Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations inTlr4Gene
Alexander Poltorak, Xiaolong He, Irina Smirnova, Mu-Ya Liu, Christophe Van Huffel, Xin Du, Dale Birdwell, Erica Alejos, Maria Silva, Chris Galanos, Marina Freudenberg, Paola Ricciardi-Castagnoli, Betsy Layton, Bruce Beutler- Multidisciplinary
Mutations of the geneLpsselectively impede lipopolysaccharide (LPS) signal transduction in C3H/HeJ and C57BL/10ScCr mice, rendering them resistant to endotoxin yet highly susceptible to Gram-negative infection. The codominantLpsdallele of C3H/HeJ mice was shown to correspond to a missense mutation in the third exon of the Toll-like receptor-4 gene (Tlr4), predicted to replace proline with histidine at position 712 of the polypeptide chain. C57BL/10ScCr mice are homozygous for a null mutation ofTlr4. Thus, the mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane. Destructive mutations ofTlr4predispose to the development of Gram-negative sepsis, leaving most aspects of immune function intact.