title: Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease.
abstract: 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.
authors: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892;
authors: Qing
authors: Q
authors: Zhou
authors: Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892;
authors: Xiaomin
authors: X
authors: Yu
authors: Familial Mediterranean Fever Arthritis Vasculitis and Orphan Disease Research Center, Institute of Health Sciences, R&D Center, Gulhane Military Medical Academy, Ankara 06018, Turkey;
authors: Erkan
authors: E
authors: Demirkaya
authors: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892;
authors: Natalie
authors: N
authors: Deuitch
authors: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892;
authors: Deborah
authors: D
authors: Stone
authors: Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892;
authors: Wanxia Li
authors: WL
authors: Tsai
authors: Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD 20892;
authors: Hye Sun
authors: HS
authors: Kuehn
authors: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892;
authors: Hongying
authors: H
authors: Wang
authors: Laboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, MD 20892;
authors: Dan
authors: D
authors: Yang
authors: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892;
authors: Yong Hwan
authors: YH
authors: Park
authors: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892;
authors: Amanda K
authors: AK
authors: Ombrello
authors: Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892;
authors: Mary
authors: M
authors: Blake
authors: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892;
authors: Tina
authors: T
authors: Romeo
authors: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892;
authors: Elaine F
authors: EF
authors: Remmers
authors: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892;
authors: Jae Jin
authors: JJ
authors: Chae
authors: National Institutes of Health Intramural Sequencing Center, National Human Genome Research Institute, Rockville, MD 20852;
authors: James C
authors: JC
authors: Mullikin
authors: Familial Mediterranean Fever Arthritis Vasculitis and Orphan Disease Research Center, Institute of Health Sciences, R&D Center, Gulhane Military Medical Academy, Ankara 06018, Turkey;
authors: Ferhat
authors: F
authors: Güzel
authors: Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892;
authors: Joshua D
authors: JD
authors: Milner
authors: Laboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, MD 20892;
authors: Manfred
authors: M
authors: Boehm
authors: Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD 20892;
authors: Sergio D
authors: SD
authors: Rosenzweig
authors: Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892;
authors: Massimo
authors: M
authors: Gadina
authors: Heart of England National Health Service Foundation Trust, Birmingham B9 5ST, United Kingdom;
authors: Steven B
authors: SB
authors: Welch
authors: Department of Pediatric Nephrology and Rheumatology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey;
authors: Seza
authors: S
authors: Özen
authors: Department of Pediatric Nephrology and Rheumatology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey;
authors: Rezan
authors: R
authors: Topaloglu
authors: Institute of Cellular Medicine, Newcastle University, Newcastle NE2 4HH, United Kingdom.
authors: Mario
authors: M
authors: Abinun
authors: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892; kastnerd@mail.nih.gov aksentii@mail.nih.gov.
authors: Daniel L
authors: DL
authors: Kastner
authors: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892; kastnerd@mail.nih.gov aksentii@mail.nih.gov.
authors: Ivona
authors: I
authors: Aksentijevich
mesh_terms: D017668:Age of Onset; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003872:Dermatitis / Q000503:physiopathology; D010450:Endopeptidases / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D005183:Failure to Thrive / Q000503:physiopathology; D005260:Female; D005334:Fever / Q000503:physiopathology; D005347:Fibroblasts / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D056660:Hereditary Autoinflammatory Diseases / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D008297:Male; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D015434:Panniculitis / Q000503:physiopathology; D010375:Pedigree; D015398:Signal Transduction; D025801:Ubiquitin / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D025801:Ubiquitin; D010450:Endopeptidases; C582107:OTULIN protein, human
keywords: NF-κB pathway; OTULIN; autoinflammatory disease; cytokines; linear deubiquitinase