibitor ARF. Inhibition of Mule phosphorylation by silencing Syk prevents this, thereby inhibiting Mule E3 ligase activity and TNF-induced JNK activation and cell death. (PMID:26212014)
• HUWE1 and NEDD4-1 are two E3 ligases that are fundamental enzymes in the post-translational regulation of ABCG1 and ABCG4 protein levels and cellular cholesterol export activity (PMID:26296893)
• miR-542-5p plays a critical role in the proliferation of osteosarcoma and targets HUWE1. (PMID:26498360)
• Results reveal a pathway controlled by ATM, SIRT6, and SNF2H to block HUWE1, which stabilizes H2AX and induces its incorporation into chromatin only when cells are damaged. (PMID:26711340)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	huwe1	ENSDARG00000016782
mus_musculus	Huwe1	ENSMUSG00000025261
rattus_norvegicus	Huwe1	ENSRNOG00000061262
drosophila_melanogaster	HUWE1	FBGN0030674
caenorhabditis_elegans		WBGENE00022069

Paralogs (24): HECW1 (ENSG00000002746), UBE3C (ENSG00000009335), NEDD4L (ENSG00000049759), NEDD4 (ENSG00000069869), ITCH (ENSG00000078747), HACE1 (ENSG00000085382), HECTD1 (ENSG00000092148), UBR5 (ENSG00000104517), SMURF2 (ENSG00000108854), UBE3A (ENSG00000114062), AREL1 (ENSG00000119682), WWP1 (ENSG00000123124), HERC2 (ENSG00000128731), HECW2 (ENSG00000138411), HERC3 (ENSG00000138641), HERC6 (ENSG00000138642), HERC5 (ENSG00000138646), HERC4 (ENSG00000148634), UBE3B (ENSG00000151148), TRIP12 (ENSG00000153827), HECTD2 (ENSG00000165338), HECTD4 (ENSG00000173064), WWP2 (ENSG00000198373), SMURF1 (ENSG00000198742)

Protein

Protein identifiers

E3 ubiquitin-protein ligase HUWE1 — Q7Z6Z7 (reviewed: Q7Z6Z7)

Alternative names: ARF-binding protein 1, HECT, UBA and WWE domain-containing protein 1, HECT-type E3 ubiquitin transferase HUWE1, Homologous to E6AP carboxyl terminus homologous protein 9, Large structure of UREB1, Mcl-1 ubiquitin ligase E3, Upstream regulatory element-binding protein 1

All UniProt accessions (8): Q7Z6Z7, A0A087X146, A0A087X1S3, A0A1B0GXC7, A0A994J483, A0A994J4V6, A0A994J6V7, H0Y659

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins. Regulates apoptosis by catalyzing the polyubiquitination and degradation of MCL1. Mediates monoubiquitination of DNA polymerase beta (POLB) at ‘Lys-41’, ‘Lys-61’ and ‘Lys-81’, thereby playing a role in base-excision repair. Also ubiquitinates the p53/TP53 tumor suppressor and core histones including H1, H2A, H2B, H3 and H4. Ubiquitinates MFN2 to negatively regulate mitochondrial fusion in response to decreased stearoylation of TFRC. Ubiquitination of MFN2 also takes place following induction of mitophagy; AMBRA1 acts as a cofactor for HUWE1-mediated ubiquitination. Regulates neural differentiation and proliferation by catalyzing the polyubiquitination and degradation of MYCN. May regulate abundance of CDC6 after DNA damage by polyubiquitinating and targeting CDC6 to degradation. Mediates polyubiquitination of isoform 2 of PA2G4. Acts in concert with MYCBP2 to regulate the circadian clock gene expression by promoting the lithium-induced ubiquitination and degradation of NR1D1. Binds to an upstream initiator-like sequence in the preprodynorphin gene. Mediates HAPSTR1 degradation, but is also a required cofactor in the pathway by which HAPSTR1 governs stress signaling. Acts as a regulator of the JNK and NF-kappa-B signaling pathways by mediating assembly of heterotypic ‘Lys-63’-/‘Lys-48’-linked branched ubiquitin chains that are then recognized by TAB2: HUWE1 mediates branching of ‘Lys-48’-linked chains of substrates initially modified with ‘Lys-63’-linked conjugates by TRAF6. ‘Lys-63’-/‘Lys-48’-linked branched ubiquitin chains protect ‘Lys-63’-linkages from CYLD deubiquitination. Ubiquitinates PPARA in hepatocytes.

Subunit / interactions. Interacts with isoform p14ARF of CDKN2A which strongly inhibits HUWE1 ubiquitin ligase activity. Interacts with MYCN, POLB and CDC6. Interacts with isoform 2 of PA2G4. Interacts with NR1D1. Interacts with AMBRA1. Interacts with HAPSTR1. Interacts with HAPSTR2. In hepatocytes, interacts with PAQR3; the interaction promotes PPARA poylubiquitination and STUB1-mediated degradation.

Subcellular location. Cytoplasm. Nucleus. Mitochondrion.

Tissue specificity. Weakly expressed in heart, brain and placenta but not in other tissues. Expressed in a number of cell lines, predominantly in those from colorectal carcinomas.

Post-translational modifications. Phosphorylated on tyrosine; phosphorylation is probably required for its ability to inhibit TP53 transactivation.

Disease relevance. Intellectual developmental disorder, X-linked, syndromic, Turner type (MRXST) [MIM:309590] An X-linked neurodevelopmental disorder with highly variable clinical manifestations. Common features consist of moderate to profound intellectual disability, delayed or absent speech, short stature with small hands and feet, and non-specific but recurrent dysmorphic facial features such as macrocephaly, microcephaly, a broad nasal tip, deep set eyes, epicanthic folds, short palpebral fissures and a short philtrum. Patients may manifest other features, such as hypotonia, seizures and delayed bone age. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The HECT domain mediates inhibition of the transcriptional activity of p53.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the UPL family. TOM1/PTR1 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q7Z6Z7-1	1, LASU1, Large structure of UREB1	yes
Q7Z6Z7-2	2
Q7Z6Z7-3	3

RefSeq proteins (1): NP_113584* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000569	HECT_dom	Domain
IPR004170	WWE_dom	Domain
IPR009060	UBA-like_sf	Homologous_superfamily
IPR010309	E3_Ub_ligase_DUF908	Domain
IPR010314	E3_Ub_ligase_DUF913	Domain
IPR015940	UBA	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR025527	HUWE1/Rev1_UBM	Conserved_site
IPR035983	Hect_E3_ubiquitin_ligase	Homologous_superfamily
IPR037197	WWE_dom_sf	Homologous_superfamily
IPR041918	UBA_HUWE1	Domain
IPR050409	E3_ubiq-protein_ligase	Family

Pfam: PF00632, PF02825, PF06012, PF06025, PF14377, PF22562

Enzyme classification (BRENDA):

• EC 2.3.2.26 — HECT-type E3 ubiquitin transferase (BRENDA: 14 organisms, 64 substrates, 19 inhibitors, 5 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBC5B]-L-LYSINE	0.0046–0.037	5

UniProt features (357 total): helix 149, modified residue 53, strand 43, compositionally biased region 28, turn 24, sequence variant 23, region of interest 18, domain 7, sequence conflict 6, splice variant 2, mutagenesis site 2, chain 1, active site 1

Structure

Experimental structures (PDB)

19 structures.

PDB	Method	Resolution (Å)
8RD7	X-RAY DIFFRACTION	1.31
8R7O	X-RAY DIFFRACTION	1.36
8RD0	X-RAY DIFFRACTION	1.76
3H1D	X-RAY DIFFRACTION	1.89
8RD1	X-RAY DIFFRACTION	1.9
6MIW	X-RAY DIFFRACTION	2
5C6H	X-RAY DIFFRACTION	2.05
6PFL	X-RAY DIFFRACTION	2.1
7AZX	X-RAY DIFFRACTION	2.25
3G1N	X-RAY DIFFRACTION	2.6
5LP8	X-RAY DIFFRACTION	2.7
6FYH	X-RAY DIFFRACTION	2.91
7JQ9	ELECTRON MICROSCOPY	3.1
7MOP	ELECTRON MICROSCOPY	3.3
7MWF	ELECTRON MICROSCOPY	3.3
7MWE	ELECTRON MICROSCOPY	3.4
7MWD	ELECTRON MICROSCOPY	3.7
2EKK	SOLUTION NMR
2MUL	SOLUTION NMR

Predicted structure (AlphaFold)

No AlphaFold model available for Q7Z6Z7 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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): 4341 (glycyl thioester intermediate)

Post-translational modifications (53): 3816, 3827, 3830, 3906, 3919, 3924, 3927, 4271, 648, 649, 740, 1084, 1368, 1370, 1382, 1395, 1722, 1907, 2035, 2266 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
4268	loss of activity.
4341	loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 405 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, LU_IL4_SIGNALING, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOCC_SECRETORY_GRANULE, MORF_UBE2I, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_MEMBRANE_FUSION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (26): protein polyubiquitination (GO:0000209), base-excision repair (GO:0006284), ubiquitin-dependent protein catabolic process (GO:0006511), protein monoubiquitination (GO:0006513), Golgi organization (GO:0007030), negative regulation of mitochondrial fusion (GO:0010637), cell differentiation (GO:0030154), positive regulation of protein ubiquitination (GO:0031398), circadian regulation of gene expression (GO:0032922), negative regulation of peroxisome proliferator activated receptor signaling pathway (GO:0035359), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), membrane fusion (GO:0061025), protein K48-linked ubiquitination (GO:0070936), protein branched polyubiquitination (GO:0141198), obsolete positive regulation of protein targeting to mitochondrion (GO:1903955), positive regulation of type 2 mitophagy (GO:1905091), DNA repair (GO:0006281), chromatin remodeling (GO:0006338), DNA damage response (GO:0006974), canonical NF-kappaB signal transduction (GO:0007249), protein ubiquitination (GO:0016567), peroxisome proliferator activated receptor signaling pathway (GO:0035357), defense response to bacterium (GO:0042742), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), rhythmic process (GO:0048511)

GO Molecular Function (8): DNA binding (GO:0003677), RNA binding (GO:0003723), ubiquitin-protein transferase activity (GO:0004842), ubiquitin-ubiquitin ligase activity (GO:0034450), ubiquitin protein ligase activity (GO:0061630), histone ubiquitin ligase activity (GO:0140852), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (14): Golgi membrane (GO:0000139), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), membrane (GO:0016020), secretory granule lumen (GO:0034774), extracellular exosome (GO:0070062), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Innate Immune System	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
protein ubiquitination	4
sperm flagellum	3
protein polyubiquitination	2
nucleic acid binding	2
ubiquitin protein ligase activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
DNA repair	1
modification-dependent protein catabolic process	1
organelle organization	1
endomembrane system organization	1
mitochondrial fusion	1
regulation of mitochondrial fusion	1
negative regulation of organelle organization	1
negative regulation of developmental process	1
cellular developmental process	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
circadian rhythm	1
regulation of gene expression	1
peroxisome proliferator activated receptor signaling pathway	1
regulation of peroxisome proliferator activated receptor signaling pathway	1
negative regulation of intracellular signal transduction	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
membrane organization	1
type 2 mitophagy	1
positive regulation of mitophagy	1
regulation of type 2 mitophagy	1
DNA metabolic process	1
DNA damage response	1
chromatin organization	1
cellular response to stress	1
ubiquitin-like protein transferase activity	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1

Protein interactions and networks

STRING

4068 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HUWE1	HSD17B10	Q99714	964
HUWE1	TOM1	O60784	789
HUWE1	UBE2D2	P51669	753
HUWE1	CDKN2A	P42771	743
HUWE1	MDM2	Q00987	737
HUWE1	USP9X	Q93008	703
HUWE1	UBR4	Q5T4S7	674
HUWE1	RCHY1	Q96PM5	664
HUWE1	MYCBP2	O75592	654
HUWE1	MFN2	O95140	649
HUWE1	USP7	Q93009	604
HUWE1	FSIP1	Q8NA03	594
HUWE1	WIPI2	Q9Y4P8	573
HUWE1	UBA1	P22314	566
HUWE1	RNF181	Q9P0P0	559

IntAct

186 interactions, top by confidence:

A	B	Type	Score
VHL	ELOC	psi-mi:“MI:0914”(association)	0.920
MCL1	HUWE1	psi-mi:“MI:0914”(association)	0.880
MCL1	HUWE1	psi-mi:“MI:0915”(physical association)	0.880
HUWE1	MCL1	psi-mi:“MI:0914”(association)	0.880
HUWE1	MCL1	psi-mi:“MI:0915”(physical association)	0.880
MCL1	HUWE1	psi-mi:“MI:0220”(ubiquitination reaction)	0.880
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
RNF146	TNKS	psi-mi:“MI:0914”(association)	0.790
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
USP9X	MCL1	psi-mi:“MI:0914”(association)	0.680
CDKN2A	HUWE1	psi-mi:“MI:0915”(physical association)	0.680
HUWE1	CDKN2A	psi-mi:“MI:0915”(physical association)	0.680
MCL1	PRKAB2	psi-mi:“MI:0914”(association)	0.640
CDKN2A	NPM1	psi-mi:“MI:0914”(association)	0.560
VCPIP1	VCP	psi-mi:“MI:0914”(association)	0.530
PRKCZ	IPO5	psi-mi:“MI:0914”(association)	0.530
ARRDC4	WWP2	psi-mi:“MI:0914”(association)	0.530
MCL1	PRKAG1	psi-mi:“MI:0914”(association)	0.530
SEM1	PSMC2	psi-mi:“MI:0914”(association)	0.530

BioGRID (1539): HUWE1 (Affinity Capture-Western), HUWE1 (Affinity Capture-Western), UBC (Affinity Capture-MS), MYH9 (Affinity Capture-MS), DDB1 (Affinity Capture-MS), USP7 (Affinity Capture-MS), HUWE1 (Affinity Capture-Western), DDIT4 (Affinity Capture-Western), UBB (Affinity Capture-MS), SNRPD3 (Affinity Capture-MS), RPL15 (Affinity Capture-MS), RPS9 (Affinity Capture-MS), EPRS (Affinity Capture-MS), PSMA6 (Affinity Capture-MS), ACACB (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IES7, A0JN62, A0JNW5, A2AAE1, A2AGL3, A2RSJ4, A2RT67, A2RUS2, A2RV80, B0LPN4, B1H2P5, E7F240, E9Q401, O00507, O94967, P30957, P48553, P51593, Q14161, Q2LD37, Q3TLI0, Q3UHE1, Q3UVG3, Q3UX43, Q5F361, Q5M7Q1, Q5RAQ5, Q5ZJK1, Q658Y4, Q68CL5, Q6BDS2, Q6P6Y1, Q6TEP1, Q6VNB8, Q7TMY8, Q7TSG1, Q7Z6Z7, Q8BHY8, Q8CB44, Q8CGF6

Diamond homologs: A0A8C0NGY6, A1CQG2, A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B8N7E5, D3ZBM7, D6C652, E1B7Q7, E1C656, F1LP64, F1N6G5, F8W2M1, G0S9J5, G5E870, H2LBU8, O00308, O08759, O13834, O14326, O15033, P39940, P40985, P46934, P46935, P46937, P46938, P51593, P53119, Q03280, Q05086, Q08CZ0, Q09291, Q0CCL1, Q14669, Q15034, Q15386, Q1K9C4

SIGNOR signaling

21 interactions.

A	Effect	B	Mechanism
HUWE1	“down-regulates quantity by destabilization”	MCL1	ubiquitination
Ub:E2	“up-regulates activity”	HUWE1	ubiquitination
HUWE1	“down-regulates quantity by destabilization”	POLL	polyubiquitination
AMBRA1	“up-regulates activity”	HUWE1	relocalization
HUWE1	“down-regulates quantity by destabilization”	MFN2	ubiquitination
HUWE1	“down-regulates quantity by destabilization”	TP53	ubiquitination
HUWE1	“down-regulates quantity by destabilization”	CHEK1	ubiquitination
HUWE1	“down-regulates quantity by destabilization”	BRCA1	ubiquitination
HUWE1	“down-regulates quantity by destabilization”	KAT7	ubiquitination
HUWE1	“down-regulates quantity”	ATOH1	ubiquitination
HUWE1	“down-regulates quantity”	MYOD1	ubiquitination
HUWE1	“down-regulates quantity by destabilization”	NEIL1	ubiquitination
HUWE1	“down-regulates quantity”	TBP	ubiquitination
HUWE1	“down-regulates quantity by destabilization”	ZBTB17	ubiquitination
HUWE1	“down-regulates quantity by destabilization”	KLF4	ubiquitination
HUWE1	“down-regulates quantity by destabilization”	MYCN	ubiquitination
HUWE1	“down-regulates quantity”	PTOV1	ubiquitination
HUWE1	“down-regulates quantity by destabilization”	PPARA	ubiquitination
SYK	“up-regulates activity”	HUWE1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 200 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
VEGFR2 mediated cell proliferation	5	21.5×	6e-04
Chaperone Mediated Autophagy	5	18.7×	6e-04
Dengue Virus Genome Translation and Replication	6	14.3×	6e-04
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	5	13.8×	2e-03
Ovarian tumor domain proteases	6	12.6×	6e-04
Late endosomal microautophagy	5	12.3×	2e-03
AUF1 (hnRNP D0) binds and destabilizes mRNA	6	11.2×	1e-03
Degradation of AXIN	6	11.2×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
Ras protein signal transduction	7	8.2×	5e-03
protein deubiquitination	8	8.1×	2e-03
regulation of protein stability	11	7.9×	2e-04
ubiquitin-dependent protein catabolic process	12	5.1×	2e-03
protein stabilization	13	5.0×	1e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	16	4.8×	2e-04
protein phosphorylation	11	4.3×	9e-03
protein ubiquitination	15	3.5×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

2544 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	62
Uncertain significance	976
Likely benign	542
Benign	255

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1320047	NM_031407.7(HUWE1):c.12404A>C (p.His4135Pro)	Pathogenic
1334036	NM_031407.7(HUWE1):c.646-1G>A	Pathogenic
145164	GRCh38/hg38 Xp11.22(chrX:53532771-53764152)x2	Pathogenic
145165	GRCh38/hg38 Xp11.22(chrX:53532771-53764152)x3	Pathogenic
146020	GRCh38/hg38 Xp11.22(chrX:53532587-53595587)x3	Pathogenic
1703066	NM_031407.7(HUWE1):c.2960del (p.Gly987fs)	Pathogenic
3393024	NM_031407.7(HUWE1):c.12091T>C (p.Tyr4031His)	Pathogenic
372628	NM_031407.7(HUWE1):c.12680T>C (p.Leu4227Ser)	Pathogenic
375709	NM_031407.7(HUWE1):c.329G>A (p.Arg110Gln)	Pathogenic
375711	NM_031407.7(HUWE1):c.567+1G>C	Pathogenic
841299	NM_031407.7(HUWE1):c.9209G>A (p.Arg3070His)	Pathogenic
977636	NM_031407.7(HUWE1):c.12408C>G (p.Ile4136Met)	Pathogenic
1344905	NM_031407.7(HUWE1):c.12559C>A (p.Arg4187Ser)	Likely pathogenic
1679378	NM_031407.7(HUWE1):c.9883G>A (p.Gly3295Ser)	Likely pathogenic
1805743	NM_031407.7(HUWE1):c.6311A>G (p.Glu2104Gly)	Likely pathogenic
2136294	NM_031407.7(HUWE1):c.12946G>C (p.Gly4316Arg)	Likely pathogenic
216942	NM_031407.7(HUWE1):c.4013C>T (p.Ala1338Val)	Likely pathogenic
2505506	NM_031407.7(HUWE1):c.2320-19A>G	Likely pathogenic
2572050	NM_031407.7(HUWE1):c.12227C>G (p.Pro4076Arg)	Likely pathogenic
2577165	NM_031407.7(HUWE1):c.12619G>A (p.Val4207Ile)	Likely pathogenic
2580158	NM_031407.7(HUWE1):c.12719C>T (p.Ser4240Phe)	Likely pathogenic
2628723	NM_031407.7(HUWE1):c.5974C>T (p.Arg1992Trp)	Likely pathogenic
2629233	NM_031407.7(HUWE1):c.2329G>A (p.Val777Met)	Likely pathogenic
2631240	NM_031407.7(HUWE1):c.6652A>G (p.Lys2218Glu)	Likely pathogenic
2633761	NM_031407.7(HUWE1):c.1129C>T (p.Pro377Ser)	Likely pathogenic
2690952	NM_031407.7(HUWE1):c.5632G>T (p.Ala1878Ser)	Likely pathogenic
3252157	NM_031407.7(HUWE1):c.1981A>T (p.Ser661Cys)	Likely pathogenic
3254790	NM_031407.7(HUWE1):c.12577G>A (p.Gly4193Arg)	Likely pathogenic
3337166	NM_031407.7(HUWE1):c.12708G>C (p.Lys4236Asn)	Likely pathogenic
3342370	NM_031407.7(HUWE1):c.4141A>G (p.Met1381Val)	Likely pathogenic

SpliceAI

10653 predictions. Top by Δscore:

Variant	Effect	Δscore
X:53533407:TAAAA:T	acceptor_gain	1.0000
X:53533408:AAAA:A	acceptor_gain	1.0000
X:53533412:C:CC	acceptor_gain	1.0000
X:53533998:T:TA	donor_gain	1.0000
X:53534512:TCA:T	donor_loss	1.0000
X:53534515:C:CT	donor_loss	1.0000
X:53534532:TGG:T	donor_gain	1.0000
X:53534693:GGCTC:G	acceptor_gain	1.0000
X:53534695:CTC:C	acceptor_gain	1.0000
X:53534696:TC:T	acceptor_gain	1.0000
X:53534697:CCT:C	acceptor_loss	1.0000
X:53534697:CCTGG:C	acceptor_gain	1.0000
X:53534698:C:CC	acceptor_gain	1.0000
X:53534698:CTG:C	acceptor_loss	1.0000
X:53534701:G:C	acceptor_gain	1.0000
X:53534701:G:GC	acceptor_gain	1.0000
X:53534711:C:CT	acceptor_gain	1.0000
X:53535382:A:AT	donor_loss	1.0000
X:53535383:CC:C	donor_loss	1.0000
X:53535396:T:C	donor_gain	1.0000
X:53535417:A:AC	donor_gain	1.0000
X:53535417:ACT:A	donor_gain	1.0000
X:53535418:C:CC	donor_gain	1.0000
X:53535418:CT:C	donor_gain	1.0000
X:53535418:CTC:C	donor_gain	1.0000
X:53535420:C:CA	donor_gain	1.0000
X:53535427:ATTCT:A	donor_gain	1.0000
X:53535497:TGGAC:T	acceptor_gain	1.0000
X:53535498:GGAC:G	acceptor_gain	1.0000
X:53535499:GAC:G	acceptor_gain	1.0000

AlphaMissense

28654 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:53533321:A:C	F4371L	1.000
X:53533321:A:T	F4371L	1.000
X:53533322:A:C	F4371C	1.000
X:53533322:A:G	F4371S	1.000
X:53533323:A:G	F4371L	1.000
X:53533326:C:G	G4370R	1.000
X:53533346:G:T	A4363D	1.000
X:53533355:A:C	L4360R	1.000
X:53533355:A:G	L4360P	1.000
X:53533367:A:G	L4356P	1.000
X:53533367:A:T	L4356H	1.000
X:53533391:G:C	P4348R	1.000
X:53533391:G:T	P4348H	1.000
X:53533394:A:C	L4347R	1.000
X:53533394:A:G	L4347P	1.000
X:53533394:A:T	L4347Q	1.000
X:53533400:A:G	L4345P	1.000
X:53533400:A:T	L4345Q	1.000
X:53533403:T:G	Q4344P	1.000
X:53533405:A:C	N4343K	1.000
X:53533405:A:T	N4343K	1.000
X:53533408:A:C	F4342L	1.000
X:53533408:A:T	F4342L	1.000
X:53533409:A:G	F4342S	1.000
X:53533410:A:G	F4342L	1.000
X:53533410:A:T	F4342I	1.000
X:53534008:A:G	C4341R	1.000
X:53534014:G:C	H4339D	1.000
X:53534016:G:T	A4338D	1.000
X:53534022:G:C	P4336R	1.000

dbSNP variants (sampled 300 via entrez): RS1000072944 (X:53630633 G>C), RS1000165445 (X:53574361 G>C), RS1000196992 (X:53574908 A>G), RS1000257903 (X:53639788 T>C), RS1000421707 (X:53640173 A>G), RS1000488354 (X:53586579 A>G,T), RS1000497543 (X:53565615 A>G), RS1000503705 (X:53572457 G>A,T), RS1000520515 (X:53584848 T>C), RS1000535906 (X:53572842 A>T), RS1000758583 (X:53646792 A>G), RS1000796020 (X:53535552 G>C), RS1000839648 (X:53665061 T>C), RS1000999231 (X:53656233 G>A), RS1001064813 (X:53674508 T>C)

Disease associations

OMIM: gene MIM:300697 | disease phenotypes: MIM:300612, MIM:300706, MIM:309590, MIM:314320, MIM:309580, MIM:309530, MIM:300919, MIM:308350, MIM:614429, MIM:108800

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, X-linked syndromic, Turner type	Definitive	X-linked
syndromic intellectual disability	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
non-syndromic X-linked intellectual disability	Definitive	XL

Mondo (15): intellectual disability, X-linked syndromic, Turner type (MONDO:0010407), trigonocephaly-short stature-developmental delay syndrome (MONDO:0010749), intellectual disability-hypotonic facies syndrome, X-linked, 1 (MONDO:0010663), autism spectrum disorder (MONDO:0005258), non-syndromic X-linked intellectual disability (MONDO:0019181), intellectual disability, X-linked 99 (MONDO:0010487), intellectual disability (MONDO:0001071), X-linked intellectual disability (MONDO:0100284), non-syndromic intellectual disability (MONDO:0000509), genetic developmental and epileptic encephalopathy (MONDO:0100062), blepharophimosis (MONDO:0001008), ventricular septal defect (MONDO:0002070), hypothyroidism (MONDO:0005420), atrial septal defect (MONDO:0006664), syndromic intellectual disability (MONDO:0000508)

Orphanet (17): X-linked intellectual disability, Brooks type (Orphanet:3056), X-linked intellectual disability, Turner type (Orphanet:85328), Trigonocephaly-short stature-developmental delay syndrome (Orphanet:3369), X-linked intellectual disability-hypotonic face syndrome (Orphanet:73220), Holmes-Gang syndrome (Orphanet:93970), Chudley-Lowry-Hoar syndrome (Orphanet:93971), Juberg-Marsidi syndrome (Orphanet:93972), Carpenter-Waziri syndrome (Orphanet:93973), Smith-Fineman-Myers syndrome (Orphanet:93974), OBSOLETE: Renier-Gabreels-Jasper syndrome (Orphanet:93975), X-linked non-syndromic intellectual disability (Orphanet:777), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805), Interatrial communication (Orphanet:1478), Rare genetic intellectual disability (Orphanet:183757), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000154	Wide mouth
HP:0000160	Narrow mouth
HP:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000243	Trigonocephaly
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000325	Triangular face
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000378	Cupped ear
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000455	Broad nasal tip
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004904_11	Body mass index	3.000000e-08
GCST006442_458	Educational attainment (years of education)	4.000000e-10
GCST008103_88	Bipolar disorder	1.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004784	self reported educational attainment

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D016569	Blepharophimosis	C11.250.090; C11.338.190; C16.131.384.190
D006344	Heart Septal Defects, Atrial	C14.240.400.560.375; C14.280.400.560.375; C16.131.240.400.560.375
D006345	Heart Septal Defects, Ventricular	C14.240.400.560.540; C14.280.400.560.540; C16.131.240.400.560.540
D007037	Hypothyroidism	C19.874.482
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)
C567476	Mental Retardation, X-Linked, Syndromic, Turner Type (supp.)
C537445	Mental retardation Smith Fineman Myers type (supp.)
C536620	Say Meyer syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295881 (SINGLE PROTEIN)

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.05	IC50	900	nM	CHEMBL5723352
5.50	Kd	3186	nM	CHEMBL5653589
5.50	ED50	3186	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 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	2148561: Binding affinity to human HUWE1 incubated for 45 mins by Kinobead based pull down assay	kd	3.1861	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects expression, affects methylation, increases expression, increases mutagenesis	4
bisphenol A	decreases methylation, increases expression	3
sodium arsenite	increases reaction, increases abundance, affects cotreatment, decreases expression, affects binding	3
bisphenol S	increases expression, affects cotreatment, decreases expression, affects expression	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
Lipopolysaccharides	increases expression, affects expression, affects response to substance	2
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
FR900359	affects phosphorylation	1
AZD5991	affects binding, decreases reaction, decreases expression	1
tapotoclax	increases ubiquitination, affects binding, decreases reaction, decreases expression, affects cotreatment	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects binding, decreases reaction	1
2-bromopalmitate	increases palmitoylation, decreases reaction, increases abundance	1
manganese chloride	decreases expression, increases abundance	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation, increases methylation	1
coumarin	affects phosphorylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases 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
marinopyrrole A	affects cotreatment, increases ubiquitination	1
LDN 193189	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
bisphenol AF	increases expression	1

ChEMBL screening assays

4 unique, capped per target: 3 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118628	Binding	Binding affinity to HUWE1 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem
CHEMBL5723313	Functional	Affinity Biochemical interaction: (DELFIA assay) EUB0002788a HUWE1	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0EJ	Ubigene HeLa HUWE1 KO	Cancer cell line	Female
CVCL_SR89	HAP1 HUWE1 (-) 1	Cancer cell line	Male
CVCL_SR90	HAP1 HUWE1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder