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CROHN'S DISEASE - ASSOCIATED NOD2 VARIANTS SHARE A SIGNALING DEFECT IN RESPONSE TO LIPOPOLYSACCHARIDE AND PEPTIDOGLYCAN

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  • Sarah Krein
    CROHN S DISEASE - ASSOCIATED NOD2 VARIANTS SHARE A SIGNALING DEFECT IN RESPONSE TO LIPOPOLYSACCHARIDE AND PEPTIDOOGLYCAN Background & Aims: The NOD2 variants
    Message 1 of 1 , Jan 4, 2003
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      CROHN'S DISEASE - ASSOCIATED NOD2 VARIANTS SHARE A SIGNALING DEFECT IN
      RESPONSE TO LIPOPOLYSACCHARIDE AND PEPTIDOOGLYCAN

      Background & Aims: The NOD2 variants R702W, G908R, and L1007fsinsC are
      strongly associated with Crohn's disease (CD) in both European and American
      populations, but whether this susceptibility extends to all ethnic groups
      remains unknown. Except for the L1007fsinsC mutation, which produces a
      truncated NOD2 protein, the functional activity of the major CD-associated
      variants G908R and R702W is unknown.

      Methods: Individuals were genotyped for R702W, G908R, and L1007fsinsC. The
      ability of G908R, R702W, and L1007fsinsC variants in the presence and
      absence of P268S to confer responsiveness to lipopolysaccharide (LPS) and
      peptidoglycan (PGN) was determined in HEK293T kidney cells.

      Results: G908R and L1007fsinsC, but not R702W, were associated with disease
      susceptibility in Ashkenazi Jews. Ashkenazi Jews with CD had significantly
      higher allele frequency carriage of G908R and lower carriage of R702W
      compared with non-Jewish whites with CD. Functional studies revealed that
      the G908R, R702W, and L1007fsinsC variants in the presence and absence of
      P268S are defective in their ability to respond to bacterial LPS and PGN,
      whereas P268S alone exhibited wild-type activity.

      Conclusions: R702W is not associated with susceptibility to CD in Ashkenazi Jews. The G908R, R702W, and L1007fsinsC variants share a common signaling defect in response to bacterial components, providing evidence for a unifying molecular mechanism whereby NOD2 mutations contribute to disease susceptibility.
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