Paediatrics Publications

Title

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

Authors

Qing Zhou, National Human Genome Research Institute (NHGRI)
Xiaomin Yu, National Institute of Allergy and Infectious Diseases (NIAID)
Erkan Demirkaya, Gulhane Military Medical AcademyFollow
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

Journal

Proceedings of the National Academy of Sciences of the United States of America

Volume

113

Issue

36

First Page

10127

Last Page

10132

URL with Digital Object Identifier

10.1073/pnas.1612594113

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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