The role and regulation of Hepatocyte Nuclear Factor-1 Beta in man

The major causes of kidney failure in children and young adults are problems in the development of the kidney resulting in it not working properly. Research by the Exeter team and other international groups has shown that the commonest cause (approximately 30%) of poor development of the kidney is a change in the Hepatocyte Nuclear Factor-1 Beta (HNF1B) gene. Development of other organs is also affected when HNF1B is changed, including the pancreas, which means many patients also develop diabetes.
This project will study a large group of patients with changes in the HNF1B gene to enable us to understand the role HNF1B plays in humans. Additional genetic studies will be undertaken to find which other genes regulate HNF1B and to find other genes that can cause kidney disease.
This work will help us to better understand kidney disease in patients with mutations in HNF1B, provide information about their long-term prognosis and will potentially lead to improvements in management of a condition which affects the kidney and other organs. The identification of new genes of importance to renal developmental disorders will improve our understanding of how kidney disease develops in man.

Aims and objectives:
1) To study phenotypic variation in patients with Hepatocyte Nuclear Factor-1 Beta (HNF1B) mutations, as well as develop biomarkers to aid diagnosis.
2) To extend genetic studies to define regulatory and non-coding HNF1B mutations.
3) To identify novel genes involved in renal development.

Methodology:
-Phenotypic variation in patients with HNF1B mutations will be studied. We will also assess 3 potential biomarkers (magnesium; urate; faecal elastase and pancreatic exocrine function) to distinguish HNF1B developmental kidney disease from other forms. The sensitivity and specificity will be determined by testing 100 patients with 100 age- and sex-matched controls.
-To explore the possibility of intronic, promoter and regulatory mutations of HNF1B, long-range PCR products will be generated from patients who are HNF1B negative but have a phenotype that is highly suggestive and undergo next generation sequencing.
-Exome sequencing will be used to identify novel causes of renal developmental disorders.

Important outcomes from this project should include:
-Improvements in diagnosis through integration of diagnostic clinical criteria with biomarkers.
-Advancements in genetic analysis following extended analysis of the regulatory regions of HNF1B.
-Development of novel genetic tests for developmental renal disease.

We feel the following groups will benefit from our research:

1) Patients
This project will provide more information about the long-term prognosis of patients with mutations in HNF1B and lead to improvements in their management. This should help to empower patients and ultimately improve their quality of life.
The data generated from this project can be used by patient-centred charities (such as Kidney Research UK, the British Kidney Patient Association and the UK Polycystic Kidney Disease Charity) to provide useful information to patients and their families, as well as tailor the support they provide for them. This will also help to increase awareness of the condition. In view of the multi-system nature of HNF1B mutations, several charities may find information from this project useful.

2) Clinicians and other healthcare workers
The detailed multi-system phenotyping and documentation of prognosis of patients with HNF1B mutations will benefit the clinicians caring for these patients on a day-to-day basis. As a number of different organs can be affected, including the kidney, pancreas, liver, genital tract and gut, our work is likely to impact on not only nephrologists (both adult and paediatric) but diabetologists, gastroenterologists, obstetricians/gynaecologists, geneticists and general practitioners too. We will also be assessing the specificity and sensitivity of clinical characteristics to determine the HNF1B phenotype so this will help healthcare workers determine which patients with developmental kidney disease would be appropriate to refer for genetic testing.

3) National policy-makers
In June 2009, the EU Council adopted the final recommendation for European action in the field of rare diseases. This required member states to improve the access of patients with rare diseases to high quality health care. The importance placed on this in the UK is reflected in the 2009 Annual Report of the Chief Medical Officer in the chapter "Rare is Common". The Renal Association and the British Association for Paediatric Nephrology have developed a strategy for patients with rare kidney diseases, which aims to improve standards of care and equality of access. A special aspect of the strategy is the integration of clinical care pathways, diagnostic services, disease registers, translational research and audit. Implementation of this strategy depends on three key developments, including development of 1) disease-specific working groups, 2) care pathways and 3) a UK Registry for Rare Kidney Diseases. The collection of informative clinical data is an essential first step to understanding any disease. A comprehensive UK Registry for rare kidney diseases (eponym Renal RaDaR) is being developed with MRC and Kidney Research UK funding and we will enter our HNF1B cohort's data into the RaDaR database.
This integrated strategy addresses the needs of both children and adults equally and should help to resolve some of the difficult issues of transition of adolescents. This is particularly relevant to patients with mutations and deletions in HNF1B as abnormalities are often present from childhood. It will help to advance the commissioning of services to patients through a better understanding of rare diseases, response to treatment and the impact on individuals and families.