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

TLDR

Systemic autoinflammatory diseases arise from mutations in genes that regulate innate immunity. The study reports a novel autoinflammatory disorder caused by loss‑of‑function mutations in OTULIN, a linear‑linkage deubiquitinase. Genetic analysis identified two missense and one frameshift OTULIN mutations in four patients from Pakistani and Turkish families. Affected patients exhibited neonatal fever, neutrophilic dermatitis, and failure to thrive; OTULIN mutations led to reduced enzyme activity, impaired linear ubiquitin removal, heightened NF‑κB signaling, linear ubiquitin aggregates, and elevated pro‑inflammatory cytokines, suggesting that targeted cytokine therapy may be beneficial.

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.