A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the <i>DMD</i> Gene to Simulate the Effects of Exon-Skipping Therapies: A Meta-Analysis
Dystrophinopathies are caused by mutations in the <i>DMD</i> gene. Out-of-frame deletions represent most mutational events in severe Duchenne muscular dystrophy (DMD), while in-frame deletions typically lead to milder Becker muscular dystrophy (BMD). Antisense oligonucleotide-mediated ex...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-01-01
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| Series: | Journal of Personalized Medicine |
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| Online Access: | https://www.mdpi.com/2075-4426/11/1/46 |
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| author | Saeed Anwar Merry He Kenji Rowel Q. Lim Rika Maruyama Toshifumi Yokota |
| author_facet | Saeed Anwar Merry He Kenji Rowel Q. Lim Rika Maruyama Toshifumi Yokota |
| author_sort | Saeed Anwar |
| collection | DOAJ |
| description | Dystrophinopathies are caused by mutations in the <i>DMD</i> gene. Out-of-frame deletions represent most mutational events in severe Duchenne muscular dystrophy (DMD), while in-frame deletions typically lead to milder Becker muscular dystrophy (BMD). Antisense oligonucleotide-mediated exon skipping converts an out-of-frame transcript to an in-frame one, inducing a truncated but partially functional dystrophin protein. The reading frame rule, however, has many exceptions. We thus sought to simulate clinical outcomes of exon-skipping therapies for <i>DMD</i> exons from clinical data of exon skip-equivalent in-frame deletions, in which the expressed quasi-dystrophins are comparable to those resulting from exon-skipping therapies. We identified a total of 1298 unique patients with exon skip-equivalent mutations in patient registries and the existing literature. We classified them into skip-equivalent deletions of each exon and statistically compared the ratio of DMD/BMD and asymptomatic individuals across the <i>DMD</i> gene. Our analysis identified that five exons are associated with significantly milder phenotypes than all other exons when corresponding exon skip-equivalent in-frame deletion mutations occur. Most exon skip-equivalent in-frame deletions were associated with a significantly milder phenotype compared to corresponding exon skip-amenable out-of-frame mutations. This study indicates the importance of genotype-phenotype correlation studies in the rational design of exon-skipping therapies. |
| first_indexed | 2024-03-09T04:47:59Z |
| format | Article |
| id | doaj.art-7bfb367a5e944afa8b386c4a675d293e |
| institution | Directory Open Access Journal |
| issn | 2075-4426 |
| language | English |
| last_indexed | 2024-03-09T04:47:59Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Personalized Medicine |
| spelling | doaj.art-7bfb367a5e944afa8b386c4a675d293e2023-12-03T13:13:49ZengMDPI AGJournal of Personalized Medicine2075-44262021-01-011114610.3390/jpm11010046A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the <i>DMD</i> Gene to Simulate the Effects of Exon-Skipping Therapies: A Meta-AnalysisSaeed Anwar0Merry He1Kenji Rowel Q. Lim2Rika Maruyama3Toshifumi Yokota4Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, CanadaDepartment of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, CanadaDepartment of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, CanadaDepartment of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, CanadaDepartment of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, CanadaDystrophinopathies are caused by mutations in the <i>DMD</i> gene. Out-of-frame deletions represent most mutational events in severe Duchenne muscular dystrophy (DMD), while in-frame deletions typically lead to milder Becker muscular dystrophy (BMD). Antisense oligonucleotide-mediated exon skipping converts an out-of-frame transcript to an in-frame one, inducing a truncated but partially functional dystrophin protein. The reading frame rule, however, has many exceptions. We thus sought to simulate clinical outcomes of exon-skipping therapies for <i>DMD</i> exons from clinical data of exon skip-equivalent in-frame deletions, in which the expressed quasi-dystrophins are comparable to those resulting from exon-skipping therapies. We identified a total of 1298 unique patients with exon skip-equivalent mutations in patient registries and the existing literature. We classified them into skip-equivalent deletions of each exon and statistically compared the ratio of DMD/BMD and asymptomatic individuals across the <i>DMD</i> gene. Our analysis identified that five exons are associated with significantly milder phenotypes than all other exons when corresponding exon skip-equivalent in-frame deletion mutations occur. Most exon skip-equivalent in-frame deletions were associated with a significantly milder phenotype compared to corresponding exon skip-amenable out-of-frame mutations. This study indicates the importance of genotype-phenotype correlation studies in the rational design of exon-skipping therapies.https://www.mdpi.com/2075-4426/11/1/46dystrophinopathyduchenne muscular dystrophy (DMD)becker muscular dystrophy (BMD)dystrophinreading frame ruleexon skipping |
| spellingShingle | Saeed Anwar Merry He Kenji Rowel Q. Lim Rika Maruyama Toshifumi Yokota A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the <i>DMD</i> Gene to Simulate the Effects of Exon-Skipping Therapies: A Meta-Analysis Journal of Personalized Medicine dystrophinopathy duchenne muscular dystrophy (DMD) becker muscular dystrophy (BMD) dystrophin reading frame rule exon skipping |
| title | A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the <i>DMD</i> Gene to Simulate the Effects of Exon-Skipping Therapies: A Meta-Analysis |
| title_full | A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the <i>DMD</i> Gene to Simulate the Effects of Exon-Skipping Therapies: A Meta-Analysis |
| title_fullStr | A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the <i>DMD</i> Gene to Simulate the Effects of Exon-Skipping Therapies: A Meta-Analysis |
| title_full_unstemmed | A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the <i>DMD</i> Gene to Simulate the Effects of Exon-Skipping Therapies: A Meta-Analysis |
| title_short | A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the <i>DMD</i> Gene to Simulate the Effects of Exon-Skipping Therapies: A Meta-Analysis |
| title_sort | genotype phenotype correlation study of exon skip equivalent in frame deletions and exon skip amenable out of frame deletions across the i dmd i gene to simulate the effects of exon skipping therapies a meta analysis |
| topic | dystrophinopathy duchenne muscular dystrophy (DMD) becker muscular dystrophy (BMD) dystrophin reading frame rule exon skipping |
| url | https://www.mdpi.com/2075-4426/11/1/46 |
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