Identification and characterisation of a gene conferring susceptibility to Focal Segmental Glomerulosclerosis

Lead Research Organisation: University College London
Department Name: Medicine


Kidney disease is a serious and increasing health problem, especially in older people. Up to 20% of people with end-stage kidney failure have a particular pattern of kidney scarring called FSGS. This can occur spontaneously, or more commonly is due to the effects of other conditions, including diabetes, obesity, and high blood pressure. Recently scientists have begun to look at a number of families where the spontaneous form of FSGS appears to be inherited. By doing this they have discovered a number of different genes that are crucial to the normal functioning of the kidney. When they go wrong, the abnormal genes cause progressive kidney scarring and FSGS.
We have identified a family with an inherited pattern of kidney failure and FSGS. Preliminary analysis shows that the genetic problem is different from those that have already been discovered. I plan to find the gene responsible for the disease in this family. I will then investigate what the gene does normally, and what goes wrong to cause this pattern of kidney disease. We hope to learn more about the scarring process that is seen in common diseases, and ultimately find a way to prevent this condition from causing kidney failure.

Technical Summary

End-stage renal failure is a serious and increasingly prevalent health problem. Although kidney failure can be treated with dialysis or transplantation, these therapies are expensive and are associated with considerable morbidity and mortality. Unfortunately our understanding of the factors that lead to end-stage renal disease remains very limited. Our strategy is based on identifying genes that cause renal disease in families with multiple affected members. The discovery of number of genes that are crucial for the normal functioning of the kidney has set the precedent for this approach.

Focal segmental glomerulosclerosis (FSGS) is a histological appearance seen in chronic kidney disease, accounting for 20% of end-stage renal failure. FSGS can be primary, or secondary to a wide variety of systemic diseases. In some rare cases, primary FSGS follows a Mendelian pattern of inheritance. We have identified a family in which affected individuals exhibit microscopic haematuria, renal impairment and proteinuria. Renal biopsy shows FSGS and the pedigree contains 12 affected subjects. A preliminary linkage study, comprising 5 affected individuals, has excluded genes previously associated with FSGS or glomerlular basement membrane abnormalities. It identified a 39cM-linked region on chromosome 3 (LOD ~1.81)

This study aims to identify the gene responsible through:
1. Recruitment and screening of additional family members in order to refine the linkage interval and increase the LOD score.
2. Sequencing the exons and intron/exon boundaries from the best candidate gene in the region (NPHP3). We would then examine any sequence variation found for a functional effect.
3. Screening for submicroscopic chromosomal alterations using a custom-built array to look for deletion or duplication which would then provide further sequencing targets.
4. Immunohistochemistry for structural proteins, including laminin, fibronectin, and type 4 collagen.
5. Comparing gene expression of micro-dissected glomeruli with controls.

We will then characterise the molecular, cellular and structural abnormalities and assess other pedigrees with similar phenotypes. It is hoped this will yield insights into the pathogenesis of not only primary but also secondary FSGS.
Description NIHR clinical lecturer
Amount £46,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 03/2014 
End 02/2018
Description PhD extension fund
Amount £10,000 (GBP)
Funding ID A300 
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 09/2012 
End 02/2013
Title Cybrid rho zero cells 
Description Culture of mitochondrially depleted rho zero 143B cells for the creation of trans-mitochondrial cybrids 
Type Of Material Cell line 
Year Produced 2013 
Provided To Others? Yes  
Impact Oral presentation at ASN 2013 
Title Inherited Kidney Disease DNA 
Description DNA collected from a number of families where at least two members have inherited the same form of renal disease 
Type Of Material Biological samples 
Provided To Others? No  
Impact Ability to date the most probable origin of CFHR5 nephropathy in the Cypriot poulation. 
Description Professor Patrick Chinnery 
Organisation Newcastle University
Department Institute of Genetic Medicine
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Collection of primary fibroblasts for biobank
Collaborator Contribution Taught range of mitochondrial assays with use of reagents
Impact Pending
Start Year 2011
Description ASN 2014 poster 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presented poster to international delegates, which generated significant interest

Sharing of scientific methodology for improved daignostic accuracy
Year(s) Of Engagement Activity 2014
Description Poster presentation at RA/ERA-EDTA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Two poster presentations at an international meeting:
1. The real-world workload and health economic considerations of initiating a treatment for adult polycystic kidney disease
2. A novel COL4A1 frame-shift mutation and kidney disease without extra-renal involvement in a large Turkish Cypriot family.
Year(s) Of Engagement Activity 2015