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Published January 1, 2016 | Version v1
Journal article Open

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

Creators

  • 1. NHGRI, Inflammatory Dis Sect, Bethesda, MD 20892 USA
  • 2. NIAID, Genet & Pathogenesis Allergy Sect, Lab Allerg Dis, Bethesda, MD 20892 USA
  • 3. Gulhane Mil Med Acad, Inst Hlth Sci, Familial Mediterranean Fever Arthrit Vasculitis &, R&D Ctr, TR-06018 Ankara, Turkey
  • 4. NIAMSD, Translat Immunol Sect, Bethesda, MD 20892 USA
  • 5. NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA
  • 6. NHLBI, Lab Cardiovasc Regenerat Med, Bethesda, MD 20892 USA
  • 7. NHGRI, NIH, Intramural Sequencing Ctr, Rockville, MD 20852 USA

Description

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-kappa B 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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