International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 215 - CPG1, A NOVEL DOMINANT MUTATION IN THE TLR9 LOCUS, CONFERS UNRESPONSIVENESS TO UNMETHYLATED DINUCLEOTIDE

Tabeta K
The Scripps Research Institute

Co-Authors: Du X, Hoebe K, Goode J, Mudd S, Sovath S, Beutler B
Institutions: The Scripps Research Institute

In an effort to identify new innate immune phenotypes, we have pursued a program of germline saturation mutagenesis with N-ethyl-N-nitrosourea (ENU) in mice. The germline mutants are produced on the C57BL/6 background, and peritoneal macrophages from individual animals are screened for their competence to respond to various inducing agents. A single strong phenodeviant was isolated as a non-responder to oligodeoxynucleotides with unmethylated CpG dinucleotides motifs, and called CpG1. The phenotype is transmissible in a dominant manner, and fully penetrant on C57BL/6 background, and was mapped to mouse chromosome 9 using a panel of microsatellite markers. An isolated T→C transition was detected in the TLR9 coding region of an affected animal, which resulted in amino acid substitution of Pro for Leu at residue 499 of the polypeptide chain. As TLR9 is the CpG receptor, and is encoded by a gene within the chromosomal interval concerned, we concluded that the mutation is responsible for the resistance to CpG stimulation found in CpG1. CpG1 provides an excellent model with which to study CpG oligodeoxynucleotide sensing by the mammalian immune system, and to determine what type of immunity (e.g., defense against viruses, bacteria, fungi, or parasites) depends upon CpG sensing. Moreover, the point mutation that we have identified may shed light upon the structural requirements for CpG sensing, which are presently unknown. The codominant character of the mutation differs from that of the knockout, which is recessive.


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