Document Detail

An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.
MedLine Citation:
PMID:  25217959     Owner:  NLM     Status:  In-Process    
Inflammasomes are innate immune sensors that respond to pathogen- and damage-associated signals with caspase-1 activation, interleukin (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 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-1β 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.
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 Grom; Zuoming Deng; Ronald M Laxer; Raphaela Goldbach-Mansky
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Publication Detail:
Type:  Case Reports; Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2014-09-14
Journal Detail:
Title:  Nature genetics     Volume:  46     ISSN:  1546-1718     ISO Abbreviation:  Nat. Genet.     Publication Date:  2014 Oct 
Date Detail:
Created Date:  2014-09-26     Completed Date:  -     Revised Date:  2014-12-06    
Medline Journal Info:
Nlm Unique ID:  9216904     Medline TA:  Nat Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1140-6     Citation Subset:  IM    
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Comment In:
Nat Genet. 2014 Oct;46(10):1048-9   [PMID:  25257084 ]

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