A coding mutation within the first exon of the human MD-2 gene results in decreased lipopolysaccharide-induced signaling

Genes Immun. 2004 Jun;5(4):283-8. doi: 10.1038/sj.gene.6364068.


MD-2 is an accessory protein of the Toll-like receptor (TLR)-4, necessary for assembling a receptor complex to sense low quantities of lipopolysaccharide in order to subsequently trigger innate immune responses. MD-2 and TLR-4 are expressed on a variety of immunocompetent cells. Mutations within the TLR-4 gene have been shown to attenuate immune responses against lipopolysaccharide in mice. In humans, a TLR-4 polymorphism has been associated with a higher risk for developing severe Gram-negative sepsis and with a lower risk for atherosclerosis. Since MD-2 is an essential part of the lipopolysaccharide receptor complex, we screened 20 patients that underwent surgical cancer therapy for novel MD-2 mutations by a single-strand conformation polymorphism technique. In one patient we found an A --> G substitution at position 103, resulting in an amino-acid exchange from Thr 35 to Ala. Reporter gene assays revealed that this mutation resulted in a reduced lipopolysaccharide-induced signaling. The patient displayed an uneventful postoperative course, with the exception of slightly decreased TNF-alpha levels after in vitro stimulation with LPS as compared to wt patients. Genotyping of a further 41 patients by a newly developed Lightcycler/FRET method failed to detect any additional polymorphism carriers, indicating that this is a rare mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / genetics
  • Antigens, Surface / genetics*
  • Antigens, Surface / metabolism
  • Humans
  • Lipopolysaccharides / immunology*
  • Lipopolysaccharides / metabolism
  • Lymphocyte Antigen 96
  • Membrane Glycoproteins / metabolism
  • Mutation*
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Receptors, Cell Surface / metabolism
  • Signal Transduction / immunology*
  • Temperature
  • Threonine / genetics
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism


  • Antigens, Surface
  • LY96 protein, human
  • Lipopolysaccharides
  • Lymphocyte Antigen 96
  • Membrane Glycoproteins
  • NF-kappa B
  • Receptors, Cell Surface
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • Threonine
  • Alanine