title: Novel CARD15/NOD2 mutations in Finnish patients with Crohn's disease and their relation to phenotypic variation in vitro and in vivo.
abstract: BACKGROUND
  Three mutations (R702W, G908R, and 1007fs) of the CARD15/NOD2 gene associate with Crohn's disease (CD). Despite a strong linkage of CD to the inflammatory bowel disease (IBD) 1 region, only 16% of the Finnish CD patients carry 1 of these 3 mutations, pointing to the possibility of yet undetected founder mutations in the genetically isolated Finns. The aim of this study was to screen for CARD15 mutations in Finnish CD patients and to assess their functional consequences and relation to clinical phenotype.
  
  
  METHODS
  We performed CARD15 mutation screening in 240 CD probands. For functional studies, blood mononuclear cells were cultured alone or with muramyl dipeptide (MDP) and IL-8 levels were determined.
  
  
  RESULTS
  We identified 30 different variants, including 12 new ones. Allele frequencies for the R702W, G908R, and 1007fs mutations were 3.3%, 0.4%, and 4.8%, respectively. The 1007fs variant was the only 1 associated significantly with CD. Five novel variants (R38M, W355X, P727L, W907R, R1019X) were found in 5 patients. The biochemical nature of these new mutations, data obtained by cross-species comparisons, as well as low IL-8 production favors their pathogenic role. All 5 patients with novel mutations presented a complicated form of ileal or ileocolonic disease.
  
  
  CONCLUSIONS
  In conclusion, we identified 5 novel CARD15 mutations with an apparent pathophysiological role, but could not identify a putative Finnish founder mutation. It is still possible that regulatory mutations present in the flanking or intronic areas of the CARD15 gene contribute to the genetic susceptibility of CD. Homozygosity or compound heterozygosity for CARD15 gene mutations must be considered especially in complicated CD patients.
authors.affiliation: Research Program for Molecular Medicine, Biomedicum Helsinki, Finland.
authors.forename: Maarit
authors.initials: M
authors.lastname: Lappalainen
authors.forename: Paulina
authors.initials: P
authors.lastname: Paavola-Sakki
authors.forename: Leena
authors.initials: L
authors.lastname: Halme
authors.forename: Ulla
authors.initials: U
authors.lastname: Turunen
authors.forename: Martti
authors.initials: M
authors.lastname: Färkkilä
authors.forename: Heikki
authors.initials: H
authors.lastname: Repo
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kontula
mesh_terms: D016022:Case-Control Studies; D003424:Crohn Disease / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D005387:Finland / Q000453:epidemiology; D018703:Founder Effect; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010641:Phenotype; D044465:White People / Q000235:genetics*
chemical_list: D016209:Interleukin-8; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein