Functional recovery of a novel knockin mouse model of dysferlinopathy by readthrough of nonsense mutation
| Autor: | Dae-Seong Kim, Jaeil Choi, Jin-Hong Shin, Kyo-Won Seo, Eun Kyoung Kim |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
muscular dystrophy
0301 basic medicine Dysferlinopathy nonsense readthrough media_common.quotation_subject Nonsense Nonsense mutation QH426-470 medicine.disease_cause knockin mouse Dysferlin 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Genetics medicine Muscular dystrophy Molecular Biology media_common Mutation QH573-671 biology business.industry Skeletal muscle ataluren medicine.disease dysferlinopathy Ataluren 030104 developmental biology medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis biology.protein Cancer research Molecular Medicine Original Article Cytology business |
| Zdroj: | Molecular Therapy. Methods & Clinical Development Molecular Therapy: Methods & Clinical Development, Vol 21, Iss, Pp 702-709 (2021) |
| ISSN: | 2329-0501 |
| Popis: | 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. Graphical abstract Biallelic mutations in the dysferlin gene cause progressive muscle diseases. Many of the patients harbor nonsense mutation, which may be mitigated by readthrough therapy by ataluren. The authors report the first evidence of physical functional recovery by facilitation of nonsense readthrough in a dysferlin-deficient mouse model. |
| Databáze: | OpenAIRE |
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