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Molecular genetic study of hereditary retinoblastoma

Onadim, Zerrin; (1993) Molecular genetic study of hereditary retinoblastoma. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

This thesis describes a molecular genetic analysis of retinoblastoma (Rb), the commonest ophthalmic malignancy in childhood, that has both familial and non-familial forms. In familial cases the disease is transmitted as an autosomal dominant trait with incomplete penetrance. At the start of the study the gene responsible, RB1, which was also the first tumour suppressor gene identified, was available together with several intragenic probes. The aim of the study was to analyse mutations in patients predisposed to Rb to gain an insight into the mechanism of mutagenesis and to offer screening for carrier status. The first part of the study involved family linkage analysis with Restriction Fragment Length Polymorphisms (RFLP) and other intragenic polymorphisms of the RB1 gene using Southern blotting techniques and the Polymerase Chain Reaction (PCR). The results indicated that, using the combination of available polymorphisms, it is possible to offer screening to 95 % of Rb families. Using PCR, it was also possible to use formalin- fixed, paraffin-embedded tissue samples from archival material. During the course of this analysis, five pre-natal and six post-natal screenings were carried out the results of which indicated inheritance of the predisposing allele in three cases. In search of a suitable technique to identify causative mutations in the RB1 gene various techniques were assessed for their usefulness. These techniques were Ribonuclease (RNase) protection, PCR sequencing of individual exons, Carbodiimide (CDI) modified heteroduplex analysis and Single Strand Conformation Polymorphism (SSCP) analysis. SSCP analysis proved to be the most successful in this study and six germ-line mutations were identified in the RB1 gene. Four of the mutations were from typical Rb families with bilaterally affected individuals and the other two from families with "mild" phenotypes. The analyses of these mutations provided insights into the mechanisms of mutagenesis in RB1 and the phenotype-genotype relationship in Rb.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Molecular genetic study of hereditary retinoblastoma
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10102635
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