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

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Item Type:	Article
Title:	A coding mutation within the first exon of the human MD-2 gene results in decreased lipopolysaccharide-induced signaling
Creators Name:	Hamann, L., Kumpf, O., Mueller, M., Visintin, A., Eckert, J., Schlag, P.M. and Schumann, R.R.
Abstract:	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 right arrow 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.
Keywords:	MD-2, TLR-4, Inflammation, LPS, Polymorphism
Source:	Genes and Immunity
ISSN:	1466-4879
Publisher:	Nature Publishing Group
Volume:	5
Number:	4
Page Range:	283-288
Date:	1 June 2004
Official Publication:	https://doi.org/10.1038/sj.gene.6364068
PubMed:	View item in PubMed

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