A Point Mutation in the IL-12Rβ2 Gene Underlies the IL-12 Unresponsiveness of Lps-Defective C57BL/10ScCr Mice
Copyright policy )A Point Mutation in the IL-12Rβ2 Gene Underlies the IL-12 Unresponsiveness of Lps-Defective C57BL/10ScCr Mice
Abstract Lps-defective C57BL/10ScCr (Cr) mice are homozygous for a deletion encompassing Toll-like receptor 4 that makes them refractory to the biological activity of LPS. In addition, these mice exhibit an inherited IL-12 unresponsiveness resulting in impaired IFN-γ responses to different microorganisms. By positional cloning methods, we show here that this second defect of Cr mice is due to a mutation in a single gene located on mouse chromosome 6, in close proximity to the Igκ locus. The gene is IL-12Rβ2. Cr mice carry a point mutation creating a stop codon that is predicted to cause premature termination of the translated IL-12Rβ2 after a lysine residue at position 777. The truncated β2 chain can still form a heterodimeric IL-12R that allows phosphorylation of Janus kinase 2, but, unlike the wild-type IL-12R, can no longer mediate phosphorylation of STAT4. Because the phosphorylation of STAT4 is a prerequisite for the IL-12-mediated induction of IFN-γ, its absence in Cr mice is responsible for their defective IFN-γ response to microorganisms.
- Max Planck Society Germany
- Scripps Research Institute United States
Genetic Markers, Lipopolysaccharides, Mice, Inbred BALB C, Membrane Glycoproteins, Toll-Like Receptors, Receptors, Interleukin-12, Chromosome Mapping, Receptors, Cell Surface, Receptors, Interleukin, Interleukin-12, Mice, Inbred C57BL, Interferon-gamma, Mice, Immune Tolerance, Animals, Drosophila Proteins, Point Mutation, Cells, Cultured, Gene Deletion, Signal Transduction
Genetic Markers, Lipopolysaccharides, Mice, Inbred BALB C, Membrane Glycoproteins, Toll-Like Receptors, Receptors, Interleukin-12, Chromosome Mapping, Receptors, Cell Surface, Receptors, Interleukin, Interleukin-12, Mice, Inbred C57BL, Interferon-gamma, Mice, Immune Tolerance, Animals, Drosophila Proteins, Point Mutation, Cells, Cultured, Gene Deletion, Signal Transduction
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