title: Identification of the inflammasome Nlrp1b as the candidate gene conferring diabetes risk at the Idd4.1 locus in the nonobese diabetic mouse.
abstract: Type 1 diabetes in the NOD mouse model has been linked to >30 insulin-dependent diabetes (Idd) susceptibility loci. Idd4 on chromosome 11 consists of two subloci, Idd4.1 and Idd4.2. Using congenic analysis of alleles in NOD and NOD-resistant (NOR) mice, we previously defined Idd4.1 as an interval containing >50 genes that controlled expression of genes in the type 1 IFN pathway. In this study, we report refined mapping of Idd4.1 to a 1.1-Mb chromosomal region and provide genomic sequence analysis and mechanistic evidence supporting its role in innate immune regulation of islet-directed autoimmunity. Genetic variation at Idd4.1 was mediated by radiation-sensitive hematopoietic cells, and type 1 diabetes protection conferred by the NOR allele was abrogated in mice treated with exogenous type 1 IFN-β. Next generation sequence analysis of the full Idd4.1 genomic interval in NOD and NOR strains supported Nlrp1b as a strong candidate gene for Idd4.1. Nlrp1b belongs to the Nod-like receptor (NLR) gene family and contributes to inflammasome assembly, caspase-1 recruitment, and release of IL-1β. The Nlrp1b of NOR was expressed as an alternative spliced isoform that skips exon 9, resulting in a premature stop codon predicted to encode a truncated protein. Functional analysis of the truncated NOR Nlrp1b protein demonstrated that it was unable to recruit caspase-1 and process IL-1β. Our data suggest that Idd4.1-dependent protection from islet autoimmunity is mediated by differences in type 1 IFN- and IL-1β-dependent immune responses resulting from genetic variation in Nlrp1b.
authors.affiliation: Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada;
authors.forename: Vinicius N
authors.initials: VN
authors.lastname: Motta
authors.affiliation: Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada; Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: Janet G M
authors.initials: JG
authors.lastname: Markle
authors.affiliation: Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada;
authors.forename: Omid
authors.initials: O
authors.lastname: Gulban
authors.affiliation: Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada;
authors.forename: Steven
authors.initials: S
authors.lastname: Mortin-Toth
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: Kuo-Chien
authors.initials: KC
authors.lastname: Liao
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: Jeremy
authors.initials: J
authors.lastname: Mogridge
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom; and.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Steward
authors.affiliation: Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada; Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada jayne.danska@sickkids.ca.
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Danska
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics*; D001483:Base Sequence; D002874:Chromosome Mapping; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D058847:Inflammasomes / Q000235:genetics* / Q000276:immunology; D016899:Interferon-beta / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D054730:Protein Interaction Domains and Motifs; D040641:Quantitative Trait Loci; D016415:Sequence Alignment
chemical_list: D051017:Apoptosis Regulatory Proteins; D058847:Inflammasomes; C509168:Nalp1b protein, mouse; D016899:Interferon-beta