Cutting edge: Functional characterization of the effect of the C3H/HeJ defect in mice that lack an Lps(n) gene: In vivo evidence for a dominant negative mutation

A point mutation in the Tlr4 gene, which encodes Toll-like receptor 4, has recently been proposed to underlie LPS hyporesponsiveness in C3H/HeJ mice ( Lps(d)), The data presented herein demonstrate that F-1 progeny from crosse s between mice that carry a similar to 9-cM deletion of chromosome 4 (inclu ding deletion of Lps(Tlr4)) and C3H/HeJ mice (i.e., Lps(0) x Lps(d) F-1 mic e) exhibit a pattern of LPS sensitivity, measured by TNF activity, that is indistinguishable from that exhibited by Lps(n) x Lps(d) F-1 progeny and wh ose average response is "intermediate" to parental responses. Thus, these d ata provide clear functional support for the hypothesis that the C3H/HeJ de fect exerts a dominant negative effect on LPS sensitivity; however, express ion of a normal Toll-like receptor 4 molecule is apparently not required.