Bessant, David Alfred Roger; (2003) Genotype-phenotype correlation in the inherited retinal dystrophies. Doctoral thesis (M.D), UCL (University College London).

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Abstract

This study aimed to identify novel genetic loci and genes responsible for a number of inherited retinal dystrophies and to perform a detailed analysis of the phenotype associated with each of these genotypes. After excluding existing loci, a full genome linkage analysis was carried out on a family segregating autosomal dominant retinitis pigmentosa (adRP), which resulted in the identification of a novel locus for adRP at 14q11. Screening of the retinally expressed candidate gene NRL, which lay within the disease critical interval, subsequently led to the identification of an S50T mutation as the cause of this particular inherited retinal dystrophy. The NRL gene encodes a transcription factor, NRL, which regulates promoter activity in the rod photoreceptor opsin gene, rhodopsin. Biochemical analysis suggests that the NRLS50T mutation may result in increased transcription of the rhodopsin gene in vivo, which may lead to excessive production of rhodopsin and to photoreceptor degeneration. A comprehensive phenotypic assessment of subjects with the NRLS50T mutation was then carried out, utilising a combination of clinical examination, electrophysiological assessment, psychophysical assessment, and fundus imaging. Additional studies were carried out on: 1) Patients with a sectorial form of adRP, revealing a high incidence of mutations in the rhodopsin gene, and defining the phenotype associated with these mutations; 2) A consanguineous family with Usher syndrome type 2, enabling the critical interval for the USH2A locus to be refined to approximately 400kb; 3) Several pedigrees segregating autosomal recessive retinitis pigmentosa (arRP) leading to a refinement of the RP12 arRP locus; and 4) Subjects with recessive RP and cone-rod dystrophy (arCRD), which led to the discovery of a mutation in the ABCA4 gene in a family with arCRD dystrophy.

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