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Title: HPRT deficiency in cells and mice
Author: Wu, Chao-Liang
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1993
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The hypoxanthine guanine phosphoribosyltransferase (HPRT) gene is a housekeeping gene, located on the X chromosome in both human and mouse. In humans, HPRT deficiency causes Lesch-Nyhan syndrome which is characterised by behavioural alterations, including self-injurious behaviour and mental retardation, while partial deficiency causes gouty arthritis. The use of homologous recombination to delete specific parts of the HPRT gene with the aim of studing the control of gene expression has been investigated. The size of the deletion that could be made using a simple procedure of homologous recombination was limited and there was a preference for an insertion mechanism if the targeting vectors were designed to delete more than 20 kb. However, combined with intrachromosomal recombination, the deletion size could be enlarged to at least 30 kb. Using this deletion targeting strategy, a mouse embryonic stem (ES) cell clone with a targeted deletion of the promoter and exons 1-2 in one allele of the adenine phosphoribosyltransferase (APRT) gene was also constructed. This deletion targeted ES clone provides the opportunity to generate APRT knock-out and HPRT/APRT double knock-out animal models for Lesch-Nyhan syndrome. Until recently no spontaneous behavioural abnormalities had been reported in HPRT-deficient mice generated using the embryonic stem cell system. To resolve the asymptomatic ambiguity of HPRT-deficient mice, a hypothesis that mice were more tolerant of HPRT deficiency because they were more reliant on APRT than HPRT for their purine salvage was proposed. The administration of an APRT inhibitor to HPRT-deficient mice induced persistent self-injurious behaviour. This combined genetic and biochemical model will facilitate the study of Lesch-Nyhan syndrome and the evaluation of novel therapies. A novel therapeutic strategy involving the intracerebral transplantation of ES cells was evaluated. HPRT activity was observed in the brain of HPRT-deficient mice which had received intracerebral ES cell transplantation. Some of the implanted ES cells were committed to differentiate down the neural pathway into either neurones or glial cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available