Jenkins, D; (2006) The genetics of human renal tract malformations. Doctoral thesis , UCL (University College London).

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Abstract

The identification of mechanisms by which congenital renal tract malformations arise is an important area of research given that these defects account for approximately half of all children who progress to end-stage renal failure. Understanding the genetic contribution to this pathogenesis is of particular value, facilitating the counselling of families with a history of disease, serving to highlight the critical window(s) during which the course of development is altered, and aiding in the identification of molecular pathways that might be amenable to therapy in the future. This thesis is focused on furthering our understanding of how non-syndromic renal tract malformations are genetically determined. It was hypothesised that human renal tract malformations may be caused by mutations of genes in the Uroplakin (UP) family and Sonic hedgehog (SHH), and that these genes are expressed at specific sites in tissues during normal human renal tract development. It was shown that UPIIIa, a gene expressed in early human development, is mutated in a subset of patients with severe bilateral renal adysplasia. However, no definitive evidence was found that UPII mutations cause renal tract malformations, although variants in this gene might be a rare predisposing factor. Furthermore, no support was found for SHH mutations in human persistent cloaca, although UPIIIa mutations are occasionally associated with this condition. The expression patterns of SHH signalling proteins in normal human renal tract development is consistent with a variety of signalling modes, namely epithelial-to-epithelium canonical signalling in the cloaca, epithelial-to- mesenchyme canonical signalling in the urogenital sinus and epithelial-to-epithelium non-canonical signalling in kidney medullary collecting ducts. The discovery of mutations in children with renal tract malformations will provide families with long-sought explanations regarding the pathogenesis of disease and may also have implications for genetic counselling. The proposed studies will also shed light on the cell biology of normal human renal tract development.

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