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

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.

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.