A point mutation in the IL-12R beta 2 gene underlies the IL-12 unresponsiveness of Lps-defective C57BL/10ScCr mice

Lps-defective C57BL/10ScCr (Cr) mice are homozygous for a deletion encompas sing Toll-like receptor 4 that makes them refractory to the biological acti vity of LPS. In addition, these mice exhibit an inherited IL-12 unresponsiv eness 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 Ig kappa locus. The gene is IL-12R beta2. Cr mice carry a point mutation creating a stop codon that is predicted to cause pr emature termination of the translated IL-12R beta2 after a lysine residue a t position 777. The truncated beta2 chain can still form a heterodimeric IL -12R that allows phosphorylation of Janus kinase 2, hut, unlike the wild-ty pe IL-12R, can no longer mediate phosphorylation of STAT4. Because the phos phorylation 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-ga mma response to microorganisms.