NEDD4L

Summary

NEDD4L (NEDD4 like E3 ubiquitin protein ligase, HGNC:7728) is a protein-coding gene on chromosome 18q21.31, encoding E3 ubiquitin-protein ligase NEDD4-like (Q96PU5). E3 ubiquitin-protein ligase that mediates the polyubiquitination of lysine and cysteine residues on target proteins and is thereby implicated in the regulation of various signaling pathways including autophagy, innate immunity or DNA repair.

This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein mediates the ubiquitination of multiple target substrates and plays a critical role in epithelial sodium transport by regulating the cell surface expression of the epithelial sodium channel, ENaC. Single nucleotide polymorphisms in this gene may be associated with essential hypertension. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 23327 — RefSeq curated summary.

At a glance

• Gene–disease (curated): periventricular nodular heterotopia 7 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 19
• Clinical variants (ClinVar): 1,119 total — 2 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 73
• MANE Select transcript: NM_001144967

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7728
Approved symbol	NEDD4L
Name	NEDD4 like E3 ubiquitin protein ligase
Location	18q21.31
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0439, RSP5, NEDD4-2
Ensembl gene	ENSG00000049759
Ensembl biotype	protein_coding
OMIM	606384
Entrez	23327

Gene structure

Transcript identifiers

Ensembl transcripts: 63 — 31 protein_coding, 16 protein_coding_CDS_not_defined, 15 retained_intron, 1 nonsense_mediated_decay

ENST00000256830, ENST00000356462, ENST00000357895, ENST00000382850, ENST00000400345, ENST00000431212, ENST00000435432, ENST00000456173, ENST00000456986, ENST00000585323, ENST00000585363, ENST00000585594, ENST00000585970, ENST00000586263, ENST00000586268, ENST00000587190, ENST00000587246, ENST00000587547, ENST00000587634, ENST00000587881, ENST00000588066, ENST00000588494, ENST00000588516, ENST00000588712, ENST00000589054, ENST00000589167, ENST00000590020, ENST00000590248, ENST00000590506, ENST00000590638, ENST00000590694, ENST00000591579, ENST00000591989, ENST00000592097, ENST00000592601, ENST00000592846, ENST00000617539, ENST00000635997, ENST00000674517, ENST00000674613, ENST00000674636, ENST00000674845, ENST00000674856, ENST00000674921, ENST00000675101, ENST00000675137, ENST00000675147, ENST00000675221, ENST00000675227, ENST00000675244, ENST00000675434, ENST00000675502, ENST00000675554, ENST00000675699, ENST00000675801, ENST00000675865, ENST00000676024, ENST00000676223, ENST00000676226, ENST00000676251, ENST00000676301, ENST00000679791, ENST00000936802

RefSeq mRNA: 10 — MANE Select: NM_001144967 NM_001144964, NM_001144965, NM_001144966, NM_001144967, NM_001144968, NM_001144969, NM_001144970, NM_001144971, NM_001243960, NM_015277

CCDS: CCDS45872, CCDS45873, CCDS45874, CCDS45875, CCDS45876, CCDS58632, CCDS59323

Canonical transcript exons

ENST00000400345 — 31 exons

Exon	Start	End
ENSE00000486414	58373174	58373269
ENSE00000807249	58365999	58366228
ENSE00000914600	58335478	58335537
ENSE00000914602	58341038	58341169
ENSE00002776930	58044226	58044708
ENSE00002905144	58396167	58401539
ENSE00003459135	58252001	58252054
ENSE00003475664	58389085	58389192
ENSE00003492316	58385526	58385586
ENSE00003507028	58245427	58245508
ENSE00003515446	58350991	58351045
ENSE00003519642	58165788	58165861
ENSE00003521084	58330738	58330914
ENSE00003543265	58342906	58343103
ENSE00003552336	58324996	58325162
ENSE00003563786	58322425	58322486
ENSE00003578935	58387439	58387498
ENSE00003579558	58341678	58341797
ENSE00003584289	58315982	58316032
ENSE00003593470	58323232	58323334
ENSE00003598341	58364268	58364333
ENSE00003598483	58383246	58383319
ENSE00003609303	58367746	58367867
ENSE00003621565	58248899	58248937
ENSE00003660347	58391487	58391559
ENSE00003665249	58333818	58333892
ENSE00003675956	58349537	58349614
ENSE00003680385	58357194	58357252
ENSE00003681852	58370397	58370467
ENSE00003686926	58390646	58390742
ENSE00003788532	58328995	58329127

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 98.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.5793 / max 408.4179, expressed in 1666 samples.

FANTOM5 promoters (35 alternative TSS)

Promoter ID	TPM avg	Samples expressed
170394	8.3954	920
170381	3.5404	743
170366	2.4697	1073
170367	1.5234	685
170408	0.6224	333
170401	0.5314	137
170397	0.4425	102
170388	0.3987	117
170393	0.3469	167
170383	0.2991	154

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.50	gold quality
ganglionic eminence	UBERON:0004023	98.29	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.13	gold quality
right lung	UBERON:0002167	96.97	gold quality
cortical plate	UBERON:0005343	96.89	gold quality
secondary oocyte	CL:0000655	96.58	gold quality
body of pancreas	UBERON:0001150	95.78	gold quality
upper lobe of left lung	UBERON:0008952	95.61	gold quality
rectum	UBERON:0001052	95.36	gold quality
upper lobe of lung	UBERON:0008948	95.05	gold quality
colonic epithelium	UBERON:0000397	94.80	gold quality
adult mammalian kidney	UBERON:0000082	94.53	gold quality
body of stomach	UBERON:0001161	94.06	gold quality
prostate gland	UBERON:0002367	94.06	gold quality
metanephros cortex	UBERON:0010533	93.94	gold quality
middle temporal gyrus	UBERON:0002771	93.90	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.90	gold quality
mucosa of stomach	UBERON:0001199	93.72	gold quality
stomach	UBERON:0000945	93.61	gold quality
transverse colon	UBERON:0001157	93.58	gold quality
buccal mucosa cell	CL:0002336	93.38	gold quality
pancreas	UBERON:0001264	93.33	gold quality
sperm	CL:0000019	93.21	gold quality
lung	UBERON:0002048	93.20	gold quality
pigmented layer of retina	UBERON:0001782	93.15	gold quality
retina	UBERON:0000966	93.12	gold quality
amniotic fluid	UBERON:0000173	92.77	gold quality
colonic mucosa	UBERON:0000317	92.71	gold quality
mucosa of transverse colon	UBERON:0004991	92.42	gold quality
kidney	UBERON:0002113	92.24	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	5088.82
E-GEOD-131882	yes	4601.68
E-GEOD-137537	yes	1389.13
E-MTAB-7316	yes	30.40
E-GEOD-135922	yes	27.05
E-HCAD-1	yes	22.82
E-MTAB-8410	yes	14.88
E-HCAD-10	yes	13.96
E-CURD-135	no	1848.39
E-GEOD-99795	no	182.23
E-GEOD-100618	no	34.10
E-GEOD-93593	no	11.47
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, CTNNB1, SUPT3H

miRNA regulators (miRDB)

315 targeting NEDD4L, 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-3613-3P	100.00	76.36	7965
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
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-4692	100.00	67.32	2066
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559

Literature-anchored findings (GeneRIF, showing 40)

• Candidate gene for autosomal dominant orthostatic hypotensive disorder. (PMID:11840194)
• This ubiquitin-protein ligase is expressed in mouse mandibular salivary duct cells and regulates the amiloride-sensitive Na+ conductance in these cells. (PMID:12139396)
• The ubiquitin ligase NEDD4L is a candidate gene for essential hypertension on both functional and genetic grounds (PMID:12522688)
• Alternate transcripts of Nedd4-2 may interact with ENaC differently. hNedd4-2 has role in regulation of ENaC. Protein domains are important for Nedd4-2 function. (PMID:12876068)
• Identification of multiple splice forms and 5’ variants of Nedd4l. 5’ variants inhibit ENaC-mediated Na+ transport when reconstituted in FRT epithelia. Other splice forms encode Nedd4L isoforms with 2 to 4 WW domains having varying affinity for ENaC. (PMID:12876068)
• Results describe the isolation of three new NEDD4L transcripts designated NEDD4Lf, NEDD4Lg and NEDD4Lh, which encode different forms of the NEDD4L protein. (PMID:14615060)
• SGK1 stimulates the NaPi IIb, at least in part, by phosphorylating and thereby inhibiting Nedd4-2 binding to its target. (PMID:15044175)
• The differential phosphorylation status between wild-type and mutant Nedd4-2 provides an explanation for the different potential to inhibit ENaC activity. (PMID:15140763)
• cAMP regulates ENaC in part by phosphorylation and inhibition of Nedd4-2. Moreover, Nedd4-2 is a central convergence point for kinase regulation of Na(+) transport. (PMID:15328345)
• Nedd4-2 phosphorylation induces SGK ubiquitination and degradation (PMID:15576372)
• Significant association between several SNPs and hypertension in US whites, Greek whites, and African-Americans. Genetic variation in NEDD4L may play role in development or progression of some forms of hypertension. (PMID:16103266)
• 14-3-3 inhibits the interaction between the WW domains of hNedd4-2 and the PY motif of the epithelial Na(+) channel, ENaC (PMID:16716084)
• genetic NEDD4L variation affecting cross-sectional and longitudinal blood pressure is possibly as a consequence of altered NEDD4L interaction with ENaC (PMID:16788695)
• Study identified three NEDD4-2 missense changes in highly conserved residues (S233L, E271A and H515P) in families with photosensitive generalized epilepsy. (PMID:17331106)
• Genetic NEDD4L variation seems to affect salt sensitivity and P-renin in normotensive subjects, suggesting that genotyping of NEDD4L may be clinically useful to identify subjects who benefit from dietary salt restriction in the prevention of hypertension (PMID:17487281)
• Nedd4-2 binds to and ubiquitinates ENaC at the cell surface, which targets surface ENaC for degradation, and thus, reduces epithelial Na(+) transport. (PMID:17502380)
• G-protein-coupled receptor kinase 2 interacts not only with epithelial Na(+) channels, but also with both Nedd4 and Nedd4-2 (PMID:17544362)
• The human Nedd4L gene, especially the evolutionarily new isoform I, is a candidate gene for hypertension. (PMID:18268134)
• Our results support rs3865418 but not rs4149601 polymorphism of NEDD4L gene implicated in the prevalence of hypertension in Chinese Hans. (PMID:18293164)
• These observations suggest that NEDD4L and possibly other NEDD4-like proteins can ubiquitylate and activate ESCRT-I to function in virus budding. (PMID:18321968)
• budding of various HIV-1 L-domain mutants is dramatically enhanced by ectopic Nedd4-2s, a native isoform with a truncated C2 domain. (PMID:18321969)
• Nedd4-2 reduces the half-life of epithelial sodium channel subunits and enhances the ubiquitination of alpha, beta, and gamma epithelial sodium channels (PMID:18322022)
• WW domains of Nedd4-2 bind (weakly) to a PY motif (LPXY) located within its own HECT domain and inhibit auto-ubiquitination. HECT PY-motif mutation does not affect ubiquitination or down-regulation of a known Nedd4-2 substrate, ENaC. (PMID:18498246)
• Nedd4-2 differentially interacts with and regulates TTYH1-3 (PMID:18577513)
• Physiological interaction between the ADD1 and WNK1-NEDD4L pathways influences the effects of variants in these genes on sodium-related BP regulation. (PMID:18591455)
• the interplay between Nedd4-2-related E3 ligases that regulate ACK1 levels and Cbl that modifies EGF receptor impinges on cell receptor dynamics. (PMID:19144635)
• Whereas the C2 domain-containing NEDD4L isoform is capable of shuttling between the plasma membrane and intracellular compartments in response to calcium stimulus the C2-lacking isoform can not. (PMID:19364400)
• The protein-protein interaction between the WW domain of Fe65 and the putative binding motif of Nedd4-2 down-regulates Fe65 protein stability and subcellular localization through its ubiquitylation, to contribute to cell apoptosis. (PMID:19381069)
• the loss of NEDD4 association on IL-2Rgamma(c) is accompanied by a dramatic increase of the half-life of the receptor subunit. (PMID:19615332)
• the SGK1/Nedd4-2 signaling pathway regulates both CFTR and ENaC trafficking in CF epithelial cells (PMID:19617352)
• The A allele of NEDD4L may be a useful marker for predicting hypertension, orthostatic hypotension, and antihypertensive response to hydrochlorothiazide. (PMID:19635985)
• NPC2 binds C2 domain of human Nedd4L. (PMID:19664597)
• Nedd4-2 is an E3 ligase recruited by Ndfip1 for the ubiquitination of DMT1 within human neurons. (PMID:19706893)
• Results identify Nedd4L as the ubiquitin ligase in TGF-beta induced phosphorylation of the transcription factors Smad2 and Smad3. (PMID:19917253)
• Although several substrates were recognized by both Nedd4-1 and Nedd4-2, others were specific to only one, with several Tyr kinases preferred by Nedd4-1 and some ion channels by Nedd4- (PMID:19953087)
• two common SNPs of NEDD4L (296921-296923delTTG and rs2288775), were found to be associated with essential hypertension in Kazakh females (PMID:20003179)
• role of WW3 and WW4 domains of Nedd4-2 in dopamine transporter ubiquitination was demonstrated; siRNA analysis demonstrated that this polyubiquitination is mediated by Nedd4-2 cooperation with UBE2D and UBE2L3 E2 ubiquitin-conjugating enzymes (PMID:20051513)
• Results describe the crystal structure of a complex between the HECT domain of NEDD4L and the E2 UbcH5B bearing a covalently linked Ub at its active site (UbcH5B approximately Ub). (PMID:20064473)
• the role of NEDD4L-mediated ubiquitination in the pathogenesis of hypertension is disscussed (PMID:20090362)
• analysis of phosphorylatable residues that activate Nedd4-2 and may work together with residues targeted by inhibitory kinases (SGK1 and protein kinase A) to govern Nedd4-2 regulation of epithelial ion transport (PMID:20466724)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nedd4l	ENSDARG00000060006
mus_musculus	Nedd4l	ENSMUSG00000024589
rattus_norvegicus	Nedd4l	ENSRNOG00000017610

Paralogs (24): HECW1 (ENSG00000002746), UBE3C (ENSG00000009335), NEDD4 (ENSG00000069869), ITCH (ENSG00000078747), HACE1 (ENSG00000085382), HUWE1 (ENSG00000086758), 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 NEDD4-like — Q96PU5 (reviewed: Q96PU5)

Alternative names: HECT-type E3 ubiquitin transferase NED4L, NEDD4.2, Nedd4-2

All UniProt accessions (17): A0A087WVI6, A0A140TA85, A0A1B0GVY1, Q96PU5, A0A6Q8PFI7, A0A6Q8PG51, A0A6Q8PG81, A0A6Q8PGL4, A0A6Q8PGP5, A0A6Q8PHE7, A0A6Q8PHJ5, A0A7P0Z498, K7EKL1, K7EN51, K7ENS6, K7EQC5, K7ERN1

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that mediates the polyubiquitination of lysine and cysteine residues on target proteins and is thereby implicated in the regulation of various signaling pathways including autophagy, innate immunity or DNA repair. Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation. Downregulates autophagy and cell growth by ubiquitinating and reducing cellular ULK1 or ASCT2 levels. Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, SCN2A/Nav1.2, SCN3A/Nav1.3, SCN5A/Nav1.5, SCN9A/Nav1.7, SCN10A/Nav1.8, KCNA3/Kv1.3, KCNH2, EAAT1, KCNQ2/Kv7.2, KCNQ3/Kv7.3 or CLC5. Promotes ubiquitination and degradation of SGK1 and TNK2. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1. Plays a role in dendrite formation by melanocytes. Involved in the regulation of TOR signaling. Ubiquitinates and regulates protein levels of NTRK1 once this one is activated by NGF. Plays a role in antiviral innate immunity by catalyzing ‘Lys-29’-linked cysteine ubiquitination of TRAF3, resulting in enhanced ‘Lys-48’ and ‘Lys-63’-linked ubiquitination of TRAF3. Ubiquitinates TTYH2 and TTYH3 and regulates protein levels of TTYH2.

Subunit / interactions. Interacts with UBE2E3. Interacts with NDFIP1; this interaction activates the E3 ubiquitin-protein ligase. Interacts with NDFIP2; this interaction activates the E3 ubiquitin-protein ligase. Interacts (via WW domains) with SCN1A. Interacts (via WW domains) with SCN2A. Interacts (via WW domains) with SCN3A. Interacts (via WW domains) with SCN5A. Interacts (via WW domains) with SCN8A. Interacts (via WW domains) with SCN9A. Interacts (via WW domains) with SCN10A. Interacts (via WW domains) with CLCN5. Interacts with SMAD2. Interacts with SMAD3. Interacts with SMAD6. Interacts with SMAD7. The phosphorylated form interacts with 14-3-3 proteins. Interacts with TNK2. Interacts with WNK1. Interacts with SGK1. Interacts (via C2 domain) with NPC2. Interacts with ARRDC4. Interacts with KCNQ1; promotes internalization of KCNQ1. Interacts (via domains WW1, 3 and 4) with USP36; the interaction inhibits ubiquitination of, at least, NTRK1, KCNQ2 and KCNQ3 by NEDD4L. Interacts with PRRG4 (via cytoplasmic domain). Interacts with LDLRAD3; the interaction is direct. Interacts with UBE2D2. Interacts with TTYH2 and TTYH3. (Microbial infection) Interacts with Epstein-Barr virus LMP2A.

Subcellular location. Cytoplasm. Golgi apparatus. Endosome. Multivesicular body.

Tissue specificity. Ubiquitously expressed, with highest levels in prostate, pancreas, and kidney. Expressed in melanocytes.

Post-translational modifications. Phosphorylated by SGK1 or PKA; which impairs interaction with SCNN. Interaction with YWHAH inhibits dephosphorylation. Auto-ubiquitinated. Deubiquitinated by USP36, no effect on NEDD4L protein levels. Both proteins interact and regulate each other’s ubiquitination levels.

Disease relevance. Periventricular nodular heterotopia 7 (PVNH7) [MIM:617201] A form of periventricular nodular heterotopia, a disorder resulting from a defect in the pattern of neuronal migration in which ectopic collections of neurons lie along the lateral ventricles of the brain or just beneath, contiguously or in isolated patches. PVNH7 is an autosomal dominant disease characterized by delayed psychomotor development, intellectual disability, and seizures in some patients. Additional features include cleft palate and toe syndactyly. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by NDFIP1- and NDFIP2-binding.

Domain organisation. WW domains are involved in recognizing PPxY motifs in substrate proteins.

Induction. By androgens in prostate, and by albumin in kidney.

Pathway. Protein modification; protein ubiquitination.

Isoforms (8)

UniProt ID	Names	Canonical?
Q96PU5-1	1, Nedd4-2c	yes
Q96PU5-2	2
Q96PU5-3	3, NEDD4Le
Q96PU5-4	4, NEDD4La, NEDD4Lb, NEDD4Lf
Q96PU5-5	5, NEDD4Ld
Q96PU5-6	6, NEDD4Lh
Q96PU5-7	7, NEDD4Lg
Q96PU5-9	8

RefSeq proteins (10): NP_001138436, NP_001138437, NP_001138438, NP_001138439, NP_001138440, NP_001138441, NP_001138442, NP_001138443, NP_001230889, NP_056092 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR000569	HECT_dom	Domain
IPR001202	WW_dom	Domain
IPR024928	E3_ub_ligase_SMURF1	Family
IPR035892	C2_domain_sf	Homologous_superfamily
IPR035983	Hect_E3_ubiquitin_ligase	Homologous_superfamily
IPR036020	WW_dom_sf	Homologous_superfamily
IPR050409	E3_ubiq-protein_ligase	Family

Pfam: PF00168, PF00397, PF00632

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)
• EC 2.3.2.B8 — (BRENDA: organisms, substrates, inhibitors, Km, 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 (114 total): strand 34, helix 25, modified residue 13, turn 12, domain 6, sequence variant 6, region of interest 5, splice variant 5, mutagenesis site 2, sequence conflict 2, initiator methionine 1, chain 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
7LP1	X-RAY DIFFRACTION	1.35
7LP3	X-RAY DIFFRACTION	1.61
6ZBT	X-RAY DIFFRACTION	1.8
2NSQ	X-RAY DIFFRACTION	1.85
7LP2	X-RAY DIFFRACTION	1.88
6ZC9	X-RAY DIFFRACTION	1.9
2ONI	X-RAY DIFFRACTION	2.2
7NMZ	X-RAY DIFFRACTION	2.3
5HPK	X-RAY DIFFRACTION	2.43
9Z5Q	ELECTRON MICROSCOPY	3.06
3JW0	X-RAY DIFFRACTION	3.1
3JVZ	X-RAY DIFFRACTION	3.3
9GIK	ELECTRON MICROSCOPY	3.58
9GIM	ELECTRON MICROSCOPY	4.11
2LAJ	SOLUTION NMR
2LB2	SOLUTION NMR
2LTY	SOLUTION NMR
2MPT	SOLUTION NMR
7LP4	SOLUTION NMR
7LP5	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96PU5-F1	69.76	0.30

Antibody-complex structures (SAbDab): 1 — 9Z5Q

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): 942 (glycyl thioester intermediate)

Post-translational modifications (13): 2, 312, 318, 342, 367, 446, 448, 449, 464, 475, 479, 483, 487

Mutagenesis-validated functional residues (2):

Position	Phenotype
448	abolishes interaction with 1433f.
942	abolishes activity. no effect on usp36 protein levels.

Function

Pathways and Gene Ontology

Reactome pathways

24 pathways

ID	Pathway
R-HSA-162588	Budding and maturation of HIV virion
R-HSA-2173788	Downregulation of TGF-beta receptor signaling
R-HSA-2173795	Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-2672351	Stimuli-sensing channels
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-162587	HIV Life Cycle
R-HSA-162599	Late Phase of HIV Life Cycle
R-HSA-162906	HIV Infection
R-HSA-1643685	Disease
R-HSA-168256	Immune System
R-HSA-170834	Signaling by TGF-beta Receptor Complex
R-HSA-212436	Generic Transcription Pathway
R-HSA-2173789	TGF-beta receptor signaling activates SMADs
R-HSA-2173793	Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
R-HSA-382551	Transport of small molecules
R-HSA-5663205	Infectious disease
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9006936	Signaling by TGFB family members
R-HSA-9824446	Viral Infection Pathways
R-HSA-983169	Class I MHC mediated antigen processing & presentation
R-HSA-983712	Ion channel transport

MSigDB gene sets: 697 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_DENDRITE_DEVELOPMENT, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, AP1_01, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, MYOGENIN_Q6, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_NEURON_PROJECTION_EXTENSION

GO Biological Process (31): regulation of membrane depolarization (GO:0003254), ubiquitin-dependent protein catabolic process (GO:0006511), protein monoubiquitination (GO:0006513), neuromuscular junction development (GO:0007528), protein ubiquitination (GO:0016567), neuron projection development (GO:0031175), receptor internalization (GO:0031623), regulation of protein stability (GO:0031647), receptor catabolic process (GO:0032801), monoatomic ion transmembrane transport (GO:0034220), regulation of membrane potential (GO:0042391), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of protein catabolic process (GO:0045732), regulation of dendrite morphogenesis (GO:0048814), regulation of synapse organization (GO:0050807), regulation of membrane repolarization (GO:0060306), protein K48-linked ubiquitination (GO:0070936), ventricular cardiac muscle cell action potential (GO:0086005), negative regulation of potassium ion transmembrane transport (GO:1901380), regulation of sodium ion transmembrane transport (GO:1902305), negative regulation of sodium ion transmembrane transport (GO:1902306), negative regulation of potassium ion export across plasma membrane (GO:1903765), negative regulation of sodium ion import across plasma membrane (GO:1903783), positive regulation of dendrite extension (GO:1903861), negative regulation of protein localization to cell surface (GO:2000009), positive regulation of caveolin-mediated endocytosis (GO:2001288), monoatomic ion transport (GO:0006811), cell differentiation (GO:0030154), regulation of transport (GO:0051049), regulation of biological quality (GO:0065008), sodium ion import across plasma membrane (GO:0098719)

GO Molecular Function (8): ubiquitin-protein transferase activity (GO:0004842), sodium channel regulator activity (GO:0017080), potassium channel inhibitor activity (GO:0019870), sodium channel inhibitor activity (GO:0019871), transmembrane transporter binding (GO:0044325), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (9): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), multivesicular body (GO:0005771), Golgi apparatus (GO:0005794), cytosol (GO:0005829), apical plasma membrane (GO:0016324), extracellular exosome (GO:0070062), endosome (GO:0005768), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Signaling by TGF-beta Receptor Complex	2
Late Phase of HIV Life Cycle	1
TGF-beta receptor signaling activates SMADs	1
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1
Ion channel transport	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
HIV Infection	1
HIV Life Cycle	1
Viral Infection Pathways	1
Signaling by TGFB family members	1
RNA Polymerase II Transcription	1
Generic Transcription Pathway	1
Disease	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of membrane potential	2
protein ubiquitination	2
synapse organization	2
regulation of biological quality	2
sodium channel activity	2
ion channel inhibitor activity	2
cytoplasm	2
endomembrane system	2
regulation of cellular process	1
membrane depolarization	1
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
neuron development	1
plasma membrane bounded cell projection organization	1
receptor-mediated endocytosis	1
macromolecule catabolic process	1
receptor metabolic process	1
monoatomic ion transport	1
transmembrane transport	1
monoatomic ion transmembrane transport	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
regulation of anatomical structure morphogenesis	1
dendrite morphogenesis	1
regulation of dendrite development	1
regulation of synapse structure or activity	1
regulation of cellular component organization	1
regulation of biological process	1
membrane repolarization	1
protein polyubiquitination	1
cardiac muscle cell action potential involved in contraction	1
negative regulation of potassium ion transport	1
potassium ion transmembrane transport	1
regulation of potassium ion transmembrane transport	1
negative regulation of cation transmembrane transport	1

Protein interactions and networks

STRING

2608 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NEDD4L	SGK1	O00141	952
NEDD4L	SMAD3	P84022	945
NEDD4L	UBE2D2	P51669	939
NEDD4L	SCNN1G	P51170	915
NEDD4L	YBX1	P16990	898
NEDD4L	SCNN1A	P37088	885
NEDD4L	SCNN1B	P51168	858
NEDD4L	NDFIP1	Q9BT67	853
NEDD4L	NDFIP2	Q9NV92	849
NEDD4L	SMAD7	O15105	829
NEDD4L	TNK2	Q07912	822
NEDD4L	SMAD2	Q15796	804
NEDD4L	SAG	P10523	778
NEDD4L	UBE2S	Q16763	767
NEDD4L	SCN5A	Q14524	766

IntAct

162 interactions, top by confidence:

A	B	Type	Score
ARRDC1	WWP2	psi-mi:“MI:0914”(association)	0.850
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
CCDC22	VPS26C	psi-mi:“MI:0914”(association)	0.790
ARRDC3	NEDD4L	psi-mi:“MI:0915”(physical association)	0.770
ARRDC3	WWP2	psi-mi:“MI:0914”(association)	0.770
YWHAH	NEDD4L	psi-mi:“MI:0914”(association)	0.740
NEDD4L	YWHAE	psi-mi:“MI:0915”(physical association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
ENTREP1	NEDD4	psi-mi:“MI:0914”(association)	0.690
LDLRAD4	NEDD4	psi-mi:“MI:0914”(association)	0.690
PRRG4	NEDD4L	psi-mi:“MI:0407”(direct interaction)	0.660
PRRG4	NEDD4L	psi-mi:“MI:0915”(physical association)	0.660
NEDD4L	ENTREP1	psi-mi:“MI:0915”(physical association)	0.660
ARRDC1	NEDD4	psi-mi:“MI:0914”(association)	0.640
SLC39A5	FAM171A2	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAE	RGS12	psi-mi:“MI:0914”(association)	0.610
MS4A10	NEDD4	psi-mi:“MI:0914”(association)	0.590
DAZAP2	NEDD4L	psi-mi:“MI:0915”(physical association)	0.560
NEDD4L	DAZAP2	psi-mi:“MI:0915”(physical association)	0.560
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
NEDD4L	LAPTM5	psi-mi:“MI:0915”(physical association)	0.550

BioGRID (688): UBE2D1 (Reconstituted Complex), NEDD4L (Biochemical Activity), NEDD4L (Two-hybrid), NEDD4L (Affinity Capture-RNA), Pi4k2a (Reconstituted Complex), NEDD4L (Affinity Capture-MS), NEDD4L (Reconstituted Complex), NEDD4L (Reconstituted Complex), SMAD3 (Reconstituted Complex), NEDD4L (Biochemical Activity), NEDD4L (Biochemical Activity), HGS (Affinity Capture-Western), NEDD4L (Affinity Capture-MS), NEDD4L (Affinity Capture-MS), NEDD4L (Affinity Capture-MS)

ESM2 similar proteins: A1CQG2, A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B4GEU5, B8N7E5, G0S9J5, G5ECY0, H2L056, O00308, O14326, O42643, P10823, P39055, P39940, P46935, Q0CCL1, Q2TAS2, Q2UBP1, Q45FX5, Q4WTF3, Q5BDP1, Q5RBF2, Q5RD78, Q5U5R9, Q62940, Q757T0, Q8BZZ3, Q8C863, Q8CFI0, Q92462, Q96J02, Q96PU5, Q9CUN6, Q9DBH0, Q9H0M0, Q9HAU4, Q9HCE7

Diamond homologs: A0A8C0NGY6, A0A8I3PQN6, A1A5G4, A1CQG2, A1D3C5, A2QQ28, A4IIJ3, B0XQ72, B3LWS4, B3P3M8, B4HEJ6, B4K6I9, B4M5X4, B4NAD3, B4PSQ2, B8N7E5, D6C652, G0S9J5, H2LBU8, O14326, O88382, P39940, P46934, P46935, P46936, P46937, P46938, Q0CCL1, Q19404, Q1L8J7, Q2EJA0, Q2UBP1, Q32NJ6, Q45VV3, Q4L1J4, Q4WTF3, Q54T86, Q5BDP1, Q5F488, Q5RBF2

SIGNOR signaling

34 interactions.

A	Effect	B	Mechanism
SGK1	up-regulates	NEDD4L	phosphorylation
PRKACA	down-regulates	NEDD4L	phosphorylation
SGK1	down-regulates	NEDD4L	phosphorylation
NEDD4L	down-regulates	SMAD2	ubiquitination
NEDD4L	down-regulates	SMAD3	ubiquitination
NEDD4L	“down-regulates activity”	SMAD2	ubiquitination
NEDD4L	“down-regulates activity”	SMAD3	ubiquitination
NEDD4L	“down-regulates quantity by destabilization”	SCNN1A	ubiquitination
SGK1	“down-regulates activity”	NEDD4L	phosphorylation
NEDD4L	“up-regulates activity”	NF2	ubiquitination
Ub:E2	“up-regulates activity”	NEDD4L	ubiquitination
NEDD4L	“down-regulates quantity by destabilization”	TTYH2	polyubiquitination
NEDD4L	“down-regulates quantity by destabilization”	TTYH3	polyubiquitination
NEDD4L	“down-regulates quantity by destabilization”	ULK1	ubiquitination
NEDD4L	“up-regulates activity”	TRAF3	ubiquitination
NEDD4L	“down-regulates quantity by destabilization”	OGG1	ubiquitination
NEDD4L	“down-regulates quantity by destabilization”	SPHK2	ubiquitination
NEDD4L	“down-regulates quantity”	SLC1A2	ubiquitination
NEDD4L	“down-regulates quantity by destabilization”	KCNH2	ubiquitination
SGK3	“down-regulates activity”	NEDD4L	phosphorylation
NEDD4L	“down-regulates quantity by destabilization”	SCN5A	ubiquitination
NEDD4L	“down-regulates quantity by destabilization”	SCN1A	ubiquitination
NEDD4L	“down-regulates quantity by destabilization”	SCN9A	ubiquitination
NEDD4L	“down-regulates quantity by destabilization”	SCN2A	ubiquitination
NEDD4L	“down-regulates quantity by destabilization”	SCN4A	ubiquitination
NEDD4L	“down-regulates quantity by destabilization”	SCN8A	ubiquitination
NEDD4L	“down-regulates quantity by destabilization”	SCN11A	ubiquitination
NEDD4L	“down-regulates quantity by destabilization”	SCN10A	ubiquitination
NEDD4L	“down-regulates quantity by destabilization”	SCN3A	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 158 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
Activation of BAD and translocation to mitochondria	7	56.7×	4e-09
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	50.0×	6e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	50.0×	6e-09
Activation of BH3-only proteins	7	37.0×	5e-08
Signaling by Hippo	5	28.9×	3e-05
RHO GTPases activate PKNs	7	23.6×	1e-06
Intrinsic Pathway for Apoptosis	7	21.8×	2e-06
FOXO-mediated transcription	6	21.4×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	9	6.8×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1119 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	6
Uncertain significance	363
Likely benign	499
Benign	145

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
225192	NM_001144967.3(NEDD4L):c.2082G>T (p.Gln694His)	Pathogenic
225193	NM_001144967.3(NEDD4L):c.2036A>G (p.Tyr679Cys)	Pathogenic
1176063	NM_001144967.3(NEDD4L):c.2441G>A (p.Trp814Ter)	Likely pathogenic
1684293	NM_001144967.3(NEDD4L):c.814-6T>A	Likely pathogenic
3065173	NM_001144967.3(NEDD4L):c.1126-1G>A	Likely pathogenic
3370506	NM_001144967.3(NEDD4L):c.1855G>C (p.Glu619Gln)	Likely pathogenic
592171	t(X;18)(p21.1;q21.31)	Likely pathogenic
812181	NM_001144967.3(NEDD4L):c.2245A>G (p.Met749Val)	Likely pathogenic

SpliceAI

6123 predictions. Top by Δscore:

Variant	Effect	Δscore
18:58044708:GGT:G	donor_loss	1.0000
18:58044709:G:GA	donor_loss	1.0000
18:58165783:CACA:C	acceptor_loss	1.0000
18:58165784:A:AG	acceptor_gain	1.0000
18:58165784:ACAG:A	acceptor_gain	1.0000
18:58165784:ACAGG:A	acceptor_gain	1.0000
18:58165785:C:G	acceptor_gain	1.0000
18:58165785:CA:C	acceptor_loss	1.0000
18:58165785:CAGGG:C	acceptor_gain	1.0000
18:58165786:A:AC	acceptor_loss	1.0000
18:58165786:A:AG	acceptor_gain	1.0000
18:58165786:AG:A	acceptor_gain	1.0000
18:58165786:AGG:A	acceptor_gain	1.0000
18:58165786:AGGGA:A	acceptor_gain	1.0000
18:58165787:G:GG	acceptor_gain	1.0000
18:58165787:GG:G	acceptor_gain	1.0000
18:58165787:GGG:G	acceptor_gain	1.0000
18:58165787:GGGA:G	acceptor_gain	1.0000
18:58165787:GGGAG:G	acceptor_gain	1.0000
18:58165857:GCCAG:G	donor_gain	1.0000
18:58165858:CCAGG:C	donor_loss	1.0000
18:58165859:CAGG:C	donor_loss	1.0000
18:58165860:AGGTA:A	donor_loss	1.0000
18:58165861:GGTA:G	donor_loss	1.0000
18:58165862:G:GG	donor_gain	1.0000
18:58165862:GT:G	donor_loss	1.0000
18:58165863:T:G	donor_loss	1.0000
18:58245421:TTACA:T	acceptor_loss	1.0000
18:58245422:TACA:T	acceptor_loss	1.0000
18:58245424:CA:C	acceptor_loss	1.0000

AlphaMissense

6428 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:58165804:T:C	L22P	1.000
18:58165824:G:A	G29R	1.000
18:58165824:G:C	G29R	1.000
18:58165825:G:A	G29E	1.000
18:58165834:T:C	L32P	1.000
18:58245432:C:A	P43Q	1.000
18:58245444:T:C	L47P	1.000
18:58248914:T:A	W74R	1.000
18:58248914:T:C	W74R	1.000
18:58248916:G:C	W74C	1.000
18:58248916:G:T	W74C	1.000
18:58252023:T:C	L89P	1.000
18:58252037:T:C	F94L	1.000
18:58252039:T:A	F94L	1.000
18:58252039:T:G	F94L	1.000
18:58252040:G:C	D95H	1.000
18:58252041:A:C	D95A	1.000
18:58252041:A:T	D95V	1.000
18:58252044:A:T	E96V	1.000
18:58252050:G:C	R98T	1.000
18:58252051:A:C	R98S	1.000
18:58252051:A:T	R98S	1.000
18:58315988:G:C	D102H	1.000
18:58315989:A:T	D102V	1.000
18:58315991:G:C	D103H	1.000
18:58315992:A:T	D103V	1.000
18:58315994:T:C	F104L	1.000
18:58315996:C:A	F104L	1.000
18:58315996:C:G	F104L	1.000
18:58315998:T:C	L105P	1.000

dbSNP variants (sampled 300 via entrez): RS1000001041 (18:58215129 T>A,G), RS1000017176 (18:58252730 AT>A,ATT), RS1000030181 (18:58378928 C>T), RS1000033390 (18:58148186 G>C,T), RS1000037690 (18:58295241 A>G), RS1000046514 (18:58138424 T>A), RS1000049033 (18:58177124 C>T), RS1000052310 (18:58256402 G>A,C), RS1000083317 (18:58156998 T>C), RS1000085298 (18:58148521 T>G), RS1000090352 (18:58252394 CTT>C), RS1000095740 (18:58210101 G>A), RS1000131722 (18:58108869 C>T), RS1000132842 (18:58308611 A>G), RS1000135497 (18:58281122 C>T)

Disease associations

OMIM: gene MIM:606384 | disease phenotypes: MIM:617201, MIM:612881

GenCC curated gene-disease

Disease	Classification	Inheritance
periventricular nodular heterotopia 7	Definitive	Autosomal dominant
periventricular nodular heterotopia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
periventricular nodular heterotopia 7	Definitive	AD

Mondo (6): periventricular nodular heterotopia 7 (MONDO:0014966), intellectual disability (MONDO:0001071), chromosome 5Q14.3 deletion syndrome, distal (MONDO:0013031), autism spectrum disorder (MONDO:0005258), dilated cardiomyopathy (MONDO:0005021), periventricular nodular heterotopia (MONDO:0020341)

Orphanet (4): Nodular neuronal heterotopia (Orphanet:2149), Dilated cardiomyopathy (Orphanet:217604), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

73 total (30 of 73 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000201	Pierre-Robin sequence
HP:0000268	Dolichocephaly
HP:0000276	Long face
HP:0000308	Microretrognathia
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000407	Sensorineural hearing impairment
HP:0000463	Anteverted nares
HP:0000490	Deeply set eye
HP:0000520	Proptosis
HP:0000543	Optic disc pallor
HP:0000545	Myopia
HP:0000666	Horizontal nystagmus
HP:0000678	Dental crowding
HP:0000750	Delayed speech and language development
HP:0000963	Thin skin
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001344	Absent speech
HP:0001382	Joint hypermobility
HP:0001508	Failure to thrive
HP:0001629	Ventricular septal defect

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST001277_18	Liver enzyme levels (gamma-glutamyl transferase)	3.000000e-12
GCST001586_8	Insomnia (caffeine-induced)	7.000000e-06
GCST001651_88	Response to amphetamines	3.000000e-06
GCST002337_20	Amyotrophic lateral sclerosis (sporadic)	3.000000e-06
GCST002875_145	Diisocyanate-induced asthma	2.000000e-06
GCST002932_27	Manganese levels	2.000000e-06
GCST006019_9	Gamma glutamyl transferase levels	8.000000e-32
GCST006627_81	Diastolic blood pressure	4.000000e-09
GCST011349_28	Gamma glutamyl transferase levels	3.000000e-31
GCST011353_28	Serum alkaline phosphatase levels	4.000000e-08
GCST90002409_23	Childhood body mass index	4.000000e-06
GCST90011898_86	Alanine aminotransferase levels	2.000000e-38
GCST90011899_87	Aspartate aminotransferase levels	9.000000e-15
GCST90011900_156	Serum alkaline phosphatase levels	5.000000e-20
GCST90013405_17	Liver enzyme levels (alanine transaminase)	4.000000e-63
GCST90013406_87	Liver enzyme levels (alkaline phosphatase)	6.000000e-35
GCST90013407_75	Liver enzyme levels (gamma-glutamyl transferase)	4.000000e-251
GCST90013663_95	Alanine aminotransferase levels	3.000000e-46
GCST90013664_8	Aspartate aminotransferase levels	7.000000e-30

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0007876	insomnia measurement
EFO:0006995	response to diisocyanate
EFO:0006336	diastolic blood pressure
EFO:0004533	alkaline phosphatase measurement
EFO:0004340	body mass index
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D054091	Periventricular Nodular Heterotopia	C10.500.507.450.750; C16.131.666.507.450.750
C567876	Heterotopia, Periventricular, Associated With Chromosome 5q Deletion (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs292449	Efficacy	3	hydrochlorothiazide
rs4149601	Efficacy	3	hydrochlorothiazide	Hypertension
rs4149601	Efficacy	3	diuretics;hydrochlorothiazide	Hypertension
rs520210	Efficacy	3	citalopram	Depression

PharmGKB variants

5 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs292449	NEDD4L	3	2.25	1	hydrochlorothiazide
rs520210	NEDD4L	3	2.50	1	citalopram
rs1008899	NEDD4L		0.00	0
rs4149601	NEDD4L	3	3.00	2	hydrochlorothiazide;diuretics;hydrochlorothiazide
rs75982813	NEDD4L		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	4
Aflatoxin B1	decreases expression, decreases methylation, increases methylation	4
trichostatin A	affects cotreatment, increases expression	3
Estradiol	affects expression, affects cotreatment, increases expression, decreases expression	3
Cisplatin	affects cotreatment, decreases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, affects expression	2
Tretinoin	decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
Particulate Matter	increases expression, affects cotreatment, increases abundance	2
TH5487	increases expression, affects reaction, decreases expression, decreases reaction	1
TL8-506	affects cotreatment, increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
deoxynivalenol	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C7DB	Abcam A-549 NEDD4L KO	Cancer cell line	Male
CVCL_C7E1	Abcam HCT 116 NEDD4L KO	Cancer cell line	Male
CVCL_TA24	HAP1 NEDD4L (-) 1	Cancer cell line	Male
CVCL_XQ90	HAP1 NEDD4L (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
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
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
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)