Investigating the genetic interaction between Pkhd1 and Pkd1

The lack of rapidly progressive murine models reflecting the classical infantile disease in ARPKD inhibits progress to understanding pathogenesis. The role that primary cilia play in PKD is also controversial. Here new mouse and rat models, generated by interbreeding appropriate ARPKD and ADPKD strains are characterized; better reflecting the severe human disease. Analysis of mRNA expression in the individual ARPKD and ADPKD models, and the combined mice highlighted different disrupted pathways but with a commonality of dysregulated mechanisms associated with primary cilia. These models will help understand ARPKD and improve preclinical testing for this disease. The study also, in unbiased way, reinforces that cilia are important for pathogenesis in both disorders. Methods: Transcriptome profiles from whole kidney tissue extracted from post-natal day 0, 3 and 12 aged mice extracted from single homozygous (Pkhd1-/- and Pkd1RC/RC), digenic (Pkhd1-/-;Pkd1RC/RC) and WT controls were generated, in triplicate, using Illumina HiSeq4000 platform. The sequence reads that passed quality filters were processed through Mayo Clinic's MAP-RSeq (v2.1.0) pipeline using TopHat2 with the bowtie option. Gene set enrichment analysis was performed to reveal common biological processes between mutant datasets compared to WT controls.