Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene

Science. 1998 Dec 11;282(5396):2085-8. doi: 10.1126/science.282.5396.2085.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Chromosome Mapping
  • Cloning, Molecular
  • Drosophila Proteins*
  • Genes, Dominant
  • Gram-Negative Bacterial Infections / immunology
  • Homozygote
  • Lipopolysaccharides / metabolism*
  • Lipopolysaccharides / pharmacology
  • Macrophages / metabolism
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Mutation, Missense
  • Point Mutation
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism
  • Signal Transduction*
  • Toll-Like Receptor 4
  • Toll-Like Receptors

Substances

  • Drosophila Proteins
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • RNA, Messenger
  • Receptors, Cell Surface
  • Toll-Like Receptor 4
  • Toll-Like Receptors

Associated data

  • GENBANK/AF095353