Information on OTULIN

Basic details

Alt. symbols: FAM105B | FLJ34884

Approved name: OTU deubiquitinase with linear linkage specificity
Alt. names: family with sequence similarity 105, member B | gumby, ubiquitin thioesterase otulin

Location: 5p15.2: 14664664 - 14716529 (+)
Gene type: protein_coding, 8 transcripts.

Scores: LoFtool: 0.115000 | pLI: 0.96968128 | LOEUF: 0.579

HGNC: 25118

NCBI: 90268, RefSeq: NG_051625.1

Ensembl: ENSG00000154124.7

LRG_ | Status: none

OMIM: 615712

Expression | ProteinAtlas

Normal function

OTULIN encodes a deubiquitinase enzyme (DUB) that specifically cleaves linear (Met1-linked) polyubiquitin chains from substrates. It plays a key role in regulating the NF-κB signaling pathway and in innate immune homeostasis by restricting linear polyubiquitin formation on the LUBAC complex in response to NOD2 stimulation, thus preventing the latter’s inactivation (PMID: 26670046, 23806334). It acts as a key negative regulator of NF-kappaB signaling via LUBAC modulation (PMID: 23746843, 23806334, 27523608) thus preventing excessive NF-κB signaling pathway activation and excesive inflammatory responses. It is also required for angiogenesis, craniofacial and neuronal development through regulation of canonical Wnt signaling (PMID: 23708998). Additionally, OTULIN has been implicated in the regulation of cell death pathways and the maintenance of genomic stability.

Dysfunction and disease

First biallelic and then monoallelic variants in this gene have been associated with disease. Biallelic loss-of-function and monoallelic dominant-negative mutations are associated with a syndrome known as autoinflammation, panniculitis, and dermatosis syndrome (AIPDS) or OTULIN-related autoinflmmatory syndrome (ORAS). However heterozygous loss-of-function mutations leading to OTULIN haploinsufficiency may also lead to disease in some individuals (penetrance about 35-38%) and manifest as an incre ased susceptibility to invasive S. aureus infections. Molecularly, these mutations compromise OTULIN's deubiquitination capacity and its caspase-like proteasome activity and lead to an accumulation of M1-Ub chains, which results in the loss of inhibiton of the NF-kB siganlling pathway, an enhancement of TNF production, an increased expression of interferon-stimulated genes, and in a sensitization of fibroblasts to TNF-mediated cell death. [Load More]

[Reviewed by Andrés Caballero-Oteyza on 2023-12-01 13:34:11]

Associated conditions

Acronym Condition's_name MOI Mode_of_actionwww icon OMIM_ID No.cases
AIPDS Autoinflammation, panniculitis, and dermatosis syndrome ARdict. icon Loss of Function 617099www icon 9 (7 fams)
IMD107 Immunodeficiency 107 ADdict. icon Haploinsufficiency 619986www icon 17 (11 fams)
AIPDS2 Autoinflammation, panniculitis, and dermatosis syndrome 2 ADdict. icon Negative Dominance 621030www icon 3 (3 fams)

Transcripts of OTULIN

Name ENSEMBL_ID LRG_ID CCDS_ID MANE Transcript.type Exons Canonical CDS_length REFSEQ_ID
201 ENST00000284274.5 CCDS43302 Select protein_coding 7 Yes 7969 NM_138348
208 ENST00000850613.1 protein_coding No XM_011514151

Published variants

Found 44 variants

Var.name Exon/Intron cDNA_pos. CDS_change Prot.change Var.type Var.class. Patients
Q8* EX1 130 c.22C>T p.Gln8Ter stop_gained Likely Pathogenic 0
Q40R EX1 227 c.119A>G p.Gln40Arg missense_variant Likely Benign 0
I70T EX2 317 c.209T>C p.Ile70Thr missense_variant Uncertain significance 0
V82I EX3 352 c.244G>A p.Val82Ile missense_variant Uncertain significance 0
M86I EX3 366 c.258G>A p.Met86Ile missense_variant Pathogenic 1
Y91F EX3 380 c.272A>T p.Tyr91Phe missense_variant Likely Pathogenic 0
E95* EX3 391 c.283G>T p.Glu95Ter stop_gained Pathogenic 5
W96A EX3 394-395 c.286_287delinsGC p.Trp96Ala missense_variant Likely Pathogenic 0
EX4-2A>G IN3 433 c.325-2A>G splice_acceptor_variant Likely Pathogenic 0
Q115H EX4 453 c.345G>T p.Gln115His missense_variant Benign 0
C129S EX4 493 c.385T>A p.Cys129Ser missense_variant Pathogenic 1
C129A EX4 493-494 c.385_386delinsGC p.Cys129Ala missense_variant Likely Pathogenic 0
C129S EX4 494 c.386G>C p.Cys129Ser missense_variant Pathogenic 1
Q141R EX4 530 c.422A>G p.Gln141Arg missense_variant Uncertain significance 0
P147S EX4 547 c.439C>T p.Pro147Ser missense_variant Likely Benign 0
W148* EX4 551 c.443G>A p.Trp148Ter stop_gained Likely Pathogenic 1
P152L EX4 563 c.455C>T p.Pro152Leu missense_variant Benign 0
M155L EX4 571 c.463A>T p.Met155Leu missense_variant Likely Benign 0
I162T EX5 593 c.485T>C p.Ile162Thr missense_variant Uncertain significance 0
W167S EX5 608 c.500G>C p.Trp167Ser missense_variant Pathogenic 1
G174Dfs*2 EX5 625 c.517del p.Gly174AspfsTer2 frameshift_variant Pathogenic 2
V185F EX5 661 c.553G>T p.Val185Phe missense_variant Uncertain significance 0
W199R EX6 703 c.595T>A p.Trp199Arg missense_variant Likely Pathogenic 1
L202F EX6 714 c.606G>C p.Leu202Phe missense_variant Uncertain significance 0
A240V EX6 827 c.719C>T p.Ala240Val missense_variant Likely Pathogenic 1
Y244C EX6 839 c.731A>G p.Tyr244Cys missense_variant Pathogenic 2
D246V EX6 845 c.737A>T p.Asp246Val missense_variant Pathogenic 2
P254S EX6 868 c.760C>T p.Pro254Ser missense_variant Pathogenic 2
L259E EX6 883-885 c.775_777delinsGAA p.Leu259Glu missense_variant Likely Pathogenic 0
L259E EX6 883-885 c.775_777delinsGAG p.Leu259Glu missense_variant Likely Pathogenic 0
R263Q EX6 896 c.788G>A p.Arg263Gln missense_variant Pathogenic 1
D268Tfs*6 EX6 910 c.802del p.Asp268ThrfsTer6 frameshift_variant Pathogenic 1
L272P EX6 923 c.815T>C p.Leu272Pro missense_variant Pathogenic 3
G281R EX6 949 c.841G>A p.Gly281Arg missense_variant Pathogenic 1
EX6+2T>C IN6 972 c.864+2T>C p.(Trp199-Gln288del) ALTERS SPLICING! Pathogenic 2
R306Q EX7 1025 c.917G>A p.Arg306Gln missense_variant Pathogenic 1
N311S EX7 1040 c.932A>G p.Asn311Ser missense_variant Likely Benign 0
E314R EX7 1048-1049 c.940_941delinsAG p.Glu314Arg missense_variant Likely Pathogenic 0
E314R EX7 1048-1049 c.940_941delinsCG p.Glu314Arg missense_variant Likely Pathogenic 0
D336A EX7 1115 c.1007A>C p.Asp336Ala missense_variant Likely Pathogenic 0
H339A EX7 1123-1124 c.1015_1016delinsGC p.His339Ala missense_variant Likely Pathogenic 0
N341D EX7 1129 c.1021A>G p.Asn341Asp missense_variant Pathogenic 1
N341A EX7 1129-1130 c.1021_1022delinsGC p.Asn341Ala missense_variant Likely Pathogenic 0
R345Kfs*4 EX7 1140-1141 c.1033dup p.Arg345LysfsTer4 frameshift_variant Likely Benign 0

Diagnostic pitfalls & paradigms

Considerations to take into account when analyzing this gene

Year Paradigm ⓘ PMID Notes
- Regions of Homology -
2022Incomplete penetrance35587511The authors report a total of 9 families carrying heterozygous LOF variants in OTULIN. Some of these carriers are the parents of previously reported ORAS patients. Disease penetrance is only about 35-38% and disease severity is variable, even in the same family.
-Cryptic splicing-Unreported or not recorded in our DB.
-Uniparental disomy-Unreported or not recorded in our DB.
-Mosaicism-Unreported or not recorded in our DB.
-Di-/oligo-genic inheritance-Unreported or not recorded in our DB.
-Somatic reversion-Unreported or not recorded in our DB.

References linked to variants in OTULIN

ID Year Title Journal PMID Variants
837 2016 The Deubiquitinase OTULIN Is an Essential Negative Regulator... Cell 27523608 1
838 2020 OTULIN protects the liver against cell death, inflammation, ... Cell death & differ. 32231246 1
839 2019 OTULIN deficiency in ORAS causes cell type-specific LUBAC de... EMBO Mol. Med. 30804083 2
840 2022 Compound heterozygous variants in OTULIN are associated with... EMBO Mol. Med. 35170849 4
841 2019 Auto-inflammation in a Patient with a Novel Homozygous OTULI... JoCI 30796585 1
842 2022 Screening of OTULIN gene mutation with targeted next generat... Mol. Biol. Rep. 35294702 12
843 2016 Biallelic hypomorphic mutations in a linear deubiquitinase d... PNAS 27559085 3
844 2022 Human OTULIN haploinsufficiency impairs cell-intrinsic immun... Science 35587511 13
850 2016 OTULIN deficiency causes auto-inflammatory syndrome... Cell Res. 27686184 1
852 2021 Deubiquitination of proteasome subunits by OTULIN regulates ... Sci. Adv. 34797715 4
870 Internal data from the Center for Chronic Immunodeficiency (... UKF-DBs 2
903 2024 OTULIN-related conditions: Report of a new case and review o... Clin. Immunol. 38914362 41
912 2024 Dominant negative OTULIN Related Autoinflammatory Syndrome... JEM 38630025 5
913 2013 OTULIN antagonizes LUBAC signaling by specifically hydrolyzi... Cell 23746843 11
1015 2022 Whole-Exome Sequencing in 10 Unrelated Patients with Syndrom... Dermatology 35034021 2
1016 2023 OTULIN Haploinsufficiency-Related Fasciitis and Skin Necrosi... JoCI 38129331 1
1153 2024 OTULIN Haploinsufficiency Causes Hyperinflammatory Responses... JoCI 38578307 1
1270 2024 A de novo dominant-negative variant is associated with OTULI... JEM 38652464 5

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