Cargando…

A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the DMD Gene to Simulate the Effects of Exon-Skipping Therapies: A Meta-Analysis

Dystrophinopathies are caused by mutations in the DMD 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 convert...

Descripción completa

Detalles Bibliográficos
Autores principales: Anwar, Saeed, He, Merry, Lim, Kenji Rowel Q., Maruyama, Rika, Yokota, Toshifumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830903/
https://www.ncbi.nlm.nih.gov/pubmed/33466756
http://dx.doi.org/10.3390/jpm11010046
_version_ 1783641517954433024
author Anwar, Saeed
He, Merry
Lim, Kenji Rowel Q.
Maruyama, Rika
Yokota, Toshifumi
author_facet Anwar, Saeed
He, Merry
Lim, Kenji Rowel Q.
Maruyama, Rika
Yokota, Toshifumi
author_sort Anwar, Saeed
collection PubMed
description Dystrophinopathies are caused by mutations in the DMD 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 DMD 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 DMD 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.
format Online
Article
Text
id pubmed-7830903
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-78309032021-01-26 A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the DMD Gene to Simulate the Effects of Exon-Skipping Therapies: A Meta-Analysis Anwar, Saeed He, Merry Lim, Kenji Rowel Q. Maruyama, Rika Yokota, Toshifumi J Pers Med Article Dystrophinopathies are caused by mutations in the DMD 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 DMD 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 DMD 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. MDPI 2021-01-14 /pmc/articles/PMC7830903/ /pubmed/33466756 http://dx.doi.org/10.3390/jpm11010046 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Anwar, Saeed
He, Merry
Lim, Kenji Rowel Q.
Maruyama, Rika
Yokota, Toshifumi
A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the DMD Gene to Simulate the Effects of Exon-Skipping Therapies: A Meta-Analysis
title A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the DMD 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 DMD 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 DMD 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 DMD 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 DMD 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 dmd gene to simulate the effects of exon-skipping therapies: a meta-analysis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830903/
https://www.ncbi.nlm.nih.gov/pubmed/33466756
http://dx.doi.org/10.3390/jpm11010046
work_keys_str_mv AT anwarsaeed agenotypephenotypecorrelationstudyofexonskipequivalentinframedeletionsandexonskipamenableoutofframedeletionsacrossthedmdgenetosimulatetheeffectsofexonskippingtherapiesametaanalysis
AT hemerry agenotypephenotypecorrelationstudyofexonskipequivalentinframedeletionsandexonskipamenableoutofframedeletionsacrossthedmdgenetosimulatetheeffectsofexonskippingtherapiesametaanalysis
AT limkenjirowelq agenotypephenotypecorrelationstudyofexonskipequivalentinframedeletionsandexonskipamenableoutofframedeletionsacrossthedmdgenetosimulatetheeffectsofexonskippingtherapiesametaanalysis
AT maruyamarika agenotypephenotypecorrelationstudyofexonskipequivalentinframedeletionsandexonskipamenableoutofframedeletionsacrossthedmdgenetosimulatetheeffectsofexonskippingtherapiesametaanalysis
AT yokotatoshifumi agenotypephenotypecorrelationstudyofexonskipequivalentinframedeletionsandexonskipamenableoutofframedeletionsacrossthedmdgenetosimulatetheeffectsofexonskippingtherapiesametaanalysis
AT anwarsaeed genotypephenotypecorrelationstudyofexonskipequivalentinframedeletionsandexonskipamenableoutofframedeletionsacrossthedmdgenetosimulatetheeffectsofexonskippingtherapiesametaanalysis
AT hemerry genotypephenotypecorrelationstudyofexonskipequivalentinframedeletionsandexonskipamenableoutofframedeletionsacrossthedmdgenetosimulatetheeffectsofexonskippingtherapiesametaanalysis
AT limkenjirowelq genotypephenotypecorrelationstudyofexonskipequivalentinframedeletionsandexonskipamenableoutofframedeletionsacrossthedmdgenetosimulatetheeffectsofexonskippingtherapiesametaanalysis
AT maruyamarika genotypephenotypecorrelationstudyofexonskipequivalentinframedeletionsandexonskipamenableoutofframedeletionsacrossthedmdgenetosimulatetheeffectsofexonskippingtherapiesametaanalysis
AT yokotatoshifumi genotypephenotypecorrelationstudyofexonskipequivalentinframedeletionsandexonskipamenableoutofframedeletionsacrossthedmdgenetosimulatetheeffectsofexonskippingtherapiesametaanalysis