Genetic investigation of kidney disease.
Doctoral thesis, UCL (University College London).
Kidney disease is an important contributor to the burden of ill-health worldwide. Genetic factors have an important role in determining which people are affected by kidney disease, and this study aimed to identify the genes responsible for disease in families in which unusual kidney diseases were transmitted in a pattern suggesting autosomal dominant inheritance. I performed genome-wide single nucleotide polymorphism-based linkage studies and identified two new human disease genes. Hypoxia Inducible Factor-2α (HIF2α) is a widely expressed transcription factor which is rapidly broken down in the presence of oxygen. When oxygenation is reduced it activates the transcription of many genes, including erythropoietin which stimulates red blood cell production. I identified a heterozygous activating mutation of HIF2α which cosegregated with autosomal dominantly inherited erythrocytosis and pulmonary arterial hypertension in a British family, producing a phenotype similar to the effects of high altitude exposure. In vitro studies demonstrated that the mutant protein has increased transcriptional activity under normoxia. This suggests that HIF2α plays an important role in regulating the organism-wide responses to oxygen availability. Complement Factor H Related protein 5 (CFHR5) is a homologue of the complement regulating protein Complement Factor H and is of incompletely understood function. I uncovered an in-frame heterozygous duplication of exons 2 and 3 of the CFHR5 gene which cosegregated with autosomal dominantly inherited microscopic and synpharyngitic macroscopic haematuria, glomerulonephritis and renal failure in 2 families with ancestry in the Troodos Mountains of Cyprus. The mutation results in the production of a protein with impaired affinity for complement deposited in the kidney. This disease, which I named CFHR5 nephropathy, is endemic in Cyprus, accounting for a significant proportion of renal disease on the island, and may be amenable to systemic treatments. These findings implicate CFHR5 as a new and important regulator of complement in the human kidney.
|Title:||Genetic investigation of kidney disease|
|Open access status:||An open access version is available from UCL Discovery|
|Additional information:||Associated with patent record http://discovery.ucl.ac.uk/1300522|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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