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Novel CHM mutations in Polish patients with choroideremia - an orphan disease with close perspective of treatment.

ABSTRACT: BACKGROUND:Choroideremia (CHM) is a rare X-linked recessive retinal dystrophy characterized by progressive chorioretinal degeneration in the males affected. The symptoms include night blindness in childhood, progressive peripheral vision loss and total blindness in the late stages. The disease is caused by mutations in the CHM gene encoding Rab Escort Protein 1 (REP-1). The aim of the study was to identify the molecular basis of choroideremia in five families of Polish origin. METHODS:Six male patients from five unrelated families of Polish ethnicity, who were clinically diagnosed with choroideremia, were examined in this study. An ophthalmologic examination performed in all the probands included: best-corrected visual acuity, slit-lamp examination, funduscopy, fluorescein angiography and perimetry. The entire coding region encompassing 15 exons and the flanking intronic sequences of the CHM gene were amplified with PCR and directly sequenced in all the patients. RESULTS:Five variants in the CHM gene were identified in the five families examined. Two of the variants were new: c.1175dupT and c.83C?>?G, while three had been previously reported. CONCLUSIONS:This study provides the first molecular genetic characteristics of patients with choroideremia from the previously unexplored Polish population.

SUBMITTER: Skorczyk-Werner A

PROVIDER: S-EPMC6291982 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Novel CHM mutations in Polish patients with choroideremia - an orphan disease with close perspective of treatment.

Skorczyk-Werner Anna A Wawrocka Anna A Kochalska Natalia N Krawczynski Maciej Robert MR

Orphanet journal of rare diseases 20181212 1

<h4>Background</h4>Choroideremia (CHM) is a rare X-linked recessive retinal dystrophy characterized by progressive chorioretinal degeneration in the males affected. The symptoms include night blindness in childhood, progressive peripheral vision loss and total blindness in the late stages. The disease is caused by mutations in the CHM gene encoding Rab Escort Protein 1 (REP-1). The aim of the study was to identify the molecular basis of choroideremia in five families of Polish origin.<h4>Methods ...[more]

PMID: 30541579

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Project description:PurposeWe report the underlying genotype and explore possible genotypic-phenotypic correlations in a large cohort of choroideremia patients.MethodsWe studied prospectively a cohort of 79 patients diagnosed within a tertiary referral service for patients with retinal dystrophies. Phenotypic evaluation consisted of clinical examination, including visual acuity and residual retinal area by fundus autofluorescence (FAF). Genotype was established by sequencing. We also investigated whether particular genotypes were associated with more severe phenotypes by performing analysis of covariance (ANCOVA), with visual acuity and FAF as the dependent variables and age as the covariant.ResultsA total of 74 (94%) of patients in our cohort had causative mutations by sequencing, the majority of which were anticipated to be null. Of these, 35 (47%) had insertions and deletions, 13 (18%) had mutations predicted to affect splicing, and 26 (35%) had single point mutations. In the latter case, 13 of 21 (62%) pedigrees with single point mutations were C to T transitions at C-phosphate-G (CpG) dinucleotides. These mutations were spread across 5 of only 24 CpG dinucleotides in the entire CHM cDNA. Furthermore, these 5 locations are the only sites at which C to T transitions result in a stop codon. No clear evidence was found for genotype-phenotype correlation except in the instance of a patient with a large deletion involving neighbouring sequences.ConclusionsIn patients with a diagnosis of choroideremia made by a specialty service, there is a high likelihood of establishing a genetic diagnosis. The majority of causative mutations appear to be null and, therefore, may benefit from gene replacement therapy. A disproportionate number of single point mutations observed were C to T transitions, consistent with the evolutionary decay of CpG dinucleotides through methylation and subsequent deamination. Hence, the development of choroideremia in such patients may represent the unwanted consequence of human evolution; de novo mutations are predicted to arise at these sites in future generations. (ClinicalTrials.gov number, NCT01461213.).

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Novel CHM mutations in Polish patients with choroideremia - an orphan disease with close perspective of treatment.

Publications

Novel CHM mutations in Polish patients with choroideremia - an orphan disease with close perspective of treatment.

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