Human Molecular Genetics Advance Access published online on April 4, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm070
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Characterization and investigation of single-nucleotide polymorphisms (SNPs) and a novel TLR2 mutation in the human TLR2 gene
1 Institute for Clinical Chemistry, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany 2 Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, 81675 Munich, Germany
* Correspondence to: Parviz Ahmad-Nejad, Institute for Clinical Chemistry, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany, Phone: 0049-621-383-2222, Fax: 0049-621-383-3819, Email: parviz.ahmad-nejad{at}ikc.ma.uni-heidelberg.de
Received January 24, 2007; Revised March 16, 2007; Accepted March 16, 2007
In the innate immune system TLR2 plays a central role for the response to a wide variety of microbial and endogenous danger signals. A considerable number of genetic polymorphisms within the human TLR2 gene have been reported in non-coding and coding sequences. Except for the Arg753Gln variant, however, their clinical relevance is unclear and assessment of the effects of amino acid substitutions on receptor function is lacking. In the present study we have characterized all known single nucleotide polymorphisms (SNPs) of TLR2 for their functional relevance in transiently transfected HEK293 cells subsequently exposed to a specific stimulus. Among the known non-synonymous SNPs in the TLR2 coding sequence, four SNPs (Thr411Ile, Tyr715stop, Tyr715Lys and Arg753Gln) were found to be functionally relevant in our experimental setting.
In addition, we identified a new mutation Arg447stop leading to a premature stop codon in the extracellular portion of the receptor TLR2-specific stimulation of whole blood from two heterozygote carriers of this mutation resulted in a reduced secretion of pro-inflammatory cytokines. Finally, we tested the prevalence of these functional genetic variants in 169 healthy individuals of Caucasian origin for the mutations in extracellular domain and 106 individuals for the mutations in intracellular domain of the receptor. Except for 10 heterozygote donors of the Arg753Gln variant determined to be prevalent in 9.4 % of the tested individuals, none of the other SNPs were found in this population.
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