Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene
Abstract
Mutations of the gene Lps selectively 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 codominantLps d allele 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 of Tlr4. 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 of Tlr4 predispose to the development of Gram-negative sepsis, leaving most aspects of immune function intact.
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We acknowledge the assistance of J. Turner, A. Powelka, R. Jain, R. Clisch, and C. Brady, all summer undergraduate research fellows who worked with us to identify the Lpsd mutation. We are also grateful to the Beutler Family Charitable Trust for providing funds for the purchase of an ABI model 373 sequencer.
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Science
Volume 282 | Issue 5396
11 December 1998
11 December 1998
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Received: 30 September 1998
Accepted: 3 November 1998
Published in print: 11 December 1998
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