Related Experiment Videos
[From gene to disease; 'frame shift'-mutation in the CARD15-gene and Crohn's disease]
K van der Linde1, E J Kuipers, F W M de Rooij
1Afd. Maag-, Darm- en Leverziekten, Erasmus Medisch Centrum-locatie Dijkzigt, Dr. Molewaterplein 40, 3015 GD Rotterdam. k.v.d.linde@znb.nl
Insights
Genetic variants in the CARD15 gene are strongly linked to Crohn's disease (CD). A specific mutation (3020insC) impairs the CARD15 protein's function, potentially explaining disease development.
Area of Science:
- Genetics
- Immunology
- Gastroenterology
Context:
- The IBD1 locus on chromosome 16 is associated with Crohn's disease (CD).
- Recent studies identified three genetic variants in the CARD15 gene within the IBD1 locus, showing a strong association with CD.
- One specific frameshift mutation, 3020insC, results in a truncated CARD15 protein.
Purpose:
- To investigate the association between CARD15 gene variants and Crohn's disease.
- To understand the functional consequences of the CARD15 3020insC mutation on protein activity and its role in CD pathogenesis.
Summary:
- The CARD15 gene, expressed in monocytes, plays a role in innate immunity.
- The leucine-rich repeat (LRR) domain of CARD15 is implicated in binding bacterial lipopolysaccharide and activating nuclear factor kappa-B (NF-κB).
- The 3020insC mutation leads to reduced NF-κB activity in response to lipopolysaccharide, suggesting a mechanism for altered inflammatory responses in CD patients carrying this mutation.
Impact:
- Approximately 11-19% of CD patients are heterozygous and 3-7% are homozygous for the 3020insC mutation.
- This research provides insights into the genetic basis of Crohn's disease and the functional role of CARD15.
- Further research is needed to clarify how the reduced lipopolysaccharide response contributes to the development of CD.
Abstract:
A pericentromeric region on chromosome 16 (IBD1 locus) has been linked with Crohn's disease (CD). Very recently, three genetic variants in the CARD15 gene within the IBD1 locus have been identified which were highly associated with CD. Carriage increases the relative risk of developing CD. One specific mutation (3020insC) leads to a stop codon and truncation of the C-terminal tandem leucine-rich repeats (LRR) of the CARD15 protein. Of all patients with Crohn's disease, 11-19% are heterozygous and 3-7% homozygous for this frameshift mutation. The CARD15 gene is expressed in monocytes. The LRR-domain is thought to be involved in the binding of bacterial lipopolysaccharide and subsequent activation of nuclear factor kappa-B (NF kappa B). NF kappa B plays a central role in the regulation of the expression of other genes involved in the inflammatory response. In vitro, embryonic kidney cells transfected with the CARD15 3020insC mutant showed a reduced activity of NF kappa B after exposure to lipopolysaccharide compared to cells transfected with the wild-type CARD15 gene. How the reduced response to lipopolysaccharide contributes to CD is not yet clear.