Dataset Information

A putative frameshift variant in the CHM gene is associated with an unexpected splicing alteration in a choroideremia patient.

ABSTRACT: BACKGROUND:Due to the limited availability of mRNA analysis data, the number of exonic variants resulting in splicing impairment is underestimated although aberrant splicing correction is a promising therapeutic option to treat monogenic diseases, including choroideremia (CHM), a rare X-linked eye disorder arising from sequence alteration of the CHM gene. Herein we report an exonic frameshift variant associated with an mRNA splicing alteration that leads to a CHM hypomorphic allele. METHODS:Total RNA and genomic DNA were extracted from peripheral blood of a patient affected by a mild form of CHM. The CHM gene was analyzed by PCR-based methods and Sanger sequencing. RESULTS:Besides the known c.1335dup frameshift variant, mRNA analysis revealed a splicing alteration that restored the reading frame of the mutant transcript, likely leading to an aberrant protein with residual activity. Bioinformatic analyses identified novel putative exonic splicing enhancer elements and provided clues that also pre-mRNA secondary structure should be taken into account when exploring splicing mechanisms. CONCLUSION:A careful molecular characterization of the c.1335dup variant's effect explains the relationship between genotype and phenotype severity in a CHM patient and provides new perspectives for the study of therapeutic strategies based on splicing correction in human diseases.

SUBMITTER: Fioretti T

PROVIDER: S-EPMC7667377 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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A putative frameshift variant in the CHM gene is associated with an unexpected splicing alteration in a choroideremia patient.

Fioretti Tiziana T Ungari Silvana S Savarese Maria M Cattaneo Fabio F Pirozzi Enza E Esposito Gabriella G

Molecular genetics & genomic medicine 20200919 11

<h4>Background</h4>Due to the limited availability of mRNA analysis data, the number of exonic variants resulting in splicing impairment is underestimated although aberrant splicing correction is a promising therapeutic option to treat monogenic diseases, including choroideremia (CHM), a rare X-linked eye disorder arising from sequence alteration of the CHM gene. Herein we report an exonic frameshift variant associated with an mRNA splicing alteration that leads to a CHM hypomorphic allele.<h4>M ...[more]

PMID: 32949230

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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.).

Dataset Information

A putative frameshift variant in the CHM gene is associated with an unexpected splicing alteration in a choroideremia patient.

Publications

A putative frameshift variant in the CHM gene is associated with an unexpected splicing alteration in a choroideremia patient.

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