OTULIN
protein-codingOTU deubiquitinase with linear linkage specificity, the group of OTU domain containing
Gene summary
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. [provided by RefSeq, Sep 2016]
- FAM105B
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~51.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014912
Submitter: ClinGen
OTULIN was first reported in relation to autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive (also known as OTULIN-related autoinflammatory syndrome, ORAS/AIPDS) in 2016. OTULIN encodes a linear/Met1-linked deubiquitinase that negatively regulates linear ubiquitin signaling and downstream inflammatory signaling, including TNF/NF-kB-associated pathways. This curation was performed for the autosomal recessive phenotype only. The gene–disease relationship is supported by multiple unrelated probands/families with biallelic OTULIN variants reported across independent publications. Initial evidence came from Damgaard et al. 2016 (PMID: 27523608), which described three affected members of a consanguineous Pakistani family with a homozygous missense variant. Zhou et al. 2016 (PMID: 27559085) reported additional independent families, including one Pakistani family overlapping the original report and two Turkish families with homozygous missense and frameshift variants. Additional independent autosomal recessive cases were reported by Damgaard et al. 2019 (PMID: 30804083), describing a new patient with homozygous p.Gly281Arg; Nabavi et al. 2019 (PMID: 30796585), describing a canonical splice-site variant; and Zinngrebe et al. 2022 (PMID: 35170849), describing an atypical late-onset compound heterozygous case. Overall, the curated evidence includes both predicted/proven null and other variant types, with a total genetic evidence score of 10 points. Experimental evidence supports the mechanism that loss of OTULIN function causes dysregulated linear ubiquitin signaling and autoinflammation. Curated evidence includes biochemical function and functional alteration in patient cells, for a total experimental evidence score of 2.5 points. Across the cited studies, patient-derived cells showed abnormal linear ubiquitination and dysregulated inflammatory/TNF signaling, and variant-specific functional studies supported deleterious effects on OTULIN stability, binding, catalytic activity, or splicing.
Inheritance Pattern: AR
Disease ID:MONDO:0014912
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014912
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014912
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0017953
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014912
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014912
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0031030
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0700338
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection can involved increased risk of certain types of infections, and awareness may allow prompt management of infections; Autoinflammation, panniculitis, and dermatosis syndrome can manifest in early childhood with a variety of autoinflammatory sequelae, and patients has been described as responding to medical management (eg, with systemic steroids, IL1R antagonist, TNF inhibitor)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to OTULIN variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_138348.6. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 74 | 2 | 76 | |||
| missense | 6 | 111 | 4 | 1 | 122 | |
| nonsense | 1 | 1 | 5 | 7 | ||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 4 | 5 | |||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 4 | 1 | 8 | |
| Total | 9 | 3 | 125 | 79 | 3 | 219 |
Highest pathogenic variant AF is 6.909723e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_612357.4 | 7 | MANE Select | |
| Ensembl | ENSP00000284274.4 | 7 | MANE Select | |
| Ensembl | ENSP00000427016.1 | 2 | Standard | |
| Ensembl | ENSP00000424966.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signal Transduction
- Post-translational protein modification
- Metabolism of proteins
- Synthesis of active ubiquitin: roles of E1 and E2 enzymes
- TNF signaling
Biological Process
- sprouting angiogenesis
- regulation of tumor necrosis factor-mediated signaling pathway
- Wnt signaling pathway
- negative regulation of NF-kappaB transcription factor activity
- innate immune response
Molecular Function
- thiol-dependent ubiquitin-specific protease activity
- protein binding
- cysteine-type peptidase activity
Cellular Component
- cytoplasm
- cytosol
- LUBAC complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000284274
- Coding exons
- 7
- Length
- 35048
- Individuals with no LoFs
- 124787
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 124792
- p
- 0.0000200
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.26 | 91 | 175 | 0.520 | 0.00000971 | 2305 |
| Missense (PolyPhen) | 28 | 77.959 | 0.35917 | 886 | ||
| Synonymous | 0.646 | 60 | 66.7 | 0.899 | 0.00000381 | 668 |
| Loss of Function | 2.75 | 4 | 15.8 | 0.253 | 7.51e-7 | 212 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000056 | 0.000056 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000027 | 0.000026 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Deubiquitinase that specifically removes linear ('Met- 1'-linked) polyubiquitin chains to substrates and acts as a regulator of angiogenesis and innate immune response (PubMed:26997266, PubMed:23708998, PubMed:23746843, PubMed:23806334, PubMed:23827681, PubMed:27523608, PubMed:27559085, PubMed:24726323, PubMed:24726327, PubMed:28919039). Required during angiogenesis, craniofacial and neuronal development by regulating the canonical Wnt signaling together with the LUBAC complex (PubMed:23708998). Acts as a negative regulator of NF-kappa-B by regulating the activity of the LUBAC complex (PubMed:23746843, PubMed:23806334). 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 (PubMed:26670046). Acts as a key negative regulator of inflammation by restricting spontaneous inflammation and maintaining immune homeostasis (PubMed:27523608). In myeloid cell, required to prevent unwarranted secretion of cytokines leading to inflammation and autoimmunity by restricting linear polyubiquitin formation (PubMed:27523608). 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 proinflammatory signaling (PubMed:23806334). {ECO:0000269|PubMed:23708998, ECO:0000269|PubMed:23746843, ECO:0000269|PubMed:23806334, ECO:0000269|PubMed:23827681, ECO:0000269|PubMed:24726323, ECO:0000269|PubMed:24726327, ECO:0000269|PubMed:26670046, ECO:0000269|PubMed:26997266, ECO:0000269|PubMed:27523608, ECO:0000269|PubMed:27559085, ECO:0000269|PubMed:28919039}.;
- Disease
- DISEASE: Autoinflammation, panniculitis, and dermatosis syndrome (AIPDS) [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. {ECO:0000269|PubMed:27523608, ECO:0000269|PubMed:27559085}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.103
Intolerance Scores
- RVIS EVS
- 0.46
- RVIS percentile EVS
- 78.28
Essentials
- Essential (gene trap)
- N