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

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.Montealegre Sanchez, Hanna Kim, Dawn Chapelle, Nicole Plass, Yan Huang, Alejandro V. Villarino, Angelique Biancotto, Thomas A. Fleisher, Joseph A. Duncan, John J. O'Shea, Susanne Benseler, Alexei GromZuoming Deng, Ronald M. Laxer, Raphaela Goldbach-Mansky

Research output: Contribution to journalArticlepeer-review

390 Scopus citations


Inflammasomes are innate immune sensors that respond to pathogen-and damage-associated signals with caspase-1 activation, interleukin (IL)-1Î 2 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-1Î 2 oversecretion led to successful treatment with IL-1-blocking agents. Herein we report a de novo missense mutation (c.1009A>T, encoding p.Thr337Ser) affecting the nucleotide-binding domain of the inflammasome component NLRC4 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-1Î 2 and IL-18, with the latter exceeding the levels seen in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in cells transduced with mutant NLRC4 and increased production of IL-18 in both patient-derived and mutant NLRC4-transduced macrophages. Thus, we describe a new monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests new targets for therapy.

Original languageEnglish (US)
Pages (from-to)1140-1146
Number of pages7
JournalNature genetics
Issue number10
StatePublished - Sep 26 2014
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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