King, K.; Onnie, C.; Mirza, M.; Fisher, S.; Cuthbert, A.; Sanderson, S.; Forbes, A.; Mansfield, J.; Lewis, C.; Mathew, C.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA60
Academic Journal
Crohn's disease (CD), a subtype of inflammatory bowel disease (IBD), is a complex disorder, with both genetic and environmental aetiology. Three sequence variants in the CARD15 gene have recently been shown to be associated with susceptibility to CD. There is also evidence of an excess of rare CARD 15 variants in CD, but whether these are true disease susceptibility alleles (DSAs) is unknown. Clarification of the status of rare variants would facilitate a more accurate assessment of the extent of the contribution of CARD15 to Crohn's disease, and of the likely genetic model for the effect of CARD 15. In order to investigate the contribution of rare variants to CD we have selected 100 Crohn's patients who are heterozygous for one of the three associated DSAs (R702W, G908R, or 1007fs) for comprehensive mutation screening. The coding sequence of CARD15 was screened by denaturing HPLC for mutations to identify both common polymorphisms and rare variants. 21 patients had one or more additional rare CARD15 mutations, 10 of which were non-synonymous. One of these was a novel nonsense mutation that would produce a truncated protein (R896X), and four (R235C, S431L, A612T, R1019G) were amino acid substitutions that were predicted to alter the function of the protein. The finding that only a minority of patients who are heterozygous for common disease susceptibility alleles in CARD15 have a second mutation is consistent with the gene dosage model for CARD15 in Crohn's disease.


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