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Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):10127-32. doi: 10.1073/pnas.1612594113. Epub 2016 Aug 24.

Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease.

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Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892;
Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892;
Familial Mediterranean Fever Arthritis Vasculitis and Orphan Disease Research Center, Institute of Health Sciences, R&D Center, Gulhane Military Medical Academy, Ankara 06018, Turkey;
Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892;
Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD 20892;
Laboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, MD 20892;
National Institutes of Health Intramural Sequencing Center, National Human Genome Research Institute, Rockville, MD 20852;
Heart of England National Health Service Foundation Trust, Birmingham B9 5ST, United Kingdom;
Department of Pediatric Nephrology and Rheumatology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey;
Institute of Cellular Medicine, Newcastle University, Newcastle NE2 4HH, United Kingdom.
Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892;


Systemic autoinflammatory diseases are caused by mutations in genes that function in innate immunity. Here, we report an autoinflammatory disease caused by loss-of-function mutations in OTULIN (FAM105B), encoding a deubiquitinase with linear linkage specificity. We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency. HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with WT OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients' fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. This discovery adds to the emerging spectrum of human diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies.


NF-κB pathway; OTULIN; autoinflammatory disease; cytokines; linear deubiquitinase

[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: S.Ö. received royalties for consulting and speaking from Novartis and SOBI. All other authors declare no conflict of interest.

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