Variant Characterization

image00To determine the role of a variant seen in our and others clinical sequencing, multiple tools are currently used within the lab including evolutionary analysis, protein modeling, structural biology, biochemical assays, cell culture of common cell lines, culturing of primary patient cell lines, animal models and CRISPR/Cas9 gene modification. Samples for combining these tools can be seen in lab publications for XIAP and SHROOM3. The variant in XIAP (C203Y) was found to be the causal variant in Nicholas Volker for his previously undefined form of inflammatory bowel disease. As shown below, this variant alters apoptosis and NF-kappaB NOD2 dependent signaling.

The SHROOM3 gene has been identified to contribute to renal disease through the Jacob Lab’s rat consomic mapping efforts and by human genome-wide association studies (GWAS). Using characterization work we have been able to identify the variant within the FHH rat strain that alters kidney function relative to the control BN rat through altered actin interaction. Additionally, we found a human protein coding variant (P1244L) that contributes to kidney disease through altered interaction with 14-3-3 proteins. Ongoing studies are further characterizing the human P1244L variant and also addressing the mechanisms of the non-coding GWAS block found in human SHROOM3 intron 1.