PMID- 9851930 OWN - NLM STAT- MEDLINE DA - 19981224 DCOM- 19981224 LR - 20070319 IS - 0036-8075 (Print) IS - 0036-8075 (Linking) VI - 282 IP - 5396 DP - 1998 Dec 11 TI - Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. PG - 2085-8 AB - 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 codominant Lpsd 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. FAU - Poltorak, A AU - Poltorak A AD - Howard Hughes Medical Institute and the Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75235-9050, USA. FAU - He, X AU - He X FAU - Smirnova, I AU - Smirnova I FAU - Liu, M Y AU - Liu MY FAU - Van Huffel, C AU - Van Huffel C FAU - Du, X AU - Du X FAU - Birdwell, D AU - Birdwell D FAU - Alejos, E AU - Alejos E FAU - Silva, M AU - Silva M FAU - Galanos, C AU - Galanos C FAU - Freudenberg, M AU - Freudenberg M FAU - Ricciardi-Castagnoli, P AU - Ricciardi-Castagnoli P FAU - Layton, B AU - Layton B FAU - Beutler, B AU - Beutler B LA - eng SI - GENBANK/AF095353 PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - UNITED STATES TA - Science JT - Science (New York, N.Y.) JID - 0404511 RN - 0 (Drosophila Proteins) RN - 0 (Lipopolysaccharides) RN - 0 (Membrane Glycoproteins) RN - 0 (RNA, Messenger) RN - 0 (Receptors, Cell Surface) RN - 0 (Toll-Like Receptor 4) RN - 0 (Toll-Like Receptors) SB - IM MH - Amino Acid Sequence MH - Animals MH - Chromosome Mapping MH - Cloning, Molecular MH - *Drosophila Proteins MH - Genes, Dominant MH - Gram-Negative Bacterial Infections/immunology MH - Homozygote MH - Lipopolysaccharides/*metabolism/pharmacology MH - Macrophages/metabolism MH - Membrane Glycoproteins/chemistry/*genetics/metabolism MH - Mice MH - Mice, Inbred C3H MH - Mice, Inbred C57BL MH - Molecular Sequence Data MH - Mutation, Missense MH - Point Mutation MH - RNA, Messenger/genetics/metabolism MH - Receptors, Cell Surface/chemistry/*genetics/metabolism MH - *Signal Transduction MH - Toll-Like Receptor 4 MH - Toll-Like Receptors EDAT- 1998/12/16 MHDA- 1998/12/16 00:01 CRDT- 1998/12/16 00:00 PST - ppublish SO - Science. 1998 Dec 11;282(5396):2085-8.