Allison Cox and Katie Weihbrecht will Present their Research on Thursday, 6/25/15
Whole Exome Analysis of Individuals and Families with CRMO
For my primary research project, I am working to determine the genes and pathways involved in the development of chronic recurrent multifocal osteomyelitis (CRMO), a rare autoinflammatory bone disease presenting in infancy and childhood. We currently have whole exome sequence data from 35 individuals with CRMO. For six of the isolated cases, we have data for one or two relatives with inflammatory disease, and for three pairs of sisters and three individuals with CRMO, we have exome data for both unaffected parents, for a total of 53 exomes. Nearly all of the probands have close relatives with psoriasis or Crohn’s disease. For all of the exome data, I have processed the data from fastq to vcf format using the Burrows-Wheeler Alignment (BWA) software, SAMtools, Picard, and the Genome Analysis Toolkit (GATK). Preliminary analysis of the data suggests that variants in genes involved in IL-17 and RANK signaling are enriched in our CRMO cohort, and I am currently working on developing and analyzing a control dataset for comparison using the publicly available 1000 genomes, EVS and ExAC databases. Additionally, our laboratory will send an additional 26 samples for exome sequencing this summer – the samples are 6 individuals with CRMO and their unaffected siblings and parents. I am also performing an experiment this summer to determine the effect of a putative enhancer mutation in the first intron of a candidate gene. The variant is enriched in our CRMO cohort and likely disrupts an NR4A2 binding site.
Characterization of the NPHP10/AIMP2 interaction
Nephronophthisis (NPHP) is a recessive kidney disorder that is the leading cause of early onset, end-stage renal failure. Many proteins mutated in cystic kidney disease have been shown to localize to the primary cilia and centrosomes, providing a coalescing mechanism for NPHP-related ciliopathies (NPHP-RC). Aside from renal failure and kidney cysts, retinal degeneration and dysplasia or degeneration of the cerebellum are also seen in many NPHP-RCs. SDCCAG8 is a nephronophthisis gene (NPHP10), with patients exhibiting retinal and renal abnormalities, obesity, and learning disabilities. Mutations in SDCCAG8 were also found in several BBS patients, making SDCCAG8 the 16th BBS gene (BBS16). However, little is known about the molecular functions of NPHP10 and how loss of NPHP10 function leads to the observed phenotypes. Our research has shown that NPHP10 interacts with components of the multi-aminoacyl tRNA synthetase complex (MSC), including 8 out of 9 aminoacyl tRNA synthetases (ARS) as well as aminoacyl-tRNA-synthetase-complex interacting multifunctional protein 2 (AIMP2). Further work determined that a direct interaction likely occurs between NPHP10 and AIMP2. Our current work focuses on determining the biological significance of this interaction.