International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


POSTER 175 - POSITIONAL CLONING OF IFNM LOCUS IN LPS UNRESPONSIVE MICE REVEALS MUTATION IN IL-12R BETA2 GENE

Dr. Alexander Poltorak
The Scripps Research Institute
10550 N.Torrey Pines Road
IMM-31
La Jolla
CA 92037
USA

Co-Authors: 2)Merlin T, 2)Nielsen P, 2)Sandra O, 1)Smirnova I, 2)Schupp I, 2)Boehm T, 2)Galanos C, 1)Beutler B, 2)Freudenberg M
Institutions: 1)The Scripps Research Institute, 2)Max-Planck-Institut für Immunbiologie

Mice with mutations in the Toll-like receptor 4 gene (Tlr4) are resistant to LPS, a powerful microbial inducer of inflammation. C57BL/10ScCr (Cr), a mouse strain homozygous for a deletion encompassing Tlr4, remains LPS resistant when primed with microbes that induce interferon-gamma (IFN-gamma) synthesis, whereas a partial LPS sensitivity develops under these conditions in C3H/HeJ mice, which are homozygous for a missense mutation in Tlr4. Genetic linkage analysis showed that this phenotypic difference between Cr and C3H/HeJ strains is not linked to Tlr4 but rather to a nonsense mutation in the IL-12 receptor beta2 gene (IL12Rbeta2) located on mouse chromosome 6, in close proximity of the Igkappa locus. The truncated beta2 chain, can still form a heterodimeric IL-12 receptor (R) which, allows phosphorylation of Jak2, but unlike the wild type IL-12R, can no longer mediate phosphorylation of STAT4. This observation confirms that IL-12 signaling via STAT4 is required for IFN-gamma production after infection with certain micro-organisms. Thus, two independent genetic defects determine the impaired inflammatory response to pathogens of Cr mice.


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