Title | Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Romberg, N, Moussawi, KAl, Nelson-Williams, C, Stiegler, AL, Loring, E, Choi, M, Overton, J, Meffre, E, Khokha, MK, Huttner, AJ, West, B, Podoltsev, NA, Boggon, TJ, Kazmierczak, BI, Lifton, RP |
Journal | Nat Genet |
Volume | 46 |
Issue | 10 |
Pagination | 1135-1139 |
Date Published | 2014 Oct |
ISSN | 1546-1718 |
Keywords | Calcium-Binding Proteins, CARD Signaling Adaptor Proteins, Enterocolitis, Exome, Family Health, Fatal Outcome, Female, Humans, Inflammation, Male, Mutation, Missense, Pedigree, Sequence Analysis, DNA, Syndrome |
Abstract | Upon detection of pathogen-associated molecular patterns, innate immune receptors initiate inflammatory responses. These receptors include cytoplasmic NOD-like receptors (NLRs) whose stimulation recruits and proteolytically activates caspase-1 within the inflammasome, a multiprotein complex. Caspase-1 mediates the production of interleukin-1 family cytokines (IL1FCs), leading to fever and inflammatory cell death (pyroptosis). Mutations that constitutively activate these pathways underlie several autoinflammatory diseases with diverse clinical features. We describe a family with a previously unreported syndrome featuring neonatal-onset enterocolitis, periodic fever, and fatal or near-fatal episodes of autoinflammation. We show that the disease is caused by a de novo gain-of-function mutation in NLRC4 encoding a p.Val341Ala substitution in the HD1 domain of the protein that cosegregates with disease. Mutant NLRC4 causes constitutive IL1FC production and macrophage cell death. Infected macrophages from affected individuals are polarized toward pyroptosis and exhibit abnormal staining for inflammasome components. These findings identify and describe the cause of a life-threatening but treatable autoinflammatory disease that underscores the divergent roles of the NLRC4 inflammasome. |
DOI | 10.1038/ng.3066 |
Alternate Journal | Nat. Genet. |
PubMed ID | 25217960 |
PubMed Central ID | PMC4177367 |
Grant List | U54HG006504 01 / HG / NHGRI NIH HHS / United States R01AI081825 / AI / NIAID NIH HHS / United States R01 AI081825 / AI / NIAID NIH HHS / United States U54 HG006504 / HG / NHGRI NIH HHS / United States / / Howard Hughes Medical Institute / United States UL1 TR000142 / TR / NCATS NIH HHS / United States K12 HD001401 / HD / NICHD NIH HHS / United States K12HD0141401-10 / HD / NICHD NIH HHS / United States |