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Read-through approach for stop mutations in Duchenne muscular dystrophy. An update.

ABSTRACT: Dystrophinopathies are allelic conditions caused by deletions, duplications and point-mutations in the DMD gene, located on the X chromosome (Xp21.2). Mutations that prematurely interrupt the dystrophin protein synthesis lead to the most severe clinical form, Duchenne muscular Dystrophy, characterized by early involvement of muscle strength. There is no known cure for dystrophinopathies. In DMD, treatment with corticosteroids have changed the natural history and the progression of the disease, prolonging ambulation, and slowing the onset of respiratory and cardiac involvement and scoliosis by several years. In the last few years, new perspectives and options are deriving from the discovery of pharmacological approaches able to restore normal, full-length dystrophin and potentially reverse the course of the disease. Read-through (RT) of nonsense mutations, thanks to its ability to bypass the premature stop codon and to act on virtually any region of the dystrophin gene, independently of the location in which the mutation resides, is one of these promising approaches. This non-systematic review shows the different steps that, passing from yeast to humans, have made it possible to use this innovative successful approach to treat serious diseases such as Duchenne muscular dystrophy.

SUBMITTER: Politano L

PROVIDER: S-EPMC8033424 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common pediatric muscular dystrophies, being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, unprecedented advances are being made for the development of therapies for DMD. Some of which are already conditionally approved: exon skipping and premature stop codon read-through. The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available pharmacogenetic treatments and finally, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with clinical diagnosis of dystrophinopathy, implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exome and bioinformatics. We also performed a meta-analysis of LA's metrics for DMD available therapies. The employed algorithm resulted effective for the achievement of differential diagnosis, reaching a detection rate of 97%. Because of this, corticosteroid treatment was correctly indicated and validated in 371 patients with genetic confirmation of dystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for premature stop codon read-through therapy. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Regarding nonsense variants, UGA turned out to be the most frequent premature stop codon observed (47%). According to the meta-analysis, only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the complete molecular algorithm for dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed populations, but a more even proportion of nonsense variants (∼40%). In conclusion, this manuscript describes the theragnosis carried out in Argentinian dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of the standard of care and genetic counseling. Finally, this work contributes with the international efforts to characterize the frequencies and variants in LA, pillars of drug development and theragnosis.

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Read-through approach for stop mutations in Duchenne muscular dystrophy. An update.

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