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

Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):10127-32. doi: 10.1073/pnas.1612594113. Epub 2016 Aug 24.


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.

Keywords: NF-κB pathway; OTULIN; autoinflammatory disease; cytokines; linear deubiquitinase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Alleles*
  • Child
  • Child, Preschool
  • Consanguinity
  • Cytokines / genetics
  • Cytokines / immunology
  • Dermatitis / physiopathology
  • Endopeptidases / deficiency
  • Endopeptidases / genetics*
  • Endopeptidases / immunology
  • Failure to Thrive / physiopathology
  • Female
  • Fever / physiopathology
  • Fibroblasts / enzymology
  • Fibroblasts / immunology
  • Fibroblasts / pathology*
  • Gene Expression Regulation
  • 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
  • Mutation*
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • Panniculitis / physiopathology
  • Pedigree
  • Signal Transduction
  • Ubiquitin / genetics
  • Ubiquitin / immunology


  • Cytokines
  • NF-kappa B
  • Ubiquitin
  • Endopeptidases
  • gumby protein, human