title: Spontaneous mutation of the Dock2 gene in Irf5-/- mice complicates interpretation of type I interferon production and antibody responses.
abstract: Genome-wide studies have identified associations between polymorphisms in the IFN regulatory factor-5 (Irf5) gene and a variety of human autoimmune diseases. Its functional role in disease pathogenesis, however, remains unclear, as studies in Irf5(-/-) mice have reached disparate conclusions regarding the importance of this transcription factor in type I IFN production and antibody responses. We identified a spontaneous genomic duplication and frameshift mutation in the guanine exchange factor dedicator of cytokinesis 2 (Dock2) that has arisen in at least a subset of circulating Irf5(-/-) mice and inadvertently been bred to homozygosity. Retroviral expression of DOCK2, but not IRF-5, rescued defects in plasmacytoid dendritic cell and B-cell development, and Irf5(-/-) mice lacking the mutation in Dock2 exhibited normal plasmacytoid dendritic cell and B-cell development, largely intact type I IFN responses, and relatively normal antibody responses to viral infection. Thus, confirmation of the normal Dock2 genotype in circulating Irf5(-/-) mice is warranted, and our data may partly explain conflicting results in this field.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Whitney E
authors.initials: WE
authors.lastname: Purtha
authors.forename: Melissa
authors.initials: M
authors.lastname: Swiecki
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.forename: Deepta
authors.initials: D
authors.lastname: Bhattacharya
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D033481:Chromosomes, Mammalian / Q000235:genetics; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020440:Gene Duplication / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D050835:Interferon Regulatory Factors / Q000172:deficiency* / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010641:Phenotype
chemical_list: C471356:DOCK2 protein, mouse; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; C498178:Irf5 protein, mouse