title: Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation.
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.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Romberg
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 330 Cedar Street, New Haven, Connecticut 06510, USA.
authors.forename: Khatoun
authors.initials: K
authors.lastname: Al Moussawi
authors.affiliation: Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, 295 Congress Avenue, New Haven, Connecticut 06510, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Nelson-Williams
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Stiegler
authors.affiliation: Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Loring
authors.affiliation: Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, 295 Congress Avenue, New Haven, Connecticut 06510, USA.
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.affiliation: Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
authors.forename: John
authors.initials: J
authors.lastname: Overton
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 330 Cedar Street, New Haven, Connecticut 06510, USA.|Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, New Haven, Connecticut 06510, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.|Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
authors.forename: Mustafa K
authors.initials: MK
authors.lastname: Khokha
authors.affiliation: Department of Pathology, Yale University School of Medicine, 310 Cedar Street, New Haven, Connecticut 06510, USA.
authors.forename: Anita J
authors.initials: AJ
authors.lastname: Huttner
authors.affiliation: Department of Pathology, Yale University School of Medicine, 310 Cedar Street, New Haven, Connecticut 06510, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: West
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 330 Cedar Street, New Haven, Connecticut 06510, USA.
authors.forename: Nikolai A
authors.initials: NA
authors.lastname: Podoltsev
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 330 Cedar Street, New Haven, Connecticut 06510, USA.|Department of Microbial Pathogenesis, Yale University School of Medicine, 295 Congress Ave, New Haven, Connecticut 06520, USA.
authors.forename: Barbara I
authors.initials: BI
authors.lastname: Kazmierczak
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 330 Cedar Street, New Haven, Connecticut 06510, USA.|Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, 295 Congress Avenue, New Haven, Connecticut 06510, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D004760:Enterocolitis / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005192:Family Health; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D017422:Sequence Analysis, DNA; D013577:Syndrome
chemical_list: D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; C435692:NLRC4 protein, human