Models, modifiers and novel treatments of Joubert syndrome

Lead Research Organisation: Newcastle University
Department Name: Institute of Genetic Medicine


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.

The term "ciliopathy" covers a broad spectrum of disorders and patients typically can show a wide range of symptoms. For example, a mutation within the same gene can cause different symptoms in different individual patients. Clearly this complicates efforts to understand the cause of the disease, make accurate diagnoses, and develop specific treatments.
The archetypal ciliopathy is known as Joubert Syndrome (JS) which is predominantly caused by mutations in the CEP290 gene. We have created a mouse model of JS that more closely resembles the human condition than any other and have identified a previously unrecognized abnormality in the kidney that responds positively to drug treatment when we test kidney cells that have been isolated from diseased kidneys.
Our proposal focuses on identifying the factors involved in the complex presentation of ciliopathies to answer the question of why patients carrying mutations in the same gene show different symptoms and if they require different treatments?
To do this, we will breed our JS mutant mice with a different strain of mouse to mimic the genetic complexity of humans (note laboratory mice are inbred, whilst humans are outbred) to give mice with a range of disease severity. In this relatively simple system, it will be possible to identify the factors that affect disease severity.
In addition to the specific benefits to the field of ciliopathies, this proposal will provide a demonstration of the potential of using mouse genetics to understand complex human diseases in general.
This project is likely to provide long-term benefit to patients with inherited ciliopathies as it brings forward in a tangible way the prospect of personalized medicine and individualized treatments for patients. Specifically, the findings of this research proposal will help to categorize and precisely diagnose specific forms of cliliopathy. In parallel, we will assess novel potential treatments tailored to these specific forms. The fact that we have already identified one drug that can restore normal function to JS kidney cells suggests that this next round of research will make a significant step towards a treatment to reduce the morbidity and mortality associated with ciliopathies and reduce the need for dialysis and transplantation in affected patients.

Technical Summary

We have created a Cep290 mutant mouse model of Joubert Syndrome (JS) that accurately recapitulates human JS, including the variability of phenotype dependent upon genetic background. Furthermore, we have demonstrated that Hh signalling is disrupted in developing renal collecting duct (CDC) cells in these mice and that treatment with a Hh agonist (purmorphamine) can restore normal collecting duct cell function in mutant primary cells ex vivo.
The aim of this proposal is to understand the complexity of JS with a view to identifying potential novel therapeutic targets and compounds. This will be achieved by:
The identification of genetic modifiers of the murine phenotype. C57BL/6 (severe) mice will be crossed with 129/Ola (mild) mutant mice to generate F2 mice that will be screened (Sequenom) to broadly identify loci associated with severity of cystic kidney disease. Affymetrix gene expression arrays will be used to compare kidneys from the parent strains and from a panel of F2 mutant mice to highlight potential modifier genes within these loci.
The identification of novel disease alleles mutated in JS patients. Synentic regions in JS patients having undergone whole exome sequending will be compared with the corresponding to the candidate loci identified in mice. This approach will also serve to validate candidate genes found in mice.
Functional assessment (loss/gain of function) of modifier genes in primary CDCs from JS mice and patients. The effects of loss-of-function (siRNA knockdown) and/or gain of function (lentiviral overexpression) will be evaluated in primary cells from our mouse model and ultimately in JS patient CDCs. The effects of these modifier genes will be assessed in terms of Hh agonist rescue.
This project will address the issue of phenotypic heterogeneity in JS and determine the effects of this heterogeneity upon drug efficacy.

Planned Impact

This project will have impact in the following areas:
Health and well -being of ciliopathy patients: An improvement of day to day health and increase quality of life of patients with ciliopathies is a future benefit of this study. We anticipate this project will hasten the identification of novel treatments to for ciliopathies and cystic kidney disease. We expect our work to become translational within 5 years of this study. The impact of avoiding/postponing renal replacement therapy from an early age are self evident, in terms of health improvement and the complications from dialysis and transplantation.
General reduction in healthcare consumption: Renal replacement therapy costs the NHS 30K per patient per year. Cystic kidney disease accounts for 10% of the 40,000 UK residents on renal replacement therapy. Novel therapies that delay the progression of this disease are likely to reduce healthcare consumption overall.
Researchers within the field of ciliopathies: Identification of novel molecular pathways and disease (modifying) genes in Joubert syndrome will allow insights into related ciliopathies. Following the end of the grant cycle and after publication in peer reviewed discovery journals we would make microarray data and resources (including murine tissue samples) available to the scientific community. The research is of important interest to Rare Diseases consortia in the UK as well as the European Renal Association committee for inherited cystic kidney diseases. We anticipate new collaborations to be formed on the strength of our data and the creation of such novel and unique resources. Our studies will inform the approach to many other ciliopathy diseases as we will elucidate the important mechanistic details involved. Staff working with us on this project will develop skills in personalized medicine which will be applicable to many avenues of basic science research and current and future NHS treatments.
Mouse geneticists and human geneticists: This project will exploit the use of mouse models to probe finer aspects of human disease heterogeneity.

MRC and Genome England 100K Genomes Project: This work will link potential treatments to genetic variants affecting severity of disease and generate a reference framework of genes involved in ciliopathies to help annotate the human 100K genomes project.


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Alkanderi S (2017) Lessons learned from a multidisciplinary renal genetics clinic. in QJM : monthly journal of the Association of Physicians

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Alkanderi S (2018) ARL3 Mutations Cause Joubert Syndrome by Disrupting Ciliary Protein Composition. in American journal of human genetics

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Edwards N (2017) A novel homozygous UMOD mutation reveals gene dosage effects on uromodulin processing and urinary excretion. in Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

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Enerbäck S (2018) Acidosis and Deafness in Patients with Recessive Mutations in FOXI1. in Journal of the American Society of Nephrology : JASN

Description Kidney Research Fellowship award
Amount £186,049 (GBP)
Organisation Kidney Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2017 
End 01/2020
Description NIHR
Amount £95,659 (GBP)
Funding ID PDB058 
Organisation Barts Health NHS Trust 
Department NIHR Biomedical Research Unit
Sector Academic/University
Country United Kingdom
Start 03/2018 
End 08/2019
Description Northern Counties Kidney Research Fund
Amount £58,000 (GBP)
Organisation Northern Counties Kidney Research Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2018 
End 03/2019
Description Northern Counties Kidney Research Fund Project
Amount £24,520 (GBP)
Organisation Northern Counties Kidney Research Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2017 
End 10/2018
Description Collaboration with Friedhelm Hildbrandt 
Organisation Boston Children's Hospital
Country United States 
Sector Hospitals 
PI Contribution Sharing of Whole Exome Sequencing Data
Collaborator Contribution Friedhelm Hildebrandt has shared hole exome data so we can investigate modifier alleles in Joubert syndrome
Impact Genome sequencing
Start Year 2017
Description Collaboration with molecular basis of disease and therapeutics 
Organisation University of Leeds
Country United Kingdom 
Sector Academic/University 
PI Contribution Working with Colin Johnson Leeds with pharmacological screens of cilia length modulators
Collaborator Contribution High throughput analysis of compound library screens. Sharing of cell lines (CRISPR generated CEP290 knock downs)
Impact Successful bid for MRC DiMEN PhD studentship
Start Year 2016
Description Genetics Matters Patient Engagement Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This was a patient/public information day held at the Centre for Life Newcsatle conference centre. There were a series of talks, including an expert patient talk and then a round table discussions relating to different themes. I hosted a table where renal genetics was showcased and discussed. 90 people attended the event. "We are pleased to announce we'll be hosting our popular Genetics Matters event again on the 24th of February 2018 as part of the international Rare Disease Day. Come meet the scientists, touch real specimens, chat about rare diseases and hear about the exciting state of the art research at Newcastle University.

"Genetics Matters" annual event serves to showcase genetic research and to give the patient and charity organisations a voice and a platform to interact with the members of general public. The theme of the Rare Disease Day in 2018 is "Research", recognising the state-of-the-art research into rare diseases in the UK and the crucial role that patients play in research by voicing their needs and instigating change.

This event is free to attend, however, the places are limited. To register, please provide your details below.

Come join us for an afternoon of chatting about science, and find out about state of the art research at Newcastle University"
Year(s) Of Engagement Activity 2018
Description PKD patient information day, Freeman Hospital, Newcastle 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Raising awareness of cystic kidney disease, especially genetic factors and research methodologies.
90 patients and their carers attended for a full day of interactive talks regarding polycystic kidney disease.
Year(s) Of Engagement Activity 2018
Description Parents of patients invited to the lab for a tour and discussion 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact More awareness of laboratory research
Year(s) Of Engagement Activity 2018
Description Patient / family conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Talking to patients and their carers/family members regarding the future possible treatments of JBTS. Many family members wishing to take part in research projects.
Year(s) Of Engagement Activity 2015