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Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease
Proceedings of the National Academy of Sciences of the United States of America
  • Qing Zhou, National Human Genome Research Institute (NHGRI)
  • Xiaomin Yu, National Institute of Allergy and Infectious Diseases (NIAID)
  • Erkan Demirkaya, Gulhane Military Medical Academy
  • Natalie Deuitch, National Human Genome Research Institute (NHGRI)
  • Deborah Stone, National Human Genome Research Institute (NHGRI)
  • Wanxia Li Tsai, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
  • Hye Sun Kuehn, NIH Clinical Center (CC)
  • Hongying Wang, National Human Genome Research Institute (NHGRI)
  • Dan Yang, National Heart, Lung, and Blood Institute (NHLBI)
  • Yong Hwan Park, National Human Genome Research Institute (NHGRI)
  • Amanda K. Ombrello, National Human Genome Research Institute (NHGRI)
  • Mary Blake, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
  • Tina Romeo, National Human Genome Research Institute (NHGRI)
  • Elaine F. Remmers, National Human Genome Research Institute (NHGRI)
  • Jae Jin Chae, National Human Genome Research Institute (NHGRI)
  • James C. Mullikin, National Human Genome Research Institute (NHGRI)
  • Ferhat Güzel, Gulhane Military Medical Academy
  • Joshua D. Milner, National Institute of Allergy and Infectious Diseases (NIAID)
  • Manfred Boehm, National Heart, Lung, and Blood Institute (NHLBI)
  • Sergio D. Rosenzweig, NIH Clinical Center (CC)
  • Massimo Gadina, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
  • Steven B. Welch, University Hospitals Birmingham NHS Foundation Trust
  • Seza Özen, Hacettepe Üniversitesi
  • Rezan Topaloglu, Hacettepe Üniversitesi
  • Mario Abinun, University of Newcastle upon Tyne, Faculty of Medical Sciences
  • Daniel L. Kastner, National Human Genome Research Institute (NHGRI)
  • Ivona Aksentijevich, National Human Genome Research Institute (NHGRI)
Document Type
Article
Publication Date
9-6-2016
URL with Digital Object Identifier
10.1073/pnas.1612594113
Disciplines
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.

Citation Information
Qing Zhou, Xiaomin Yu, Erkan Demirkaya, Natalie Deuitch, et al.. "Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease" Proceedings of the National Academy of Sciences of the United States of America Vol. 113 Iss. 36 (2016) p. 10127 - 10132
Available at: http://works.bepress.com/erkan-demirkaya/20/