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

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.

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.

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.