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Title: Studies of genetic variants in monogenic renal tubular disorders
Author: Philpott, Charlotte Louise
ISNI:       0000 0004 8507 0445
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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The renal tubules are the functional unit of the kidneys, responsible for: reabsorption of many substances including ions, solutes and water; and the secretion of waste products. The molecular mechanisms underlying these processes are tightly regulated by transporters, channels and receptors, which have different expression profiles within the renal tubular segments and their disruption can lead to disorders, with local and systemic phenotypes. Thus, monogenic renal tubular disorders affecting different segments are excellent tools for the study of specific pathways and mechanisms vital to reabsorption and secretion processes; as well as for gaining an insight into the biological and molecular differences between renal tubular segments. This thesis used next generation DNA sequencing (NGS) and Sanger DNA sequencing methods to identify novel candidate genes, and hence to study the genetic and molecular mechanisms underlying three monogenic renal tubular disorders: Dent's disease (DD), familial juvenile hyperuricaemic nephropathy (FJHN) and familial hypocalciuric hypercalcaemia (FHH), each affecting different renal segments. For each of these disorders a large proportion of patients (25-55%) lack mutations in any of the known associated genes. However, one of the main issues with NGS remains accurate variant interpretation and therefore, the first aim was to investigate the effectiveness of in silico analysis tools to identify pathogenic variants and to determine the optimum parameters, which were then applied to the 'gene-discovery' studies. This thesis identified novel candidate genes for DD (CLCNKA), FJHN (CLDN3 and DENND4C) and FHH (KLOTHO) and revealed an approach for its potential successful application in the clinic for diagnosis.
Supervisor: Thakker, Rajesh ; Gorvin, Caroline ; Piret, Sian Sponsor: Kidney Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Renal tubular transport, Disorders of ; Genetics ; Medical genetics