Distribution of dystrophin gene deletions in a Chinese population

Li, Yuanyuan; Liu, Zhuo; Ouyang, Shengrong; Zhu, Yanli; Wang, Liwen; Wu, Jianxin

doi:10.1177/0300060515613223

Cited by 11 publications

(8 citation statements)

References 36 publications

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“…Exon deletions account for ~60 to 70% of human DMD mutations, with deletion of exon 50 representing one of the most common single exon deletions (25, 26). All previous studies of CRISPR/Cas9-mediated exon skipping in mice focused on mdx or mdx4 cv mice, which harbor nonsense mutations, so we used CRISPR/Cas9 to generate a new mouse model of DMD that lacks exon 50 (referred to as ΔEx50 mice).…”

Section: Introductionmentioning

confidence: 99%

Single-cut genome editing restores dystrophin expression in a new mouse model of muscular dystrophy

Amoasii¹,

Long²,

Li³

et al. 2017

Sci. Transl. Med.

214

206

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Duchenne muscular dystrophy (DMD) is a severe, progressive muscle disease caused by mutations in the dystrophin gene. The majority of DMD mutations are deletions that prematurely terminate the dystrophin protein. Deletions of exon 50 of the dystrophin gene are among the most common single exon deletions causing DMD. Such mutations can be corrected by skipping exon 51, thereby restoring the dystrophin reading frame. Using clustered regularly interspaced short palindromic repeats/CRISPR-associated 9 (CRISPR/Cas9), we generated a DMD mouse model by deleting exon 50. These ΔEx50 mice displayed severe muscle dysfunction, which was corrected by systemic delivery of adeno-associated virus encoding CRISPR/Cas9 genome editing components. We optimized the method for dystrophin reading frame correction using a single guide RNA that created reframing mutations and allowed skipping of exon 51. In conjunction with muscle-specific expression of Cas9, this approach restored up to 90% of dystrophin protein expression throughout skeletal muscles and the heart of ΔEx50 mice. This method of permanently bypassing DMD mutations using a single cut in genomic DNA represents a step toward clinical correction of DMD mutations and potentially those of other neuromuscular disorders.

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Section: Introductionmentioning

confidence: 99%

Single-cut genome editing restores dystrophin expression in a new mouse model of muscular dystrophy

Amoasii¹,

Long²,

Li³

et al. 2017

Sci. Transl. Med.

214

206

View full text Add to dashboard Cite

show abstract

“…The structures of the muscle dystrophin protein and gene are highly conserved in vertebrate species with 79 exons encoding a protein of 3684 amino acids 2,6 . There are several “hotspot” regions in the gene in which deletions result in splicing of exons that are out of frame, preventing the production of functional dystrophin protein 1,7 . The region that spans exons 45–50 is the most prevalent hotspot region, typically placing exon 51 out of frame with preceding exons and preventing expression of functional dystrophin protein.…”

Section: Introductionmentioning

confidence: 99%

In vivo non-invasive monitoring of dystrophin correction in a new Duchenne muscular dystrophy reporter mouse

Amoasii

Li²,

Zhang³

et al. 2019

Nat Commun

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Duchenne muscular dystrophy (DMD) is a fatal genetic disorder caused by mutations in the dystrophin gene. To enable the non-invasive analysis of DMD gene correction strategies in vivo, we introduced a luciferase reporter in-frame with the C-terminus of the dystrophin gene in mice. Expression of this reporter mimics endogenous dystrophin expression and DMD mutations that disrupt the dystrophin open reading frame extinguish luciferase expression. We evaluated the correction of the dystrophin reading frame coupled to luciferase in mice lacking exon 50, a common mutational hotspot, after delivery of CRISPR/Cas9 gene editing machinery with adeno-associated virus. Bioluminescence monitoring revealed efficient and rapid restoration of dystrophin protein expression in affected skeletal muscles and the heart. Our results provide a sensitive non-invasive means of monitoring dystrophin correction in mouse models of DMD and offer a platform for testing different strategies for amelioration of DMD pathogenesis.

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“…Thousands of mutations have been identified in the dystrophin gene, which spans ~2.5 megabases of DNA and contains 79 exons. Many of these mutations cluster into “hotspots,” most commonly in a region that spans exons 45 to 50, typically placing exon 51 out of frame with preceding exons and preventing expression of functional dystrophin protein (6, 7). Therapies that induce “skipping” of exon 51 restore the reading frame and in principle could benefit ~13% of DMD patients (8).…”

mentioning

confidence: 99%

Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy

Amoasii

Hildyard

et al. 2018

Science

431

383

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Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of DMD harbors a mutation corresponding to a mutational “hotspot” in the human DMD gene. We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression 6 weeks after intramuscular delivery (n = 2) or 8 weeks after systemic delivery (n = 2). After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. These large-animal data support the concept that, with further development, gene editing approaches may prove clinically useful for the treatment of DMD.

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Distribution of dystrophin gene deletions in a Chinese population

Cited by 11 publications

References 36 publications

Single-cut genome editing restores dystrophin expression in a new mouse model of muscular dystrophy

Single-cut genome editing restores dystrophin expression in a new mouse model of muscular dystrophy

In vivo non-invasive monitoring of dystrophin correction in a new Duchenne muscular dystrophy reporter mouse

Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy

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