Molecular bases of congenital bladder disease: the urofacial syndome (UFS)

Lead Research Organisation: University of Manchester
Department Name: School of Biological Sciences

Abstract

In the UK, there are 3,000-5,000 people who were born with abnormal kidneys and/or bladders who have such severe kidney failure that they can only survive by having regular dialysis or kidney transplants.

The is increasing evidence that such individuals carry abnormalities of genes which normally help the bladder and kidney grow before birth. Finding the specific genetic causes of such disorders provides families with often long-sought answers to the question "why was our child born with kidney disease".

The urofacial syndrome is a specific disease in which urinary bladder muscle does not behave normally. The condition starts before birth and people with the disease suffer life-long urinary incontinence and have a high risk of developing kidney failure.

We were the first to describe changes in two genes responsible for this disease. Affected children inherit two copies of an altered gene, one from each parent, who themselves are healthy. We believe that the normal function of these genes is to help the growth of nerves into the bladder and that these nerves control the filling and emptying of the bladder.

In this project we will search for other genes which cause the the urofacial syndrome and related conditions. These include 'primary vesicoureteric reflux', the backwards movement of urine from bladder to kidney, a condition which affects around 1 in 100 of all babies.

To understand why these diseases happen, and what the genes do, we are studying models of the human condition. We will test novel treatments in these models with the aim of similar treatments being used in the future to treat people with bladder disease.

Technical Summary

The genetic bases of lower urinary tract (LUT), especially bladder, malformations are poorly defined. Moreover, current clinical interventions for congenital bladder disorders, such as surgery to refashion the renal tract and fetal termination, do not target the primary causes of disease.
The urofacial syndrome (UFS) is an autosomal recessive disease in which urinary bladder muscle functions abnormally. We were the first to describe mutations in two genes, HPSE2 (a heparanse inhibitor) and LRIG2 (an integral membrane protein), in a proportion of affected individuals. We have published preliminary data that these genes code for proteins located in nerves which invade developing bladders. UFS is a discrete clinical disorder but its LUT abnormalities, including bladder dyssynergia and vesicoureteric relfux of urine, overlap with features of Hinman-Allen syndrome, itself at the severe end of a spectrum of LUT disorders including primary VUR which affects 1% of infants and is often familial. We will use UFS as an exemplar to not only understand the pathogenesis of a specific LUT disease but also to derive insights into other LUT disorders. We will address the following related questions and hypotheses. 1. Is there a neurogenic basis for UFS, and what is its nature? 2. Can we generate animals to model the anatomical, physiological, molecular and cell biology features of UFS and can these models be used to test potential therapies such as heparanse inhibitors and growth factors? 3. Do other UFS genes exist and are UFS genes relevant to other LUT malformations? In a separate project, we plan to generate induced pluripotent stem cells from UFS patients and derive neural tissues from them. Thus, we will be well-positioned to apply functional insights from the current project to test similar therapies on human cells.

Planned Impact

The scope of our project gives it both basic scientific and clinical relevance. It brings together the clinical disciplines of nephrology, urology and genetics with the basic sciences of developmental biology and physiology. A particularly important and interesting aspect of this project is that it investigates the pathogenesis of disease of a visceral organ (i.e. the urinary bladder) starting from a human genomic perspective which then advances through molecular and cell biology and neural physiology with the goal of developing novel therapies which target the cause of a congenital disease.
Societal impact. The prevalence of end-stage renal disease in the UK associated with kidney and/or LUT malformations is 3,000-5,000. Discoveries about the genetics of kidney malformations are beginning to impact on clinical nephrology practice through mutation testing. By contrast, the genetic bases of LUT, especially bladder, malformations are poorly defined. A major immediate societal impact of further gene identification in UFS will be the ability to define carriers within affected families and so inform reproductive choices and facilitate preimplantation or prenatal diagnosis for this potentially devastating disorder. Making specific genetic diagnoses provides families with often long-sought answers to the question "why was our child born with kidney disease". Precise genetic diagnoses will also help to define cohorts of patients for long-term clinical outcome and intervention studies.
Public sector impact. Gene identification will permit early diagnosis and facilitate early interventions with the aims of preventing end-stage renal disease thus reducing the morbidity/mortality burden for patients and the financial burden for the National Health Service which provides renal replacement therapy. Current clinical interventions for congenital bladder disorders, such as surgery to refashion the renal tract and fetal termination, do not target the primary causes of disease. The current project aims to use animal models of UFS to test novel therapies (e.g. heparanse inhibitors and growth factors) to ameliorate biological aberrations in UFS. In a separate project, we plan to generate induced pluripotent stem cells from UFS patients and derive neural tissues from them. Consequently, we will be well-positioned to apply the functional insights arising from the current project to test therapies on such human cells. These may then pave the way to human Phase I trials in the coming decade.
Third sector impact. Patient groups will be informed of results e.g. via Kidney Research UK (KRUK), of which Professor AS Woolf is a Trustee, and Kids Kidney Research (KKR), which has funded our renal genetic research in the past. Dr Emma Hilton has taken part in a Nowgen/Museum of Science/Industry collaboration and we envisage presenting our work at similar forums.
Academic impact. Data will be disseminated initially through local meetings (e.g. the Univeristy of Manchester Renal Biology Group and Nephrology, Physiology and Genetics laboratory meetings and seminars). More complete work will be presented at national and international genetics (e.g. European and American Societies of Human Genetics), nephrology (e.g. The Renal Association and American Society of Nephrology), physiology (e.g. The Physiological Society UK) and developmental biology (e.g. International Xenopus Conference) meetings. Definitive data will be submitted to, and published in, high-impact journals in these disciplines, as we have done before (e.g. Nature Genetics, Am J Hum Genet, J Am Soc Nephrol, Development, Hum Mol Genetics, Am J Physiol and Mol Cell Neurosci). As detailed in the Case for Support, all the investigators are highly active in public engagement in science, and we will present findings in these forums which include: on site activities (e.g. at the Nowgen genetics centre), school seminars and museum displays and media activities.

Publications

10 25 50
 
Description Co authored the first UK Renal Research Strategy
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Newlife Annual Project grant round Molecular characterisation of bladder exstrophy and related disorders of the lower urinary tract
Amount £115,198 (GBP)
Organisation Newlife the Charity for Disabled Children 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2016 
End 02/2018
 
Description Newlife Foundation Towards novel therapies for a genetic congenital neuropathy affecting the urinary bladder
Amount £115,735 (GBP)
Organisation Newlife the Charity for Disabled Children 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2016 
End 01/2018
 
Description 26 November 2015 Bolton Boys School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Interactive lecture 'My research finding out why some people are born with abnormal kidneys'?
Year(s) Of Engagement Activity 2015
 
Description 27 February 2016 HNF1B Family Information Day Manchester 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Co0organised an took part in the second UK Renal Cysts and Diabetes Patient information day
Year(s) Of Engagement Activity 2016
 
Description Amercian Society of Nephrology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited lecture: Recent advances in understanding the genetic bases for vesicoureteric reflux. American Society of Nephrology, San Diego, USA, 2015
Year(s) Of Engagement Activity 2015
 
Description Are there genetic causes of urinary incontinence? European Society for Pediatric Nephrology, Antalya, Turkey. October 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Are there genetic causes of urinary incontinence? European Society for Pediatric Nephrology, Antalya, Turkey. October 2018
Year(s) Of Engagement Activity 2018
 
Description Association of Physicians of Great Britain and Ireland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Invited talk; Urofacial syndrome is a genetic congenital peripheral neuropathy. The Association of Physicians of Great Britain and Ireland, Cambridge, UK, 2014.
Year(s) Of Engagement Activity 2014
 
Description Bury Grammar school A level Research talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Research career talk
Year(s) Of Engagement Activity 2016
 
Description European Society for Paediatric Nephrology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited lecture: Genetics of bladder dysfunction disorders. 47th European Society for Paediatric Nephrology Annual Meeting Porto, Portugal, 2014.
Year(s) Of Engagement Activity 2014
 
Description House of Lords 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 19th January 2016
I helped represent the KRUK charity at the House of Lords to mark the launch of the charity's new report called Renal research: from a pioneering past to a positive future for kidney patients.
Year(s) Of Engagement Activity 2016
 
Description International Workshop on Developmental Nephrology 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited lecture: Molecular drivers of functional bladder innervation. International Workshop on Developmental Nephrology, Snowbird, USA, 2015
Year(s) Of Engagement Activity 2015
 
Description Keynote lecture The Renal Association 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Kidney and urinary tract malformations: from the clinic to understanding molecular mechanisms and envisioning novel therapies.
Year(s) Of Engagement Activity 2016
 
Description Kidney Research UK Regen Med day 4 Oct 2016 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Renal regenerative medicine think-tank.
Year(s) Of Engagement Activity 2016
 
Description LRIG Proteins and the Regulation of Growth Factor Signaling workshop 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited lecture: Heparanase 2 and LRIG2 in peripheral nerve development. LRIG Proteins and the Regulation of Growth Factor Signaling, Abisko, Sweden, 2014
Year(s) Of Engagement Activity 2014
 
Description LRIG2, mutated in urofacial syndrome, mediates functional maturation of autonomic bladder nerves in mice and humans Annual Meeting of the Association of Physicians of Great Britain & Ireland 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact LRIG2, mutated in urofacial syndrome, mediates functional maturation of autonomic bladder nerves in mice and humans Annual Meeting of the Association of Physicians of Great Britain & Ireland 2017
Year(s) Of Engagement Activity 2017
 
Description NephroTools 2nd 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited lecture: Novel perspectives on lower renal tract differentiation and disease. NephroTools 2nd
International Conference, Turin, UK. 2014.
Year(s) Of Engagement Activity 2014
 
Description Seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Understanding diseases of human collecting duct development. UCL Centre for Experimental Nephrology
Year(s) Of Engagement Activity 2020
 
Description Seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The genetics of collecting duct development. American Society of Nephrology, Denver (virtual annual conference), 2020.
Year(s) Of Engagement Activity 2020
 
Description Seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Art-Science project, with Genevieve Tester (Multifurious Artist) Making zeotropes to show how human kidneys grow and function.
Presentation at Nowgen Centre, Manchester
Year(s) Of Engagement Activity 2020
 
Description Seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact Scarisbrick Hall School lecture on Using human stem cells to make new kidneys and model genetic disease, part of the Global Classroom scheme that is the largest digital classroom in the world and is
supported by the WHO and UNICEF. https://www.theglobalclassroom.com/about-us/
September 2020.
Year(s) Of Engagement Activity 2020
 
Description Technion Institute lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited lecture: Congenital urinary bladder neuropathies: from the human genetic diseases to the biological mechanisms. Genetic Mechanisms of Human Diseases, Technion Institute, Haifa, Israel, 2014.
Year(s) Of Engagement Activity 2014
 
Description The genetics of human urinary bladder malformations. Continuing Education Programme in Nephrology Week, UCL Great Ormond Street Institute of Child Health, April 2019. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The genetics of human urinary bladder malformations. Continuing Education Programme in Nephrology Week, UCL Great Ormond Street Institute of Child Health, April 2019.
Year(s) Of Engagement Activity 2019
 
Description Uiversity of Pittsburgh 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited lecture; Urinary tract malformations: from human genomics, to molecular mechanisms to envisioning novel therapies. University of Pittsburgh, USA, 2015
Year(s) Of Engagement Activity 2015