An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome

• DOI: 10.1038/ng.3089
• Publication Date: 2014-09-14T18:25:04Z
• Authors: Scott W Canna; Adriana A de Jesus; Sushanth Gouni; Stephen R Brooks; Bernadette Marrero; Yin Liu; Michael A DiMattia; Kristien J M Zaal; Gina A Montealegr...; Hanna Kim; Dawn Chapelle; Nicole Plass; Yan Huang; Alejandro V Villa...; Angelique Biancotto; Thomas A Fleisher; Joseph A Duncan; John J O'Shea; Susanne Benseler; Alexei Grom; Zuoming Deng; Ronald M Laxer; Raphaela Goldbach...
• Keywords: Inflammation; 0301 basic medicine; Sequence Homology, Amino Acid; Inflammasomes; Gene Expression Profiling; Macrophage Activation Syndrome; Macrophages; Calcium-Binding Proteins; Molecular Sequence Data; Interleukin-18; Mutation, Missense; Sequence Analysis, DNA; Article; 3. Good health; CARD Signaling Adaptor Proteins; 03 medical and health sciences; Humans; Exome; Female; Amino Acid Sequence; Child; Oligonucleotide Array Sequence Analysis

Inflammasomes are innate immune sensors that respond to pathogen and damage-associated signals with caspase-1 activation, IL-1β and IL-18 secretion, and macrophage pyroptosis. The discovery that dominant gain-of-function mutations in NLRP3 cause the Cryopyrin Associated Periodic Syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1β oversecretion, led to successful treatment with IL-1 blocking agents1. Herein, we report a de novo missense mutation, c.1009A>T, p.Thr337Ser, in the nucleotide-binding domain of inflammasome component NLRC4 (IPAF/CARD12) that causes early-onset recurrent fever flares and Macrophage Activation Syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1β and IL-18, the latter exceeding levels in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in transduced cells and increased production of IL-18 by both patient and NLRC4 mutant macrophages. Thus, we describe a novel monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests novel targets for therapy.