Characterisation of a novel Joubert Syndrome (JS) model to accelerate personalised medicine: from patient to a kidney-in-a-dish via iPS cells.

Providing a comprehensive training in human disease genetics, encompassing human disease modelling, bioinformatics and state-of-the-art cellular and molecular techniques, delivered by a multidisciplinary team at the forefront of ciliopathy research, this PhD project will fundamentally increase our understanding of ciliopathies, whilst providing training specifically tailored to the "genomic era". Newcastle is at the forefront of recent advances in genomic medicine, for example, delivering the first genetic diagnosis as part of the Genomics England 100,000 genomes project (http://www.genomicsengland.co.uk/first-patients-diagnosed-through-the-100000-genomes-project/).

The term ciliopathy covers a wide range of disorders characterised by various combinations of cystic kidney disease, retinal degeneration and brain abnormalities in patients, all arising from mutations affecting the primary cilium. Cystic kidney disease accounts for 10% of the 40,000 UK patients requiring dialysis/transplantation and there are currently no disease-modifying treatments for these conditions.

The archetypal ciliopathy is known as Joubert Syndrome (JS) which is predominantly caused by mutations in the CEP290 gene, discovered by Prof John Sayer (https://www.ncbi.nlm.nih.gov/pubmed/16682973). Prof Sayer and Dr Miles created a model of JS, carrying a Cep290 mutation analogous to that found in patients and demonstrated that this model faithfully recapitulates the human condition, more closely than any other model (https://www.ncbi.nlm.nih.gov/pubmed/24946806). Analysis of this model identified a previously unrecognized abnormality in the Hedgehog signalling pathway within the kidney. Treatment of kidney cells isolated from both the model, and more significantly, from JS patients with drugs that stimulate the Hedgehog signalling pathway restores normal function to these cells ex vivo. This indicates that diseased kidney cells from patients are not permanently disabled and that our model systems provide a means to identify potential treatments. (http://www.thejournal.co.uk/news/health/newcastle-university-scientists-made-first-7438749).

However, JS patients show a wide range of symptoms, such that i) mutations in one particular gene can cause any one of several different clinical phenotypes and ii) mutations in different genes can cause the same phenotype. Thus, knowing the mutation alone does not accurately predict the type of disease a patient will develop. This genotype/phenotype heterogeneity complicates efforts to understand the cause of the disease, make accurate diagnoses, and develop specific treatments.

In this project a novel model of JS will be characterised, based upon the Arl3 gene. Recently discovered in patients in our clinic, Arl3 mutations disrupt a different part of the primary cilium than Cep290, yet cause the same disease. By comparing the two models and cross-referencing with human genomic data, the mechanisms underlying heterogeneity amongst patients will be revealed. Understanding the genotype/phenotype heterogeneity of ciliopathies naturally leads to precision, personalised medicine approaches in terms of diagnosis, prognosis and tailoring specific treatments to specific, genetically defined, groups of patients.