A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease

Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to result from the effect of environmental factors in a genetically predisposed host. A gene location in the pericentromeric r egion of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies(1-6), but th e specific gene(s) has not been identified. NOD2, a gene that encodes a pro tein with homology to plant disease resistance gene products is located in the peak region of linkage on chromosome 16 (ref. 7). Here we show, by usin g the transmission disequilibium test and case-control analysis, that a fra meshift mutation caused by a cytosine insertion, 3020insC, which is expecte d to encode a truncated NOD2 protein, is associated with Crohn's disease. W ild-type NOD2 activates nuclear factor NF-kappaB, making it responsive to b acterial lipopolysaccharides; however, this induction was deficient in muta nt NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial componen ts and development of disease.