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Genetic mapping and positional candidate analysis in a autosomal dominant retinitis pigmentosa

Tarttelin, Emma E.; (1998) Genetic mapping and positional candidate analysis in a autosomal dominant retinitis pigmentosa. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Retinitis pigmentosa (RP) describes a group of inherited retinal dystrophies characterised by degeneration of the photoreceptor cells and pigment deposition in the retinal periphery. Patients experience tunnel vision and night blindness, often progressing to complete blindness later in life. RP can be inherited in X-linked, autosomal dominant and autosomal recessive forms, and there is considerable clinical and genetic heterogeneity found within each form. At the outset of this study, autosomal dominant RP (adRP), was known to be caused by mutations in 2 retinal genes, rhodopsin and peripherin/RDS, and six as yet uncharacterised genes localised to 8q, 7p, 7q, 19q, 17p and 17q. Two further loci have since been identified, on Icen and 9q. However, it has been difficult to determine the frequencies of these loci, and what proportion of dominant RP remains to be found. In order to address these questions linkage analysis was earned out on 16 new adRP families. Seven were found to show linkage to rhodopsin on 3q. A mutation screen of rhodopsin in these families identified the disease causing mutation in six of the seven families. Two of the new families appeared to be excluded for all the known loci. One family, ADRP8, showed linkage to the chromosome 1 locus. Another, ADRP2, is linked to 19q. Four of the families gave inconclusive data. These results, together with previous results from this lab, showed that rhodopsin is the commonest cause of adRP, and that around 15% of adRP results from mutations at unknown loci. One family of British origin, known as RP1729, was found to show linkage to the 17p (RP13) locus. This locus was originally described in a South African family of British origin. Critical recombination events in RP1729 and the S.A. family place the disease in a 3 cM region between the markers D17S1529 and D17S831. Haplotype comparison in the families shows they are not related, although data on a new British family, RP1650, suggests it is related to RP1729. A partial contig of YAC clones has been generated by STS-content analysis and novel markers isolated by end cloning. New markers and ESTs have been mapped on the YACs, and PAC clones have been isolated to deepen the contig. Five retinally expressed genes map to 17p: recoverin, retinal guanylate cyclase, pigment epithelium-derived factor, phosphatidylinositol transfer protein and β-arrestin 2. Each of these have been considered as candidate genes for the RP13 locus, and four have been excluded. In a separate but complementary project, a candidate gene approach was taken to map retinal ESTs. Retinal EST clones were selected from the dbEST database and subjected to BLAST analysis, so that ESTs which were unique or similar only to other retinal ESTs were selected for. As a pilot study 28 clones were considered to meet these criteria, of which data on 5 will be discussed, including localisation and expression pattern.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Genetic mapping and positional candidate analysis in a autosomal dominant retinitis pigmentosa
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Retinitis pigmentosa
URI: https://discovery.ucl.ac.uk/id/eprint/10100099
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