Unravelling clinical and biochemical aspects of CFHR5

I have recently discovered an inherited kidney disease called ‘CFHR5 nephropathy‘ among people with Cypriot ancestry living in London, and found that the disease is a common cause of kidney failure in Cyprus. The disease is caused by a change in the gene ‘CFHR5‘ which is thought to play a role in controlling a part of the immune system (the body‘s defences against infection) called complement. The aims of this project are to understand firstly the function of the CFHR5 gene in healthy people, secondly how this function is altered in people with CFHR5 nephropathy, and thirdly how the disease can best be treated. In addition, the project aims to find out what role CFHR5 plays in other common kidney diseases as it may be that CFHR5 offers a completely new type of treatment for them.
I will do this by studying the function of the gene in the laboratory and looking for other abnormalities in CFHR5 in people with unexplained kidney disease. I will also give the drug called eculizumab (currently in routine use for a different disease) to people with CFHR5 nephropathy to test whether it protects them from kidney failure.

Disordered regulation of complement contributes to a range of diseases including cardiovascular disease, age related macular degeneration and glomerulonephritis. During my MRC Clinical Research Training Fellowship I identified a novel monogenic disease, Complement Factor H-Related 5 (CFHR5) nephropathy, which causes complement dysregulation in the kidney. The disease is associated with a mutation in the CFHR5 gene (a homologue of CFH) and is a common cause of renal failure among Cypriots. As well as defining a clinical cohort with a unified disease pathophysiology, these findings implicate CFHR5 as an important regulator of complement. The mechanism by which the mutation causes disease is not understood.
CFHR5: structure and functional relationships
I will measure the affinity of CFHR5 proteins for other components of the complement system (including Factor I, C5 and C3) and initiate crystal structure determinations of the mutant and wild-type CFHR5 proteins. This will establish the major biochemical properties of CFHR5, using the mutant protein to highlight those properties with significance in CFHR5 nephropathy.
Frequency of CFHR5 nephropathy
I have identified over 100 patients with CFHR5 nephropathy in London and Cyprus, and will establish a registry of patients with this and other CFHR5 abnormalities to identify prognostic markers which correlate with outcomes. The high prevalence of CFHR5 nephropathy in Cypriots is unexplained. While this could result from genetic drift, enhanced complement activation may protect against an infectious organism present in Cyprus, selecting for the mutation. I will measure the ability of patient and control serum to opsonise microorganisms, using recombinant proteins to determine if any differences result from the CFHR5 mutation.
CFHR5 in other diseases
Complement deposition is common in glomerulonephritides, including mesangiocapillary glomerulonephritis, IgA nephropathy and lupus nephritis. I will develop an assay for circulating CFHR5 to determine its utility as a biomarker for glomerular inflammation in these diseases. In addition, I will administer the CFHR5 proteins to mice with experimentally induced glomerulonephritis to determine whether human CFHR5 can ameliorate renal injury.
Other CFHR5 mutations
I have collected DNA samples from patients and families with unexplained hereditary glomerulonephritis. I will use linkage exclusion mapping and molecular genetic techniques to determine whether other mutations in CFHR5 cause kidney disease among this population.
Treatment of CFHR5 nephropathy
I will set up an experimental study to test whether eculizumab (a clinically licensed monoclonal antibody against C5) influences the disease.