Mutation analysis of important retinal candidate genes: progression from research to diagnostic service

Roberts, Lisa Jane

Mutation analysis of important retinal candidate genes: progression from research to diagnostic service

Thesis / Dissertation

2006

Abstract

Approximately one third of all human inherited disease includes defects of the eye. Retinal degenerative disorders (RDDs) are a group of diseases characterised by photoreceptor cell death in the retina and consequent vision loss. The Division of Human Genetics at the University of Cape Town (UCT) has samples archived in the RDD DNA database from over 1000 South African families. The research in this Division currently involves mutation screening of retinal candidate genes, with the goal of identifying the causative genetic mutation in each of the families registered in the database, in order to facilitate future therapeutic intervention. The purpose of this study was to determine the distribution and clinical utility of mutations in important candidate genes in a subset of South African RDD patients. To this end, three important retinal candidate genes were selected and screened in appropriate patient cohorts. The mutation analysis included screening for large deletions which is a novel approach in the study of RDDs. The screening of Rhodopsin (RHO) in 61 individuals, retinitis pigmentosa 1 (RP1) in 70 individuals and retinal pigment epithelium-specific protein 65kDa (RPE65) in 87 individuals led to the identification of 10 families for whom a molecular diagnostic service can now be provided. For most families the amount of useful information available without further research is minimal, however for four of the families, therapeutic interventions may be possible, now or in the near future. In addition to the pathogenic mutations found, 17 single nucleotide polymorphisms (SNPs) were identified during this study. Furthermore, a significant association between ethnicity and the frequency of the high and low risk alleles of two of these SNPs (that may modify the phenotype of RDDs) was shown. This information may be useful in providing diagnostic or prognostic indicators in the future. The utility of RDD research should not be trivialised as it identifies families who may benefit from current interventions or be eligible for possible therapeutic trials, eliminates gene candidates in families, and is necessary for understanding the disease (which in itself is a requirement for development of therapies).

Keywords

Human Genetics

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