Crohn's disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan.
OBJECTIVE
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.
Bonen
Denise K
DK
Martin Boyer Laboratories, Gastroenterology Section, Department of Medicine, University of Chicago Hospitals, Chicago, Illinois, USA.
Ogura
Yasunori
Y
Nicolae
Dan L
DL
Inohara
Naohiro
N
Saab
Lisa
L
Tanabe
Tsuyoshi
T
Chen
Felicia F
FF
Foster
Simon J
SJ
Duerr
Richard H
RH
Brant
Steven R
SR
Cho
Judy H
JH
Nuñez
Gabriel
G
D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002460:Cell Line; D003424:Crohn Disease / Q000235:genetics* / Q000503:physiopathology*; D016368:Frameshift Mutation / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000502:physiology*; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007585:Jews; D008070:Lipopolysaccharides / Q000494:pharmacology*; D053473:Nod2 Signaling Adaptor Protein; D010457:Peptidoglycan / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D010457:Peptidoglycan