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Paul Freund, Mira Furgoch, Ian MacDonald; Genotype-phenotype analysis of male subjects affected by choroideremia. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1567.
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© ARVO (1962-2015); The Authors (2016-present)
To identify possible genotype-phenotype correlations in the rate of progression of choroideremia (CHM). CHM is a progressive X-linked retinal degeneration caused by mutations in the CHM gene encoding Rab escort protein-1 (REP-1). No specific genotype-phenotype correlation has been established to explain the rate of progression of the disease, which varies significantly between affected individuals.
Genotypes and linked clinical data were reviewed from 71 CHM affected males registered with eyeGene™ (National Eye Institute, NIH) and those in a database at the University of Alberta. Mutations were identified by direct sequencing of all 15 CHM exons and flanking splice sites. Age at assessment, visual acuity converted to logMAR, and the width of continuous visual field across the horizontal meridian (GVF III-4e or HVF III isopters) was recorded. Only data from the right eye were included, as were multiple entries from families carrying the same mutation. Statistical correlations were assessed with multiple linear regression analysis in SPSS 20 (IBM).
Analysis of CHM genotypes showed that 59% of CHM mutations were nonsense mutations or frameshift mutations resulting in premature truncation. The mutation detection rate in our sample was 89%. Of note, genotyping detected five previously unreported missense mutations (p.L80F, p.Q273H, p.M443V, p.L457P, and p.L550P). Interestingly, 24% of detected mutations were located in exon 6, which contains only 6% of the coding sequence. No statistically significant genotype-phenotype relationships were elucidated. In our cross-sectional sample, visual acuity deteriorated in the 5th decade. Visual fields variably remained intact until the 3rd decade, after which all affected males had severely narrowed visual fields.
In our sample, variation in male CHM phenotypes cannot be explained only by mutations in CHM, suggesting that unknown genetic modifiers or environmental factors may play roles in the onset and progression of CHM. Our description of the observed age-related visual field changes will provide clinicians with prognostic information and natural history data to assist in the selection of participants in upcoming gene therapy trials for CHM. Further investigation of the novel missense mutations may be warranted to understand their effects on expression of REP-1, prenylation of Rab proteins and intracellular trafficking.
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