Connor, TMF; (2013) A study of inherited kidney disease. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Kidney disease is a common, expensive, and growing worldwide health problem. Genetic factors play an important role in the aetiology of kidney disease. Current research suggests that these genetic factors are predominantly rare variants with large phenotypic effects. In this thesis I have used a range of genetic techniques to identify rare variants in different families with kidney disease, and to study how they might cause disease. The Turkish-Cypriot population of Northern Cyprus has a high incidence of renal disease, much of which is undiagnosed and may be inherited. I collected DNA from the entire population on renal replacement therapy and identified three individuals with the G871C mutation in COL4A3. I used conflicting homozygosity analysis to demonstrate a minimal shared haplotype, thus dating this mutation to 17 generations ago. I used linkage analysis and whole genome sequencing in a large Greek-Cypriot kindred to identify 3 novel non-synonymous variants associated with kidney disease. Expression of these variants was examined in cultured primary urothelial cells from this family. I have studied another large pedigree with maternal transmission of renal disease. Sequencing of the mitochondrial genome demonstrated the presence of a novel polymorphism in the heavy strand promoter region at homoplastic levels. Mitochondrial function in primary dermal fibroblasts demonstrated a significant reduction in baseline oxidative respiration with a compensatory increase in glycolysis. Lastly, I have studied a novel compound heterozygous mutation in VHL. This variant showed abnormal degradation of HIF without activation of HIF target genes in patient-derived B-cells. It is possible that these cells are able to employ some kind of VHL-independent HIF regulatory mechanism. These studies demonstrate, in differing ways, the challenges of linking phenotype to genotype. Understanding the pathological and therapeutic importance of genetic information will become increasingly important to our management of kidney disease in this post-genomic era.

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