Characterisation of a novel Joubert Syndrome (JS) model: dissecting genotype/phenotype heterogeneity in human disease towards personalised medicine.

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Keywords:new treatment strategies; mechanisms of resilience, repair and regeneration, chronic diseaseAbstract:Cystic kidney disease accounts for 10% of the 40,000 UK patients requiring renal replacement therapy (dialysis and transplantation). Cystic kidney disease is part of a group of disorders referred to as the "ciliopathies" that cause various combinations of cystic kidney disease, retinal degeneration and brain abnormalities in patients. There are no current disease modifying treatments for these conditions. This project focuses on the ciliopathy Joubert Syndrome (JS), in which patients present with cerebellar aplasia, retinal degeneration (RD), and typically suffer early onset cystic kidney disease (nephronophthisis, NPHP). There is clinical and genetic heterogeneity amongst patients with JS which is unexplained.We have previously described a novel mouse model of JS (using a Cep290 gene trap) that more faithfully recapitulates the human condition than any other mouse and shows that abnormal Hedgehog (Hh) signalling underlies the onset of NPHP. Treatment of primary renal collecting duct cells from these mice with chemical agonists of the Hedgehog signalling pathway rescues the effects of the mutation, indicating that the effects of the mutation can be reversed and that the Hh signalling pathway may be manipulated for therapeutic purposes. In this project we will consider the contribution of mutations in different genes underlying JS by comparing 2 disease genes to identify the similarities/differences that lead to disease heterogeneity. We will use an established JS model (CEP290 gene), and a novel JS model (CEP164 gene) (causing a more severe form of JS). We aim to understand how mutations in different genes cause the same syndrome. In this way we will identify common features underlying "ciliopathies" in general that may be exploited to develop new, broad-range therapeutic interventions for a range of different syndromes of this type.