OTULIN

Summary

OTULIN (OTU deubiquitinase with linear linkage specificity, HGNC:25118) is a protein-coding gene on chromosome 5p15.2, encoding Ubiquitin thioesterase otulin (Q96BN8). Deubiquitinase that specifically removes linear (‘Met-1’-linked) polyubiquitin chains to substrates and acts as a regulator of angiogenesis and innate immune response.

This gene encodes a member of the peptidase C65 family of ubiquitin isopeptidases. Members of this family remove ubiquitin from proteins. The encoded enzyme specifically recognizes and removes M1(Met1)-linked, or linear, ubiquitin chains from protein substrates. Linear ubiquitin chains are known to regulate the NF-kappa B signaling pathway in the context of immunity and inflammation. Mutations in this gene cause a potentially fatal autoinflammatory syndrome in human patients.

Source: NCBI Gene 90268 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 315 total — 9 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 52
• MANE Select transcript: NM_138348

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25118
Approved symbol	OTULIN
Name	OTU deubiquitinase with linear linkage specificity
Location	5p15.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ34884
Ensembl gene	ENSG00000154124
Ensembl biotype	protein_coding
OMIM	615712
Entrez	90268

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000284274, ENST00000503023, ENST00000506417, ENST00000507335, ENST00000508678, ENST00000514913, ENST00000697367, ENST00000850613, ENST00000881544, ENST00000921417, ENST00000955678

RefSeq mRNA: 1 — MANE Select: NM_138348 NM_138348

CCDS: CCDS43302

Canonical transcript exons

ENST00000284274 — 7 exons

Exon	Start	End
ENSE00001014156	14690039	14690308
ENSE00001188164	14673642	14673718
ENSE00001299524	14692854	14699850
ENSE00002020207	14664718	14664977
ENSE00003508675	14678681	14678775
ENSE00003570529	14681464	14681607
ENSE00003654219	14687521	14687646

Expression profiles

Bgee: expression breadth ubiquitous, 234 present calls, max score 89.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.0539 / max 594.9924, expressed in 1818 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
55828	22.5582	1817
55824	0.6272	64
55827	0.3818	168
55832	0.1215	37
55831	0.1153	32
55823	0.0718	33
55830	0.0592	17
55825	0.0549	23
55829	0.0489	14
55826	0.0149	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	89.66	gold quality
bone marrow cell	CL:0002092	89.35	gold quality
pancreatic ductal cell	CL:0002079	87.59	silver quality
sural nerve	UBERON:0015488	87.26	gold quality
upper arm skin	UBERON:0004263	86.89	gold quality
monocyte	CL:0000576	84.99	gold quality
leukocyte	CL:0000738	84.90	gold quality
calcaneal tendon	UBERON:0003701	84.54	gold quality
tonsil	UBERON:0002372	84.44	gold quality
skin of abdomen	UBERON:0001416	84.18	gold quality
skin of leg	UBERON:0001511	83.81	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.74	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.68	gold quality
blood	UBERON:0000178	83.66	gold quality
ileal mucosa	UBERON:0000331	83.29	gold quality
tibialis anterior	UBERON:0001385	83.13	silver quality
skin of hip	UBERON:0001554	83.09	gold quality
upper leg skin	UBERON:0004262	83.09	gold quality
lymph node	UBERON:0000029	82.96	gold quality
zone of skin	UBERON:0000014	82.82	gold quality
esophagus squamous epithelium	UBERON:0006920	82.70	gold quality
tendon of biceps brachii	UBERON:0008188	82.40	gold quality
vermiform appendix	UBERON:0001154	82.36	gold quality
tendon	UBERON:0000043	82.27	gold quality
bone marrow	UBERON:0002371	81.82	gold quality
trabecular bone tissue	UBERON:0002483	81.68	gold quality
liver	UBERON:0002107	81.47	gold quality
secondary oocyte	CL:0000655	81.32	gold quality
endothelial cell	CL:0000115	81.22	gold quality
adrenal tissue	UBERON:0018303	81.10	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.96

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

206 targeting OTULIN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-27A-3P	99.98	72.13	2955

Literature-anchored findings (GeneRIF, showing 20)

• 2.4 A and 2.8 A crystal structures of gumby (Fam105b) in the presence of free ubiquitin and linear diubiquitin substrate, respectively (PMID:23708998)
• reveal a previously unannotated human DUB, OTULIN (also known as FAM105B), which is exquisitely specific for Met1 linkages; data suggest that OTULIN regulates Met1-polyUb signaling. (PMID:23746843)
• OTULIN restricts Met1-ubiquitin formation after immune receptor stimulation to prevent unwarranted proinflammatory signaling. (PMID:23806334)
• cylindromatosis (CYLD) and OTULIN/Gumby/Fam105B, directly interact with the N-terminal PUB domain-containing region of HOIP. (PMID:24461064)
• Phosphorylation of OTULIN prevents HOIP binding, whereas unphosphorylated OTULIN is part of the endogenous LUBAC complex. (PMID:24726323)
• HOIP binding to OTULIN is required for the recruitment of OTULIN to the TNF receptor complex. (PMID:24726327)
• OTULIN is critical for restraining life-threatening spontaneous inflammation and maintaining immune homeostasis. (PMID:27523608)
• Biallelic hypomorphic mutations in OTULIN define otulipenia, an early-onset autoinflammatory disease. (PMID:27559085)
• results establish a role for the linear Ubiquitin coat around cytosolic S. Typhimurium as the local NF-kappaB signalling platform and provide insights into the function of OTULIN in NF-kappaB activation during bacterial pathogenesis (PMID:28481361)
• Authors define an additional, non-catalytic function of OTULIN in the regulation of SNX27-retromer assembly and recycling to the cell surface. (PMID:31541095)
• Post-translational Modification of OTULIN Regulates Ubiquitin Dynamics and Cell Death. (PMID:31825842)
• OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer. (PMID:32231246)
• LUBAC and OTULIN regulate autophagy initiation and maturation by mediating the linear ubiquitination and the stabilization of ATG13. (PMID:32543267)
• ABL1-dependent OTULIN phosphorylation promotes genotoxic Wnt/beta-catenin activation to enhance drug resistance in breast cancers. (PMID:32770022)
• Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal alpha-toxin. (PMID:35587511)
• Reciprocal interplay between OTULIN-LUBAC determines genotoxic and inflammatory NF-kappaB signal responses. (PMID:35939695)
• An interaction between OTULIN and SCRIB uncovers roles for linear ubiquitination in planar cell polarity. (PMID:37589075)
• Integrated Single-Cell and Transcriptome Sequencing Analyses Develop a Ubiquitination-Associated Signature in Gastric Cancer and Identified OTULIN as a Novel Biomarker. (PMID:38062820)
• OTULIN Haploinsufficiency Causes Hyperinflammatory Responses to Infectious and Non-Infectious Triggers. (PMID:38578307)
• Downregulation of otulin induces inflammasome activation in neutrophilic asthma. (PMID:38599290)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000073931
danio_rerio	otulinb	ENSDARG00000079886
mus_musculus	Otulin	ENSMUSG00000046034
rattus_norvegicus	Otulin	ENSRNOG00000012017

Paralogs (1): OTULINL (ENSG00000145569)

Protein

Protein identifiers

Ubiquitin thioesterase otulin — Q96BN8 (reviewed: Q96BN8)

Alternative names: Deubiquitinating enzyme otulin, OTU domain-containing deubiquitinase with linear linkage specificity, Ubiquitin thioesterase Gumby

All UniProt accessions (5): Q96BN8, A0A8V8TKZ0, D6RD57, H0Y8S4, H0Y9T0

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinase that specifically removes linear (‘Met-1’-linked) polyubiquitin chains to substrates and acts as a regulator of angiogenesis and innate immune response. Required during angiogenesis, craniofacial and neuronal development by regulating the canonical Wnt signaling together with the LUBAC complex. Acts as a negative regulator of NF-kappa-B by regulating the activity of the LUBAC complex. OTULIN function is mainly restricted to homeostasis of the LUBAC complex: acts by removing ‘Met-1’-linked autoubiquitination of the LUBAC complex, thereby preventing inactivation of the LUBAC complex. Acts as a key negative regulator of inflammation by restricting spontaneous inflammation and maintaining immune homeostasis. In myeloid cell, required to prevent unwarranted secretion of cytokines leading to inflammation and autoimmunity by restricting linear polyubiquitin formation. Plays a role in innate immune response by restricting linear polyubiquitin formation on LUBAC complex in response to NOD2 stimulation, probably to limit NOD2-dependent pro-inflammatory signaling.

Subunit / interactions. Interacts (via the PUB domain) with RNF31 (via the PIM motif); the interaction is direct. Interacts with DVL2.

Subcellular location. Cytoplasm.

Post-translational modifications. Ubiquitinated. Acetylated. Phosphorylated. Phosphorylation at Tyr-56 prevents interaction with RNF31; dephosphorylation promotes interaction with RNF31 and the LUBAC complex.

Disease relevance. Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive (AIPDSB) [MIM:617099] An autosomal recessive autoinflammatory disorder characterized by neonatal-onset of fever, neutrophilic dermatitis, panniculitis, painful joints, failure to thrive. Patients do not exhibit overt primary immunodeficiency. The disease is caused by variants affecting the gene represented in this entry. Autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant (AIPDSA) [MIM:621030] An autosomal dominant disorder characterized by the onset of autoinflammatory features in infancy, including fever, aseptic skin lesions, panniculitis, and poor wound healing. Patients do not exhibit signs of immunodeficiency. The disease is caused by variants affecting the gene represented in this entry. Immunodeficiency 107, susceptibility to invasive Staphylococcus aureus infection (IMD107) [MIM:619986] An autosomal dominant immunologic disorder characterized by increased susceptibility to invasive and severe Staphylococcus aureus infection, causing life-threatening skin or pulmonary necrosis. Clinically, penetrance is incomplete and expressivity is variable. Disease susceptibility is associated with variants affecting the gene represented in this entry. OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to alpha-toxin in non-leukocytic cells.

Domain organisation. The specificity for linear polyubiquitin is given by the ‘Glu-16’ residue in ubiquitin chain. The PIM (PUB-interaction motif) motif mediates interaction with the PUB domain of RNF31. Does not interact with other PUB domain-containing proteins. Phosphorylation at Tyr-56 prevents interaction with RNF31.

Similarity. Belongs to the peptidase C65 family. Otulin subfamily.

RefSeq proteins (1): NP_612357* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR023235	FAM105	Family
IPR023237	Otulin	Family

Pfam: PF16218

UniProt features (73 total): helix 18, sequence variant 15, mutagenesis site 15, strand 8, region of interest 6, active site 3, chain 1, domain 1, site 1, modified residue 1, sequence conflict 1, turn 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
3ZNV	X-RAY DIFFRACTION	1.3
3ZNX	X-RAY DIFFRACTION	1.35
4KSJ	X-RAY DIFFRACTION	1.6
6I9C	X-RAY DIFFRACTION	1.77
3ZNZ	X-RAY DIFFRACTION	1.9
6SAK	X-RAY DIFFRACTION	2
9LZX	X-RAY DIFFRACTION	2
4OYK	X-RAY DIFFRACTION	2
4KSK	X-RAY DIFFRACTION	2.4
4P0B	X-RAY DIFFRACTION	2.7
4KSL	X-RAY DIFFRACTION	2.83
5OE7	X-RAY DIFFRACTION	2.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96BN8-F1	84.76	0.74

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 (4): 126; 129 (nucleophile); 339; 314 (linear diubiquitin binding)

Post-translational modifications (1): 56

Mutagenesis-validated functional residues (15):

Position	Phenotype
54	reduced interaction with rnf31.
55	abolished interaction with rnf31.
56	abolished interaction with rnf31.
56	strongly reduced interaction with rnf31.
91	results in strong reduction of kcat while not affecting km.
96	decreased activity toward linear ubiquitin.
100–102	decreased activity toward linear ubiquitin.
129	abolishes deubiquitinase activity.
254	severely decreased nf-kappa-b inhibition and increased nf-kappa-b signaling.
259	decreased affinity for linear diubiquitin.
314	decreased affinity for linear diubiquitin.
336	stabilizes h-339 in the active conformation, generating a more reactive enzyme.
339	impaired deubiquitinase activity.
341	abolishes deubiquitinase activity.
341	stabilizes h-339 in the active conformation, generating a more reactive enzyme. severely decreased nf-kappa-b inhibition

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-8866652	Synthesis of active ubiquitin: roles of E1 and E2 enzymes

MSigDB gene sets: 320 (showing top): GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_SPROUTING_ANGIOGENESIS, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_NEGATIVE_REGULATION_OF_NF_KAPPAB_TRANSCRIPTION_FACTOR_ACTIVITY, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, TGTGTGA_MIR377, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_BLOOD_VESSEL_MORPHOGENESIS

GO Biological Process (13): sprouting angiogenesis (GO:0002040), proteolysis (GO:0006508), regulation of tumor necrosis factor-mediated signaling pathway (GO:0010803), Wnt signaling pathway (GO:0016055), protein ubiquitination (GO:0016567), obsolete negative regulation of NF-kappaB transcription factor activity (GO:0032088), innate immune response (GO:0045087), negative regulation of inflammatory response (GO:0050728), regulation of canonical Wnt signaling pathway (GO:0060828), nucleotide-binding oligomerization domain containing 2 signaling pathway (GO:0070431), protein linear deubiquitination (GO:1990108), angiogenesis (GO:0001525), immune system process (GO:0002376)

GO Molecular Function (5): cysteine-type deubiquitinase activity (GO:0004843), cysteine-type peptidase activity (GO:0008234), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), LUBAC complex (GO:0071797)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
TNF signaling	1
Protein ubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
angiogenesis	1
protein metabolic process	1
regulation of cytokine-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
cell surface receptor signaling pathway	1
protein modification by small protein conjugation	1
immune response	1
defense response to symbiont	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	1
protein deubiquitination	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
biological_process	1
cysteine-type peptidase activity	1
deubiquitinase activity	1
peptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1
ubiquitin ligase complex	1

Protein interactions and networks

STRING

1096 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OTULIN	RNF31	Q96EP0	916
OTULIN	CYLD	Q9NQC7	829
OTULIN	NGLY1	Q96IV0	810
OTULIN	SHARPIN	Q9H0F6	810
OTULIN	SNX27	Q96L92	805
OTULIN	GZMM	P51124	754
OTULIN	RBCK1	Q9BYM8	724
OTULIN	OTUD3	Q5T2D3	717
OTULIN	ZUP1	Q96AP4	699
OTULIN	OTUB1	Q96FW1	682
OTULIN	OTUD7B	Q6GQQ9	673
OTULIN	USP2	O75604	655
OTULIN	ZRANB1	Q9UGI0	646
OTULIN	OTUD5	Q96G74	626
OTULIN	OTUD1	Q5VV17	626

IntAct

179 interactions, top by confidence:

A	B	Type	Score
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
CNOT3	CNOT1	psi-mi:“MI:0914”(association)	0.740
TUBA1C	TXNDC9	psi-mi:“MI:0914”(association)	0.730
DAZAP2	OTULIN	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
SNX27	MCC	psi-mi:“MI:0914”(association)	0.700
OTULIN	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.690
INSRR	INSR	psi-mi:“MI:0914”(association)	0.650
BNIP1	NBAS	psi-mi:“MI:0914”(association)	0.640
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
OTULIN	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.590
SNX27	OTULIN	psi-mi:“MI:0407”(direct interaction)	0.590
OTULIN	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.590
OTULIN	FAM168A	psi-mi:“MI:0915”(physical association)	0.560
FAM168A	OTULIN	psi-mi:“MI:0915”(physical association)	0.560
OTULIN	SPART	psi-mi:“MI:0915”(physical association)	0.560
TMEM239	OTULIN	psi-mi:“MI:0915”(physical association)	0.560
OTUD7B	OTULIN	psi-mi:“MI:0915”(physical association)	0.560
SFT2D1	OTULIN	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (278): OTULIN (Two-hybrid), OTULIN (Two-hybrid), SELENBP1 (Affinity Capture-MS), DUSP14 (Affinity Capture-MS), LRRC15 (Affinity Capture-MS), OTULIN (Two-hybrid), UBC (Biochemical Activity), OTULIN (Affinity Capture-MS), OTULIN (Affinity Capture-MS), OTULIN (Affinity Capture-MS), OTULIN (Affinity Capture-Western), RNF31 (Affinity Capture-Western), RBCK1 (Affinity Capture-Western), SHARPIN (Affinity Capture-Western), BCL10 (Biochemical Activity)

ESM2 similar proteins: A1A4L4, A4D1B5, A8MYZ0, B2GV47, D3ZJ96, D3ZSP7, E9Q173, O15091, O55036, O70167, O70173, O75747, P54274, P70371, Q0VA42, Q1JQD6, Q32L18, Q3B7D8, Q3TVP5, Q3UCV8, Q3UQI9, Q4G0A6, Q4R657, Q4R9E9, Q53T94, Q567X9, Q5H9U9, Q5I043, Q5RF72, Q5U3U4, Q63517, Q68F54, Q692V3, Q6AXU1, Q6NSI4, Q6NVF4, Q6P2S7, Q6P3V7, Q80VH0, Q8C779

Diamond homologs: Q3B7D8, Q3TVP5, Q3UCV8, Q96BN8, Q9NUU6

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
OTULIN	“up-regulates quantity”	UBB	cleavage
OTULIN	“up-regulates quantity”	UBC	cleavage
OTULIN	“up-regulates quantity”	Ubiquitin	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 145 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
Ras activation upon Ca2+ influx through NMDA receptor	5	33.6×	4e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	32.0×	4e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	32.0×	4e-05
Long-term potentiation	5	28.0×	7e-05
Assembly and cell surface presentation of NMDA receptors	9	26.9×	2e-08
Neurexins and neuroligins	8	18.5×	3e-06
RHOQ GTPase cycle	5	10.7×	5e-03
RHOB GTPase cycle	5	9.1×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	39.0×	7e-10
protein localization to synapse	6	34.3×	3e-06
receptor clustering	7	32.6×	6e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	7	25.9×	2e-06
cell-cell adhesion	9	6.8×	6e-04
protein-containing complex assembly	8	6.8×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	3
Uncertain significance	137
Likely benign	123
Benign	15

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1027708	NM_138348.6(OTULIN):c.22C>T (p.Gln8Ter)	Pathogenic
1706581	NM_138348.6(OTULIN):c.864+2T>C	Pathogenic
1706582	NM_138348.6(OTULIN):c.841G>A (p.Gly281Arg)	Pathogenic
1706583	NM_138348.6(OTULIN):c.258G>A (p.Met86Ile)	Pathogenic
1706584	NM_138348.6(OTULIN):c.500G>C (p.Trp167Ser)	Pathogenic
254124	NM_138348.6(OTULIN):c.815T>C (p.Leu272Pro)	Pathogenic
3385324	C129S	Pathogenic
3385325	NM_138348.6(OTULIN):c.917G>A (p.Arg306Gln)	Pathogenic
563035	GRCh37/hg19 5p15.2-15.1(chr5:10515035-17607385)x1	Pathogenic
2663923	NM_138348.6(OTULIN):c.443G>A (p.Trp148Ter)	Likely pathogenic
4071519	NM_138348.6(OTULIN):c.468+1G>C	Likely pathogenic
546971	NM_138348.6(OTULIN):c.325-2A>G	Likely pathogenic

SpliceAI

1965 predictions. Top by Δscore:

Variant	Effect	Δscore
5:14664973:GAGCA:G	donor_gain	1.0000
5:14664975:GCA:G	donor_gain	1.0000
5:14664978:G:GG	donor_gain	1.0000
5:14678667:A:AG	acceptor_gain	1.0000
5:14678668:A:G	acceptor_gain	1.0000
5:14681451:T:G	acceptor_gain	1.0000
5:14681452:A:AG	acceptor_gain	1.0000
5:14681453:C:G	acceptor_gain	1.0000
5:14681460:CCAGG:C	acceptor_loss	1.0000
5:14681461:CAGG:C	acceptor_loss	1.0000
5:14681462:AGGG:A	acceptor_loss	1.0000
5:14681463:G:A	acceptor_loss	1.0000
5:14687519:A:AG	acceptor_gain	1.0000
5:14687520:G:GG	acceptor_gain	1.0000
5:14687640:G:GT	donor_gain	1.0000
5:14687673:A:G	donor_gain	1.0000
5:14712868:TCTCA:T	donor_loss	1.0000
5:14712869:CTCA:C	donor_loss	1.0000
5:14712870:TCA:T	donor_loss	1.0000
5:14712871:CACCT:C	donor_loss	1.0000
5:14712872:A:AT	donor_loss	1.0000
5:14712873:C:CA	donor_loss	1.0000
5:14712969:GCACC:G	acceptor_gain	1.0000
5:14712970:CACC:C	acceptor_gain	1.0000
5:14712970:CACCC:C	acceptor_gain	1.0000
5:14712971:ACC:A	acceptor_gain	1.0000
5:14712971:ACCC:A	acceptor_loss	1.0000
5:14712972:CC:C	acceptor_gain	1.0000
5:14712972:CCC:C	acceptor_gain	1.0000
5:14712973:CC:C	acceptor_gain	1.0000

AlphaMissense

2319 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:14678737:T:A	W96R	0.999
5:14678737:T:C	W96R	0.999
5:14678739:G:C	W96C	0.999
5:14678739:G:T	W96C	0.999
5:14681534:G:T	R132M	0.999
5:14681501:G:C	R121P	0.998
5:14681507:T:A	V123D	0.998
5:14681516:A:C	D126A	0.998
5:14681516:A:T	D126V	0.998
5:14692906:G:C	R306P	0.998
5:14693002:G:C	R338P	0.998
5:14678738:G:C	W96S	0.997
5:14681515:G:C	D126H	0.997
5:14681534:G:C	R132T	0.997
5:14690154:T:C	L237P	0.997
5:14690162:G:C	A240P	0.997
5:14690301:T:A	L286H	0.997
5:14692995:G:C	D336H	0.997
5:14692996:A:C	D336A	0.997
5:14692996:A:T	D336V	0.997
5:14692997:C:A	D336E	0.997
5:14692997:C:G	D336E	0.997
5:14693004:C:G	H339D	0.997
5:14681488:T:C	F117L	0.996
5:14681490:C:A	F117L	0.996
5:14681490:C:G	F117L	0.996
5:14681535:G:C	R132S	0.996
5:14681535:G:T	R132S	0.996
5:14687563:T:A	W171R	0.996
5:14687563:T:C	W171R	0.996

dbSNP variants (sampled 300 via entrez): RS1000002826 (5:14677393 A>G), RS1000006613 (5:14704935 C>T), RS1000028786 (5:14697499 G>A), RS1000179551 (5:14711655 C>T), RS1000447171 (5:14674003 C>G), RS1000473929 (5:14713199 C>T), RS1000497735 (5:14672138 A>C), RS1000558133 (5:14683587 G>C,T), RS1000580968 (5:14681717 G>A,C,T), RS1000606944 (5:14678560 T>A,C), RS1000627381 (5:14708110 C>T), RS1000680345 (5:14679933 C>T), RS1000714022 (5:14687824 T>C), RS1000780331 (5:14672474 G>A), RS1000784929 (5:14712484 G>A,T)

Disease associations

OMIM: gene MIM:615712 | disease phenotypes: MIM:617099, MIM:619986, MIM:621030, MIM:118600, MIM:123000

GenCC curated gene-disease

Disease	Classification	Inheritance
autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive	Definitive	Autosomal recessive
autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant	Strong	Autosomal dominant
hereditary periodic fever syndrome	Limited	Autosomal dominant
immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection	Limited	Autosomal dominant

Mondo (6): autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive (MONDO:0014912), immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection (MONDO:0031030), autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant (MONDO:0700338), chondrocalcinosis 2 (MONDO:0007319), craniometaphyseal dysplasia, autosomal dominant (MONDO:0007397), hereditary periodic fever syndrome (MONDO:0017953)

Orphanet (3): Infantile-onset periodic fever-panniculitis-dermatosis syndrome (Orphanet:500062), Familial calcium pyrophosphate deposition (Orphanet:1416), Craniometaphyseal dysplasia (Orphanet:1522)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000969	Edema
HP:0000988	Skin rash
HP:0001386	Joint swelling
HP:0001510	Growth delay
HP:0001531	Failure to thrive in infancy
HP:0001873	Thrombocytopenia
HP:0001880	Increased total eosinophil count
HP:0001945	Fever
HP:0001954	Recurrent fever
HP:0001974	Increased total leukocyte count
HP:0002014	Diarrhea
HP:0002027	Abdominal pain
HP:0002028	Chronic diarrhea
HP:0002098	Respiratory distress
HP:0002615	Hypotension
HP:0002633	Vasculitis
HP:0002716	Lymphadenopathy
HP:0002720	Decreased circulating IgA concentration
HP:0002721	Immunodeficiency
HP:0002829	Arthralgia
HP:0002923	Rheumatoid factor positive
HP:0003261	Increased circulating IgA concentration
HP:0003326	Myalgia
HP:0003493	Antinuclear antibody positivity
HP:0003496	Increased circulating IgM level
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003623	Neonatal onset

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST007995_21	Asthma (childhood onset)	9.000000e-16
GCST008916_104	Asthma	4.000000e-12
GCST009517_1	Cerebrospinal fluid neurofilament light levels	5.000000e-07
GCST009798_56	Asthma	5.000000e-13
GCST90014325_19	Asthma	3.000000e-13
GCST90093090_2	DHEAS levels	5.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007001	dehydroepiandrosterone sulphate measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D056660	Hereditary Autoinflammatory Diseases	C16.320.382; C17.800.827.368
C563162	Chondrocalcinosis 2 (supp.)
C565145	Craniometaphyseal Dysplasia, Autosomal Dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — C101: OTULIN peptidase

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	increases expression	2
Valproic Acid	decreases expression, decreases methylation	2
bisphenol A	affects cotreatment, decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	affects expression	1
Calcitriol	increases expression	1
Drugs, Chinese Herbal	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Naphthoquinones	increases expression	1
Rotenone	decreases expression	1
Acrylamide	increases expression	1

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_E0UQ	Ubigene Hep G2 OTULIN KO	Cancer cell line	Male
CVCL_YM89	NIHTVBi014-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05413096	EARLY_PHASE1	COMPLETED	Combination of Diclofenac Potassium and Propolis in the Therapy of Oral Aphthosis
NCT06838143	Not specified	RECRUITING	Ilaris NIS in Korea
NCT06529848	Not specified	RECRUITING	Impact of Exercise Training on Ischemia With Non-Obstructive Coronary Arteries (INOCA): The ExINOCA Study