Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264477
Title: The identification and analysis of mutation in the Cockayne Syndrome B gene
Author: Mallery, Donna Louise
ISNI:       0000 0001 3617 5898
Awarding Body: Open University
Current Institution: Open University
Date of Award: 1999
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Abstract:
Cockayne Syndrome (CS) is a rare autosomal recessive disorder characterised by neurodegeneration, dwarfism and at least three of the following; hearing loss, dental caries, pigmentary retinopathy, characteristic facial appearance and photosensitivity. Cells from CS patients fail to recover RNA synthesis after irradiation and exhibit a loss of transcription-coupled repair, with overall genome repair being unaffected. There are two genetic complementation groups of CS alone, A and B, with the majority of patients belonging to group B. The genes defective in each of the complementation groups have been cloned, the CSA gene in 1995 and CSB in 1990. For the purposes of this study the CSB gene was sequenced in patients from complementation group B, in an attempt to identify the causative mutations. The analysis of thirteen patients from different backgrounds has revealed a wide variety of mutations in the CSB gene. A considerable number of the mutations found in CS-B patients resulted in severely truncated products. Several patients possessed two alleles affected in this way and it is unlikely that any functional protein is produced, confirming that CSB is a nonessential gene. The mutations identified did not reveal any regions within the gene that could be termed as hotspots. There was, however a tendency for the mutations to be located towards the 3' two thirds of the gene, indicated by the clustering of the mutations in this region. The severity of the mutation does not however correlate with the site or type of mutation. Clustering of the mutations towards the 3' end and the high levels of conservation in the central part of the gene prompted a study into the functional significance of the N- and Cterminal ends of the protein. Also, the presence of a highly acidic region of amino acids and a stretch of glycine residues led to a study of the effects of removing and replacing these regions. Removal of the glycine domain results in non-functional protein with respect to cell survival after UV irradiation, whereas the removal of seven glutamic acid residues from the acidic rich region, does not appear to have a particularly dramatic effect. Deletion of the C-terminal 25 amino acids of CSB totally destroys the repair ability of the gene. In contrast, cDNAs deleted at the N-terminus are able to at least, partially retain repair activity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.264477  DOI: Not available
Keywords: Genetics
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