OTULIN

OTU deubiquitinase with linear linkage specificity, the group of OTU domain containing

Basic information

Region (hg38): 5:14664663-14699850

Previous symbols: [ "FAM105B" ]

Links

ENSG00000154124 ∙ NCBI:90268 ∙ OMIM:615712 ∙ HGNC:25118 ∙ Uniprot:Q96BN8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• infantile-onset periodic fever-panniculitis-dermatosis syndrome (Definitive), mode of inheritance: AR
• infantile-onset periodic fever-panniculitis-dermatosis syndrome (Strong), mode of inheritance: AR
• infantile-onset periodic fever-panniculitis-dermatosis syndrome (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection; Autoinflammation, panniculitis, and dermatosis syndrome	AD/AR	Allergy/Immunology/Infectious	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)	Allergy/Immunology/Infectious	27523608; 27559085; 35587511

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the OTULIN gene.

• not provided (137 variants)
• Inborn genetic diseases (7 variants)
• Infantile-onset periodic fever-panniculitis-dermatosis syndrome (6 variants)
• not specified (4 variants)
• Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection;Infantile-onset periodic fever-panniculitis-dermatosis syndrome (1 variants)
• OTULIN-related condition (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the OTULIN gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	36	4	41
missense			57		4	61
nonsense	1					1
start loss			1			1
frameshift			2			2
inframe indel			3		1	4
splice donor/acceptor (+/-2bp)		1		1		2
splice region			3	4		7
non coding			1	19	7	27
Total	1	1	65	56	16

Variants in OTULIN

This is a list of pathogenic ClinVar variants found in the OTULIN region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
5-14664712-G-A		not specified	Benign (Jan 24, 2024)
5-14664823-C-T		OTULIN-related disorder	Likely benign (Sep 09, 2019)
5-14664825-CA-C			Uncertain significance (Nov 10, 2020)
5-14664830-G-A			Uncertain significance (May 20, 2022)
5-14664832-C-T			Uncertain significance (Oct 24, 2022)
5-14664832-C-CG			Uncertain significance (Aug 04, 2023)
5-14664837-G-A		OTULIN-related disorder	Likely benign (Sep 29, 2023)
5-14664840-T-A			Likely benign (Jan 28, 2023)
5-14664842-T-C		not specified	Uncertain significance (Dec 28, 2023)
5-14664846-C-A			Likely benign (Sep 10, 2023)
5-14664847-C-T		Infantile-onset periodic fever-panniculitis-dermatosis syndrome	Pathogenic (Mar 06, 2020)
5-14664852-C-T			Likely benign (Oct 19, 2023)
5-14664862-C-T			Uncertain significance (Oct 12, 2021)
5-14664866-G-A		not specified	Uncertain significance (Aug 09, 2022)
5-14664879-C-T			Likely benign (Oct 05, 2023)
5-14664882-G-C			Uncertain significance (Jan 14, 2022)
5-14664886-C-G			Uncertain significance (Jul 12, 2022)
5-14664886-C-T			Uncertain significance (Jun 11, 2022)
5-14664886-CCGGCGCGGGAGGCGGCGGCCA-C			Benign (Jan 31, 2024)
5-14664888-G-T			Likely benign (Oct 05, 2021)
5-14664890-C-A			Uncertain significance (Apr 11, 2023)
5-14664890-C-T			Uncertain significance (Jun 22, 2021)
5-14664892-C-A			Likely benign (Mar 04, 2023)
5-14664895-GAGGCGGCGGCCACGGCGCGGGACGGCGGGA-G			Uncertain significance (Jul 17, 2022)
5-14664896-AGGC-A			Uncertain significance (Jun 13, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
OTULIN	protein_coding	protein_coding	ENST00000284274	7	35048

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.220	0.778	124787	0	5	124792	0.0000200

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.26	91	175	0.520	0.00000971	2305
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000556	0.0000556
Finnish	0.00	0.00
European (Non-Finnish)	0.0000267	0.0000265
Middle Eastern	0.0000556	0.0000556
South Asian	0.00	0.00
Other	0.000166	0.000165

dbNSFP

Source: dbNSFP

• 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.
• Pathway: Signal Transduction;Post-translational protein modification;Metabolism of proteins;Synthesis of active ubiquitin: roles of E1 and E2 enzymes;TNF signaling;Death Receptor Signalling;Regulation of TNFR1 signaling;Protein ubiquitination (Consensus)

Recessive Scores

• pRec: 0.103

Intolerance Scores

• rvis_EVS: 0.46
• rvis_percentile_EVS: 78.28

Haploinsufficiency Scores

• pHI: 0.106
• hipred: Y
• hipred_score: 0.728
• ghis: 0.436

Essentials

• essential_gene_gene_trap: N

Mouse Genome Informatics

• Gene name: Otulin
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); skeleton phenotype; embryo phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); growth/size/body region phenotype; craniofacial phenotype; cellular phenotype

Gene ontology

• 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;negative regulation of inflammatory response;regulation of canonical Wnt signaling pathway;nucleotide-binding oligomerization domain containing 2 signaling pathway;protein linear deubiquitination
• Cellular component: cytoplasm;cytosol;LUBAC complex
• Molecular function: thiol-dependent ubiquitin-specific protease activity;protein binding;cysteine-type peptidase activity