McClements, M.; (2012) Genetic analysis of inherited retinal dystrophies. Doctoral thesis , UCL (University College London).

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Abstract

This thesis describes the genetic analysis conducted to investigate the cause of six autosomal dominant macular dystrophies (North Carolina macular dystrophy, MCDR1; North Carolina-like macular dystrophy, MCDR3; North Carolina-like macular dystrophy with progressive sensorineural hearing loss, MCDR4; progressive bifocal chorioretinal atrophy, PBCRA; bull’s-eye maculopathy, MCDR2 and split-hand/foot malformations with associated North Carolina macular dystrophy, SHFM and NCMD) and one cone dysfunction with associated myopia and dichromacy (Bornholm eye disease, BED). The method of using Affymetrix SNP chips was tested for its usefulness in conducting genetic analysis on the macular disorders. The chips were used to see if disorders previously linked to large genomic regions could have their loci refined to help determine where the genetic error for each disorder lies. The genotyping results reveal the analysis is more informative when including genotyping data of affected offspring and their parents. MCDR1 analysis without such samples did not refine the disease locus. The copy number variation (CNV) analysis conducted was novel for the disorders and highlighted interesting regions of CNV, particularly in the SHFM and NCMD analysis at 5p15.33 for which QPCR confirmed loss of one copy of a novel microRNA. For MCDR2 analysis, new families were identified as carrying the mutation Arg373Cys in exon 10 of the PROM1 gene. Genetic analysis conducted on various families with BED has revealed the genetic cause of the disorder. Genetic changes leading to the amino acid combination of leucine, isoleucine/valine, alanine, valine and alanine at residues 153, 170, 174, 178 and 180, respectively, in the L or M opsin genes were consistently found in BED patients and are believed to result in the disease phenotype. Additionally, a family with a BEDrelated phenotype was found to carry a novel mutation in exon 2 of a hybrid M opsin gene that would lead to a Glu41Lys substitution.

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