NPHP-related polycystic kidney disease in man and mice

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Our recent demonstration, that mutations of orthologous genes result in cystic kidney disease in mice and man, gives now a unique opportunity to study pathogenesis and therapy. We have shown that recessive hypomorphic mutations of NPHP3 cause cystic kidney disease (adolescent nephronophthisis) in children and adults, whereas more severe NPHP3 mutations result in either lethal congenital disease (heterotaxia) and/or renal-hepaticpancreatic dysplasia syndrome. Likewise we demonstrated that orthologous mutations in mice result in similar renal phenotypes. We recapitulated these distinct renal disorders and generated three distinct mouse models with stable expression of phenotypes: i) hypomorphic Nphp3pcy/pcy mutant mice (adult onset); ii) Nphp3ko/ko deficient mice (congenital disease); iii) compound mutant Nphp3ko/pcy mice (early onset). In addition we have contributed to the understanding that NPHP proteins function as gatekeepers at the ciliary base. Now we will utilize our mouse models as well as patient material to decipher the specific function of NPHP proteins on the cellular level. For that purpose we will perform immuno- EM and high resolution IF to study the NPHP protein network at the ciliary gate and analyze the functional sequelae of NPHP mutations for the ultrastructure of the ciliary necklace as well as the y-connectors using transmission and freeze fracture EM. In addition we will analyze in mutant and control cilia to determine which ciliary proteins are affected by altered NPHP gate function in man and mice.