Characterisation of a novel Joubert Syndrome (JS) model: dissecting genotype/phenotype heterogeneity in human disease towards personalised medicine.
Lead Research Organisation:
Newcastle University
Department Name: Institute of Human Genetics
Abstract
Keywords:new treatment strategies; mechanisms of resilience, repair and regeneration, chronic disease
Abstract:
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.
Abstract:
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.
Publications
Devlin LA
(2019)
Renal ciliopathies.
in Current opinion in genetics & development
Devlin LA
(2020)
Embryonic and foetal expression patterns of the ciliopathy gene CEP164.
in PloS one
Molinari E
(2019)
Targeted exon skipping rescues ciliary protein composition defects in Joubert syndrome patient fibroblasts.
in Scientific reports
Ramsbottom SA
(2018)
Targeted exon skipping of a CEP290 mutation rescues Joubert syndrome phenotypes in vitro and in a murine model.
in Proceedings of the National Academy of Sciences of the United States of America
Ramsbottom SA
(2020)
Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome.
in Proceedings of the National Academy of Sciences of the United States of America
Description | Flexible Funding Grant - Internship |
Amount | £3,350 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2019 |
End | 02/2020 |
Description | Flexible Funding Grant - MRC Course |
Amount | £850 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2018 |
End | 01/2018 |
Description | Colloboration on Barttin Paper |
Organisation | Harvard University |
Department | Harvard Medical School |
Country | United States |
Sector | Academic/University |
PI Contribution | The Sayer Team conceived the project, and carried out all of the murine studies and genetic analysis, as well as wrote the manuscript. |
Collaborator Contribution | F.Hildebrandt performed the human tissue studies and data analysis for the project. They provided human kidney biopsy samples for use in histological studies. |
Impact | Publication - doi.org/10.1073/pnas.1912602117 |
Start Year | 2018 |
Description | Genetics Matters - Public Engagement Event |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Genetics Matters is a public engagement event held and arranged by the engagement committee of the Institute of Genetic Medicine, Newcastle University. Approx. 100 of the general public attended the event in both 2018 and 2019 (years which I participated and helped to organise). They experienced research activities that occur at the Institute. This enabled the general public, including patients, carers and their family or friends to understand the reasons behind the research that we complete, which in turn helps gain support for the research. |
Year(s) Of Engagement Activity | 2018,2019 |
URL | https://blogs.ncl.ac.uk/igmengagement/genetics-matters-presentations/ |
Description | Lab Visits - Sixth Formers |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Sixth formers visited the lab for a couple of days to observe research activities. This sparked discussion about education in different scientific subject areas, but also career options in science and research. |
Year(s) Of Engagement Activity | 2018,2019 |
Description | North East Postgraduate Conference (NEPG) Organising Committee |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | North East Postgraduate Conference is a conference organised by postgraduate students of Newcastle University, providing a platform for medical/biological/life science postgraduate students to disseminate their research to peers. Workshops are also provided to students, such as mindfulness, stress relief during studies, IMPACT during research, career panel, engagement, and sustainability. There were also talks from keynote speakers such as Prof Doug Turnball and Dr Zoe Williams. Those that have attended the conference have been able to network and share ideas in different subject areas. They also have gained skills, such as how to create more IMPACT within their research and how to use mindfulness and stress-relief techniques in order to increase effective productivity. Working on the organisation panel of the NEPG conference has also helped me develop numerous skills, including finance and budgeting, engagement, scientific communication, leadership and management. |
Year(s) Of Engagement Activity | 2019 |
URL | https://ne-pg.co.uk |
Description | Patient/Patients Family Visits |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Visits to our lab and facilities by patients or their carers. This so they can understand the work that we are doing, ultimately towards helping get better diagnosis/prognosis or treatment for the disease that they/family/patients have. It also means that patients get to see first hand what their DNA/urine is used for (if they donate), and how this is directly contributing to the research and research outcomes. Discussions with the patients/carers also helps us as researchers to really understand the motivation behind our research. This means that we can still get precious urine/DNA samples which allows us to continue with research. Note: Appropriate ethical approval is gained for collection of patient samples. |
Year(s) Of Engagement Activity | 2017,2018,2019 |
Description | Research Publication Engagement |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Press coverage based upon our publications. 1) Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome https://www.pnas.org/content/pnas/117/2/1113.full.pdf - Newcastle University Press Release. Article in the Newcastle Chronicle. Press coverage on BBC Look North News. https://www.chroniclelive.co.uk/news/north-east-news/siblings-who-developed-kidney-failure-17535415 2) Targeted exon skipping of a CEP290 mutation rescues Joubert syndrome phenotypes in vitro and in a murine model https://www.pnas.org/content/pnas/115/49/12489.full.pdf - Newcastle University Press Release. Article in the Newcastle Chronicle. https://www.ncl.ac.uk/press/articles/archive/2018/11/joubertsyndromekidneydisease/ https://www.chroniclelive.co.uk/news/health/newcastle-university-kidney-research-sayer-15431046 |
Year(s) Of Engagement Activity | 2016,2018,2020 |
Description | Research Publication Engagement |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Articles written for kidney research UK regarding the recent publications for the lab. https://kidneyresearchuk.org/2019/05/10/research-breakthrough-brings-new-hope-for-the-treatment-of-genetic-kidney-disease/ https://kidneyresearchuk.org/2020/01/16/treating-joubert-syndrome-paving-the-way-for-a-personalised-approach/ |
Year(s) Of Engagement Activity | 2019,2020 |
URL | https://kidneyresearchuk.org/2020/01/16/treating-joubert-syndrome-paving-the-way-for-a-personalised-... |
Description | Vist of KRUK to lab |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Supporters |
Results and Impact | Kidney Research UK visit to the lab, including those who volunteer for the charity. They were allowed to see what research we complete, how we do it, and why we do it. Lots of discussion was completed, which allowed those who volunteer, and those who work for the charity to gain a deeper understanding of the scientific background to our projects. They left with a understanding of why funding for research is soo important, and what the potential research outcomes are. |
Year(s) Of Engagement Activity | 2017 |