Familial erythrocytosis and altered oxygen sensing - a genetic and clinical investigation.

Lead Research Organisation: University College London
Department Name: Unlisted

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

Central to the cellular response to hypoxia is the von Hippel-Lindau (VHL) - hypoxia-inducible factor (HIF) pathway. Studies of patients with inherited abnormalities of this pathway (eg Von Hippel Lindau disease and Chuvash polycythaemia) have given insights into the role that these proteins play in oxygen sensing and the cellular response to hypoxia.

Physiological studies of patients with Chuvash polycythaemia have demonstrated highly abnormal cardiopulmonary physiology with abnormally elevated basal pulmonary vascular tone and an exaggerated response to hypoxia. The VHL-HIF system has been implicated in hypoxia regulation in many different tissues and it may be that a deeper understanding of this system would open avenues of treatment for conditions as diverse as cancer, acute tubular necrosis, pulmonary hypertension and the anaemia of renal failure.

A family has been identified in which raised erythropoietin levels have been found in association with polycythaemia, implicating an abnormality in an upstream regulator of erythropoietin expression. The index case has subsequently developed clinically significant pulmonary hypertension and the pedigree contains 7 informative meioses. Investigations have not demonstrated a functionally significant mutation in VHL or PHD 2 (the only two genes known to be associated with hereditary erythrocytosis and elevated erythropoietin levels). It seems likely that a novel mutation in one of the components of the VHL-HIF system is responsible.

The aim of this proposal is to determine which gene is responsible and characterise the genetic, molecular, cellular, haematological and cardiopulmonary abnormalities in order to provide further insights into the oxygen sensing system, and particularly to understand why these patients do not have a predisposition to cancer.

In order to investigate this, the following investigations will be performed:
1. Identify the gene responsible and investigate mechanism of action of the altered protein.
2. Characterise the clinical phenotype of these patients with echocardiography, abdominal ultrasound imaging and measurement of circulating proteins (including VEGF, ferritin and urinary hepcidin) which may be affected by altered HIF activity.
3. Perform cell based assays to determine how peripheral blood lymphocytes from these patients respond to different oxygen tensions.
4. Investigate cardiopulmonary physiology in this pedigree and compare it to Chuvash patients and controls.
5. Investigate iron handling and erythropoiesis in PHD knockout mice.

Publications

10 25 50

publication icon
Athanasiou Y (2011) Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees. in Clinical journal of the American Society of Nephrology : CJASN

publication icon
Busbridge M (2009) Development of a novel immunoassay for the iron regulatory peptide hepcidin. in British journal of biomedical science

publication icon
Feehally J (2010) HLA has strongest association with IgA nephropathy in genome-wide analysis. in Journal of the American Society of Nephrology : JASN

publication icon
Formenti F (2011) Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha gain-of-function mutation. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

publication icon
Gale DP (2010) The role of HIF in immunity. in The international journal of biochemistry & cell biology

 
Description GIKD Research Grant
Amount £125,000 (GBP)
Funding ID M260-CD1 
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2012 
End 08/2017
 
Description MCKD Research Grant
Amount £10,000 (GBP)
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2010 
End 01/2012
 
Description MRC Clinical Research Training Fellowship (2006)
Amount £250,000 (GBP)
Funding ID G0600420 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2006 
End 10/2009
 
Description MRC Clinician Scientist Award
Amount £1,022,548 (GBP)
Funding ID G1002528 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2012 
End 12/2015
 
Description Research Grant
Amount £25,000 (GBP)
Organisation St Peter's Trust for Kidney, Bladder and Prostate Research 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2009 
End 03/2011
 
Description Starter Grant for Clinical Lecturers
Amount £30,000 (GBP)
Organisation Academy of Medical Sciences (AMS) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2011 
End 08/2013
 
Description Genetics of IgA nephropathy 
Organisation Fudan University
Department Department of Nephrology
Country China 
Sector Academic/University 
PI Contribution SNP genotyping and statistical analysis.
Collaborator Contribution Assembly of DNA databank.
Impact Publication in seciton 1: PMID 20031928
Start Year 2007
 
Description Hepcidin in humans 
Organisation Imperial College Healthcare NHS Trust
Department Renal Medicine
Country United Kingdom 
Sector Hospitals 
PI Contribution Identification of patient groups to study; study design; sample collection; data analysis; writing paper
Collaborator Contribution Provided infrastructure for clinical studiesAssay development and validation necessary for clinical studies
Impact Publications reported in section 1: 19839227 19833632 19212416
Start Year 2008
 
Description Hepcidin in humans 
Organisation Imperial College London
Department Section of Endocrinology and Investigative Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Identification of patient groups to study; study design; sample collection; data analysis; writing paper
Collaborator Contribution Provided infrastructure for clinical studiesAssay development and validation necessary for clinical studies
Impact Publications reported in section 1: 19839227 19833632 19212416
Start Year 2008
 
Description Investigation of CFHR5 
Organisation University of Cyprus
Department Molecular Medicine Research Center
Country Cyprus 
Sector Academic/University 
PI Contribution Identification of a newly recognised genetic cause of renal failure which is endemic in Cyprus.
Collaborator Contribution Has allowed access to clinicians, patients and expertise from Cyprus for the study of CFHR5 nephropathy
Impact Helped secure further funding for the project.
Start Year 2010
 
Title Methods relating to a mutation in complement factor H-related 5 in patients with glomerulonephritis 
Description Mutation of the CFHR5 gene lead to complement activation in, and damage to, the kidney. The invention is a method to use changes in CFHR5 (either protein levels or protein sequence) to diagnose kidney disease or risk of kidney disease, and to use the CFHR5 protein (or part of it) as a way of treating kidney disease 
IP Reference WO2011004148 
Protection Patent application published
Year Protection Granted 2011
Licensed No
Impact Clinical screening for changes in CFHR5 are now standard care for some kidney diseases in which complement is activated in the kidney.
 
Title Genetic test for CFHR5 nephropathy 
Description The clinical genetic test for CFHR5 nephropathy is now in use in clinical genetic laboratories in the UK and Cyprus. Its invention and development was funded by and MRC research grant. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Small-scale adoption
Year Development Stage Completed 2010
Development Status Actively seeking support
Impact This test has provided a firm diagnosis for over 100 patients with otherwise unexplained kidney disease worldwide, obviating the need for kidney biopsy in some of these people.