Proceedings of the National Academy of Sciences · 2006 · 45 citations · 22 references
Life SciencesGeneticsImmunologyAutoimmunityGene ExpressionImmunoregulationAutoimmune Disease PathologyAutoimmune DiseasesGenomic ImprintingImmune Gene RegulationRna InterferenceSmall Interfering Rna BiologyCytotoxic T-lymphocyte Antigen 4 (Ctla-4) PathwayGenetic Modifier EffectsHuman Disease ModelsImprintingIslet AutoimmunityLentiviral TransgenesisTransgenic MiceType 1 Diabetes Models
The CTLA4 gene is important for T lymphocyte-mediated immunoregulation and has been associated with several autoimmune diseases, in particular, type 1 diabetes. To model the impact of natural genetic variants of CTLA4, we constructed RNA interference (RNAi) "knockdown" mice through lentiviral transgenesis. Variegation of expression was observed in founders but proved surmountable because it reflected parental imprinting, with derepression by transmission from male lentigenics. Unlike the indiscriminate multiorgan autoimmune phenotype of the corresponding knockout mice, Ctla4 knockdown animals had a disease primarily focused on the pancreas, with rapid progression to diabetes. As with the human disease, the knockdown phenotype was tempered by genetic-modifier loci. RNAi should be more pertinent than gene ablation in modeling disease pathogenesis linked to a gene-dosage variation.
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Expression profiling reveals off-target gene regulation by RNAi
Aimee L. Jackson, Steven R. Bartz, Janell M. Schelter et al. · Nature Biotechnology · 2003 · 2.4K citations
Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease
Hironori Ueda, Joanna M. M. Howson, Laura Esposito et al. · Nature · 2003 · 2.2K citations
Life Sciences, Genetics, Immunology +12