Characterizing the genetic interaction between the recessive and dominant form of PKD

Mayo Clinic Rochester, Rochester MN

Investigators

Abstract

? DESCRIPTION (provided by applicant): Autosomal recessive polycystic kidney disease (ARPKD) is the most common renal ciliopathy affecting children (incidence ~1:20,000). Classically, the disease presents in the neonatal period with massive enlargement of the kidneys, causing perinatal death in ~30% of those affected. Mutations at a single locus, PKHD1, are responsible for all typical forms of the disease. However, the function of the PKHD1 gene product, fibrocystin, and the pathogenesis of the disease remain unknown. Previous data have indicated a genetic interaction between the causative genes of ARPKD and autosomal dominant polycystic kidney disease (ADPKD), (PKD1 and PKD2); however, only preliminary data is available about interactions between these protein groups, and whether they regulate common cellular pathways or have autonomous cellular functions to maintain kidney homeostasis. A critical barrier to revealing the pathomolecular mechanism of ARPKD has been the lack of tools necessary to critically study the function of fibrocystin and the cellular pathways that are dysregulated due to pathogenic alleles. Here, we have used genetically modified mouse models to overcome these barriers to make known the pathomolecular mechanism of ARPKD. To achieve this objective, we will test our central hypothesis that PKHD1 is a genetic modifier of ADPKD through autonomous cellular mechanisms. To test our hypothesis, we will pursue three aims. In our first aim, we will determine the maturation, sub-cellular localization and protein interactors of fibrocystin to reveal protein function. In the second aim, we will characterize the genetic interaction between PKHD1 and PKD1. In the third aim, we will reveal the pathomolecular mechanism of this genetic interaction to reveal cellular pathways dysregulated due to the loss of PKHD1. The long-term goal of our research is to reveal functionality of fibrocystin to gain an understanding of the mechanism by which PKHD1 alleles cause ARPKD. The overall impact of this project will broaden our understanding of pathomolecular mechanisms of PKD, leading to the identification of new cellular pathways that are dysregulated and the identification of novel therapeutic targets.