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

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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 region of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies1,2,3,4,5,6, but the specific gene(s) has not been identified. NOD2, a gene that encodes a protein 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 using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. Wild-type NOD2 activates nuclear factor NF-κB, making it responsive to bacterial lipopolysaccharides; however, this induction was deficient in mutant NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease.

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Figure 1: Identification of a frameshift NOD2 mutation in affected individuals from CD families.
Figure 2: Determination of transmission of the 3020insC mutation in a CD family by allele-specific PCR.
Figure 3: Differential responsiveness of wild-type and mutant NOD2 to LPS.


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We thank the patients and their families that participated in this study. We acknowledge the contributions of J. B. Kirsner and M. Boyer. We thank T. Ross. P. Lucas and L. McAllister-Lucas for critically reading the manuscript; and A. Moran and M. Apicella for LPS samples. The work was supported by grants from the NIH (G.N. and J.H.C.), the Crohn's and Colitis Foundation of American (J.H.C.), the Reva and David Logan Foundation (J.H.C.) and the Gastrointestinal Research Foundation (J.H.C). Y.O. was supported by funds from Tokushima University, Japan. G.N. and J.H.C. contributed equally to this work and share senior authorship.

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Correspondence to Gabriel Nuñez.

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