title: A point mutation in the IL-12R beta 2 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-gamma 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 Igkappa locus. The gene is IL-12Rbeta2. Cr mice carry a point mutation creating a stop codon that is predicted to cause premature termination of the translated IL-12Rbeta2 after a lysine residue at position 777. The truncated beta2 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-gamma, its absence in Cr mice is responsible for their defective IFN-gamma response to microorganisms.
authors.affiliation: The Scripps Research Institute, La Jolla, CA 92037. Max-Planck-Institut für Immunbiologie, Freiburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Poltorak
authors.forename: T
authors.initials: T
authors.lastname: Merlin
authors.forename: P J
authors.initials: PJ
authors.lastname: Nielsen
authors.forename: O
authors.initials: O
authors.lastname: Sandra
authors.forename: I
authors.initials: I
authors.lastname: Smirnova
authors.forename: I
authors.initials: I
authors.lastname: Schupp
authors.forename: T
authors.initials: T
authors.lastname: Boehm
authors.forename: C
authors.initials: C
authors.lastname: Galanos
authors.forename: M A
authors.initials: MA
authors.lastname: Freudenberg
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002874:Chromosome Mapping; D029721:Drosophila Proteins; D017353:Gene Deletion; D005819:Genetic Markers / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics*; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL / Q000235:genetics* / Q000276:immunology*; D017354:Point Mutation; D011956:Receptors, Cell Surface / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D053707:Receptors, Interleukin-12; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors
chemical_list: D029721:Drosophila Proteins; D005819:Genetic Markers; C508443:Il12rb2 protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D051193:Toll-Like Receptors; D018664:Interleukin-12; D007371:Interferon-gamma