Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 100, Issue 6, Pages 3455-3460Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0530276100
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CARD15 is a major susceptibility gene for a frequent multifactorial chronic inflammatory bowel disorder, Crohn disease (CD). By using NF-kappaB activation assays, the cytosolic CARD15 was shown to efficiently detect bacterial peptidoglycan (PGN), reminiscent of the PGN recognition protein surveillance mechanism in Drosophila. The 3 CID-associated variants and 13 additional variants carried by CID patients demonstrated impaired PGN-dependent response revealing null, hypomorphic, or dominant-negative properties. Quantitative parametrization of this response, computed from the patients' CARD15 genotypes, was predictive of several variable CID manifestations. In contrast, CARD15 alleles associated with Blau's syndrome promoted PGN-independent NF-kappaB activation, an observation that accounts for the minimal microbial input in the etiology of this dominant, monogenic inflammatory disorder affecting solely aseptic sites.
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