Analysis of a Large Choroideremia Dataset Does Not Suggest a Preference for Inclusion of Certain Genotypes in Future Trials of Gene Therapy

Overview

Journal Mol Genet Genomic Med

Specialty Genetics

Date 2016 Jun 2

PMID 27247961

Citations 22

Authors

Paul R Freund

Yuri V Sergeev

Ian M MacDonald

Affiliations

Soon will be listed here.

Abstract

Background: Choroideremia (CHM) is an X-linked degeneration of the retinal pigment epithelium, photoreceptors, and choroid, which causes nyctalopia and progressive constriction of visual fields leading to blindness. The CHM gene encodes Rab escort protein 1 (REP-1). In this work, we reviewed the phenotypes and genotypes of affected males with the purpose of understanding the functional effects of CHM mutations and their relationship with the phenotypes.

Methods: A retrospective review of 128 affected males was performed analyzing the onset of symptoms, visual acuity, and visual fields with respect to their mutations in the CHM gene.

Results: In rank order, reflecting data from this report, the most common mutations found in the CHM gene were nonsense mutations (41%), exon deletions (37%), and splice sites (14%) associated with a loss of functional protein. In the pool of 106 CHM mutations, we discovered four novel missense mutations (c.238C>T; p.L80F, c.819G>T; p.Q273H, c.1327A>G; p.M443V, and c.1370C>T; p.L457P) predicted to be severe changes affecting protein stability and folding with the effect similar to that of other types of mutations. No significant genotype-phenotype correlation was found with respect to the onset of nyctalopia, the onset of other visual symptoms, visual acuity, or width of visual fields.

Conclusion: There is no evidence to support exclusion of CHM patients from clinical trials based on their genotypes or any potential genotype-phenotype correlations.

Citing Articles

Clinical and imaging findings of choroideremia in a pediatric patient due to a novel frameshift mutation.

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Clinical Manifestations and Genetic Analysis of 5 Korean Choroideremia Patients Initially Diagnosed With Retinitis Pigmentosa.

Kim J, Han J, Choi E, Bang J, Shin H, Jang M J Korean Med Sci. 2022; 37(3):e5.

PMID: 35040292 PMC: 8763878. DOI: 10.3346/jkms.2022.37.e5.

Bilateral visual acuity decline in males with choroideremia: a pooled, cross-sectional meta-analysis.

Bozkaya D, Zou H, Lu C, Tsao N, Lam B BMC Ophthalmol. 2022; 22(1):29.

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Molecular Therapy for Choroideremia: Pre-clinical and Clinical Progress to Date.

Kalatzis V, Roux A, Meunier I Mol Diagn Ther. 2021; 25(6):661-675.

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Molecular Characterization of Choroideremia-Associated Deletions Reveals an Unexpected Regulation of Gene Transcription.

Fioretti T, Di Iorio V, Lombardo B, De Falco F, Cevenini A, Cattaneo F Genes (Basel). 2021; 12(8).

PMID: 34440285 PMC: 8392058. DOI: 10.3390/genes12081111.

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