Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease
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 fr...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 36; pp. 10127 - 10132 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
06.09.2016
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| Subjects | |
| Online Access | Get full text |
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| 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. |
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| AbstractList | 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. 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.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. 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-kB 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. We describe a human disease linked to mutations in the linear deubiquitinase (DUB) OTULIN, which functions as a Met1-specific DUB to remove linear polyubiquitin chains that are assembled by the linear ubiquitin assembly complex (LUBAC). OTULIN has a role in regulating Wnt and innate immune signaling complexes. Hydrolysis of Met1-linked ubiquitin chains attenuates inflammatory signals in the NF-κB and ASC-mediated pathways. OTULIN-deficient patients have excessive linear ubiquitination of target proteins, such as NEMO, RIPK1, TNFR1, and ASC, leading to severe inflammation. Cytokine inhibitors have been efficient in suppressing constitutive inflammation in these patients. This study, together with the identification of haploinsufficiency of A20 (HA20), suggests a category of human inflammatory diseases, diseases of dysregulated ubiquitination. 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. |
| Author | Aksentijevich, Ivona Deuitch, Natalie Kuehn, Hye Sun Tsai, Wanxia Li Wang, Hongying Blake, Mary Gadina, Massimo Abinun, Mario Yu, Xiaomin Güzel, Ferhat Boehm, Manfred Park, Yong Hwan Stone, Deborah Özen, Seza Zhou, Qing Topaloglu, Rezan Rosenzweig, Sergio D. Welch, Steven B. Romeo, Tina Chae, Jae Jin Yang, Dan Mullikin, James C. Kastner, Daniel L. Demirkaya, Erkan Ombrello, Amanda K. Milner, Joshua D. Remmers, Elaine F. |
| Author_xml | – sequence: 1 givenname: Qing surname: Zhou fullname: Zhou, Qing organization: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892 – sequence: 2 givenname: Xiaomin surname: Yu fullname: Yu, Xiaomin organization: Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892 – sequence: 3 givenname: Erkan surname: Demirkaya fullname: Demirkaya, Erkan organization: Familial Mediterranean Fever Arthritis Vasculitis and Orphan Disease Research Center, Institute of Health Sciences, R&D Center, Gulhane Military Medical Academy, Ankara 06018, Turkey – sequence: 4 givenname: Natalie surname: Deuitch fullname: Deuitch, Natalie organization: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892 – sequence: 5 givenname: Deborah surname: Stone fullname: Stone, Deborah organization: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892 – sequence: 6 givenname: Wanxia Li surname: Tsai fullname: Tsai, Wanxia Li organization: Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892 – sequence: 7 givenname: Hye Sun surname: Kuehn fullname: Kuehn, Hye Sun organization: Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD 20892 – sequence: 8 givenname: Hongying surname: Wang fullname: Wang, Hongying organization: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892 – sequence: 9 givenname: Dan surname: Yang fullname: Yang, Dan organization: Laboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, MD 20892 – sequence: 10 givenname: Yong Hwan surname: Park fullname: Park, Yong Hwan organization: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892 – sequence: 11 givenname: Amanda K. surname: Ombrello fullname: Ombrello, Amanda K. organization: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892 – sequence: 12 givenname: Mary surname: Blake fullname: Blake, Mary organization: Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892 – sequence: 13 givenname: Tina surname: Romeo fullname: Romeo, Tina organization: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892 – sequence: 14 givenname: Elaine F. surname: Remmers fullname: Remmers, Elaine F. organization: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892 – sequence: 15 givenname: Jae Jin surname: Chae fullname: Chae, Jae Jin organization: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892 – sequence: 16 givenname: James C. surname: Mullikin fullname: Mullikin, James C. organization: National Institutes of Health Intramural Sequencing Center, National Human Genome Research Institute, Rockville, MD 20852 – sequence: 17 givenname: Ferhat surname: Güzel fullname: Güzel, Ferhat organization: Familial Mediterranean Fever Arthritis Vasculitis and Orphan Disease Research Center, Institute of Health Sciences, R&D Center, Gulhane Military Medical Academy, Ankara 06018, Turkey – sequence: 18 givenname: Joshua D. surname: Milner fullname: Milner, Joshua D. organization: Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892 – sequence: 19 givenname: Manfred surname: Boehm fullname: Boehm, Manfred organization: Laboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, MD 20892 – sequence: 20 givenname: Sergio D. surname: Rosenzweig fullname: Rosenzweig, Sergio D. organization: Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD 20892 – sequence: 21 givenname: Massimo surname: Gadina fullname: Gadina, Massimo organization: Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892 – sequence: 22 givenname: Steven B. surname: Welch fullname: Welch, Steven B. organization: Heart of England National Health Service Foundation Trust, Birmingham B9 5ST, United Kingdom – sequence: 23 givenname: Seza surname: Özen fullname: Özen, Seza organization: Department of Pediatric Nephrology and Rheumatology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey – sequence: 24 givenname: Rezan surname: Topaloglu fullname: Topaloglu, Rezan organization: Department of Pediatric Nephrology and Rheumatology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey – sequence: 25 givenname: Mario surname: Abinun fullname: Abinun, Mario organization: Institute of Cellular Medicine, Newcastle University, Newcastle NE2 4HH, United Kingdom – sequence: 26 givenname: Daniel L. surname: Kastner fullname: Kastner, Daniel L. organization: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892 – sequence: 27 givenname: Ivona surname: Aksentijevich fullname: Aksentijevich, Ivona organization: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD 20892 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27559085$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | Volumes 1–89 and 106–113, copyright as a collective work only; author(s) retains copyright to individual articles Copyright National Academy of Sciences Sep 6, 2016 |
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| DocumentTitleAlternate | Biallelic mutations in OTULIN define otulipenia |
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| Issue | 36 |
| Keywords | linear deubiquitinase cytokines autoinflammatory disease NF-κB pathway OTULIN |
| Language | English |
| License | Freely available online through the PNAS open access option. |
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| Notes | SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 1Q.Z. and X.Y. contributed equally to this work. Reviewers: S.G., University of California, Irvine; and A.M., University of California, San Francisco. Contributed by Daniel L. Kastner, August 2, 2016 (sent for review June 21, 2016; reviewed by Sudhir Gupta and Averil Ma) Author contributions: Q.Z., D.L.K., and I.A. designed research; Q.Z., X.Y., N.D., D.S., W.L.T., H.S.K., H.W., D.Y., Y.H.P., M. Blake, E.F.R., and F.G. performed research; E.D., A.K.O., T.R., J.C.M., S.B.W., S.Ö., R.T., and M.A. contributed new reagents/analytic tools; Q.Z., X.Y., J.J.C., J.D.M., M. Boehm, S.D.R., M.G., and I.A. analyzed data; and Q.Z., D.L.K., and I.A. wrote the paper. |
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| Snippet | Systemic autoinflammatory diseases are caused by mutations in genes that function in innate immunity. Here, we report an autoinflammatory disease caused by... We describe a human disease linked to mutations in the linear deubiquitinase (DUB) OTULIN, which functions as a Met1-specific DUB to remove linear... |
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| SubjectTerms | Age of Onset Alleles Biological Sciences Cells Child Child, Preschool Consanguinity Cytokines Cytokines - genetics Cytokines - immunology Dermatitis Dermatitis - physiopathology Endopeptidases - deficiency Endopeptidases - genetics Endopeptidases - immunology Enzymatic activity Failure to Thrive - physiopathology Female Fever - physiopathology Fibroblasts - enzymology Fibroblasts - immunology Fibroblasts - pathology Gene Expression Regulation Genes HEK293 Cells Hereditary Autoinflammatory Diseases - diagnosis Hereditary Autoinflammatory Diseases - enzymology Hereditary Autoinflammatory Diseases - genetics Hereditary Autoinflammatory Diseases - pathology Humans Leukocytes, Mononuclear - enzymology Leukocytes, Mononuclear - immunology Leukocytes, Mononuclear - pathology Male Molecules Mutation NF-kappa B - genetics NF-kappa B - immunology Panniculitis - physiopathology Pedigree Signal Transduction Ubiquitin - genetics Ubiquitin - immunology |
| Title | Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease |
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