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Functional recovery of a novel knockin mouse model of dysferlinopathy by readthrough of nonsense mutation
Biallelic mutations in the dysferlin gene cause limb-girdle muscular dystrophy 2B or Miyoshi distal myopathy. We found that nonsense mutations are the most common mutation type among Korean patients with dysferlinopathy; more than half of the patients have at least one nonsense allele, which may be...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181533/ https://www.ncbi.nlm.nih.gov/pubmed/34141825 http://dx.doi.org/10.1016/j.omtm.2021.04.015 |
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author | Seo, Kyowon Kim, Eun Kyoung Choi, Jaeil Kim, Dae-Seong Shin, Jin-Hong |
author_facet | Seo, Kyowon Kim, Eun Kyoung Choi, Jaeil Kim, Dae-Seong Shin, Jin-Hong |
author_sort | Seo, Kyowon |
collection | PubMed |
description | Biallelic mutations in the dysferlin gene cause limb-girdle muscular dystrophy 2B or Miyoshi distal myopathy. We found that nonsense mutations are the most common mutation type among Korean patients with dysferlinopathy; more than half of the patients have at least one nonsense allele, which may be amenable to readthrough therapy. We generated a knockin mouse, dqx, harboring DYSF p.Q832∗ mutation. Homozygous dqx mice lacked dysferlin in skeletal muscle, while 2 weeks of oral ataluren restored dysferlin expression and ameliorated skeletal muscle pathology. Their physical performance improved, and protection against eccentric contractions was noted. The improvement was most evident in mice treated with oral ataluren of 0.9 mg/mL. These improvements were sustained for 8 weeks in ataluren-treated dqx mice, while the parameters of A/J mice treated with ataluren over the same period did not improve. These results support that readthrough therapy by oral ataluren may also be applicable to dysferlinopathy patients with nonsense mutation. |
format | Online Article Text |
id | pubmed-8181533 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-81815332021-06-16 Functional recovery of a novel knockin mouse model of dysferlinopathy by readthrough of nonsense mutation Seo, Kyowon Kim, Eun Kyoung Choi, Jaeil Kim, Dae-Seong Shin, Jin-Hong Mol Ther Methods Clin Dev Original Article Biallelic mutations in the dysferlin gene cause limb-girdle muscular dystrophy 2B or Miyoshi distal myopathy. We found that nonsense mutations are the most common mutation type among Korean patients with dysferlinopathy; more than half of the patients have at least one nonsense allele, which may be amenable to readthrough therapy. We generated a knockin mouse, dqx, harboring DYSF p.Q832∗ mutation. Homozygous dqx mice lacked dysferlin in skeletal muscle, while 2 weeks of oral ataluren restored dysferlin expression and ameliorated skeletal muscle pathology. Their physical performance improved, and protection against eccentric contractions was noted. The improvement was most evident in mice treated with oral ataluren of 0.9 mg/mL. These improvements were sustained for 8 weeks in ataluren-treated dqx mice, while the parameters of A/J mice treated with ataluren over the same period did not improve. These results support that readthrough therapy by oral ataluren may also be applicable to dysferlinopathy patients with nonsense mutation. American Society of Gene & Cell Therapy 2021-05-01 /pmc/articles/PMC8181533/ /pubmed/34141825 http://dx.doi.org/10.1016/j.omtm.2021.04.015 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Seo, Kyowon Kim, Eun Kyoung Choi, Jaeil Kim, Dae-Seong Shin, Jin-Hong Functional recovery of a novel knockin mouse model of dysferlinopathy by readthrough of nonsense mutation |
title | Functional recovery of a novel knockin mouse model of dysferlinopathy by readthrough of nonsense mutation |
title_full | Functional recovery of a novel knockin mouse model of dysferlinopathy by readthrough of nonsense mutation |
title_fullStr | Functional recovery of a novel knockin mouse model of dysferlinopathy by readthrough of nonsense mutation |
title_full_unstemmed | Functional recovery of a novel knockin mouse model of dysferlinopathy by readthrough of nonsense mutation |
title_short | Functional recovery of a novel knockin mouse model of dysferlinopathy by readthrough of nonsense mutation |
title_sort | functional recovery of a novel knockin mouse model of dysferlinopathy by readthrough of nonsense mutation |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181533/ https://www.ncbi.nlm.nih.gov/pubmed/34141825 http://dx.doi.org/10.1016/j.omtm.2021.04.015 |
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