The emperor's new dystrophin: finding sense in the noise

Wilton, Steve D.; Veedu, Rakesh N.; Fletcher, Sue

doi:10.1016/j.molmed.2015.04.006

Cited by 36 publications

(30 citation statements)

References 118 publications

(164 reference statements)

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“…Shortened micro-dystrophins have been designed based on BMD phenotypes by deleting some repeats that were assumed to be more dispensable than others (10,12). Most of them were designed according to the less severe BMD deletion of exon 17 to 48 (8) and to the repeat phasing proposed by Harper (43).…”

Section: Discussionmentioning

confidence: 99%

“…According to the Monaco rule (5), DMD is mostly due to out-of-frame mutations in the DMD gene that result in a complete loss of the protein and a severe phenotype, while in-frame mutations of the DMD gene are mainly associated with BMD where modified dystrophin is produced resulting in reputed less severe phenotypes. Most BMD mutations are in-frame genomic deletions that lead to proteins lacking part of the central domain repeats (6,7) and constitute the pattern for therapeutic strategies aiming to transform DMD patients into BMD patients (8) either by exon skipping, by injection of micro-dystrophins (9)(10)(11)(12) or by CRSIPR/cas9 gene edition (13,14). Indeed, the central domain has been until now considered as a monotonous rod-shaped domain which could be internally truncated without dramatic functional effects (2,15).…”

Section: Introductionmentioning

confidence: 99%

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Dystrophin's central domain forms a complex filament that becomes disorganized by in-frame deletions

Delalande

Molza

Morais

et al. 2018

Journal of Biological Chemistry

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Dystrophin, encoded by the DMD gene, is critical for maintaining plasma membrane integrity during muscle contraction events. Mutations in the DMD gene disrupting the reading frame prevent dystrophin production and result in the high severe Duchenne muscular dystrophy (DMD); in-frame internal deletions allow production of partly functional internally deleted dystrophin and result in the less severe Becker muscular dystrophy (BMD). Many known BMD deletions occur in dystrophin's central domain, generally considered to be a monotonous rod-shaped domain based on the knowledge of spectrin-family proteins. However, effects caused by these deletions, ranging from asymptomatic to severe BMD, argue against the central domain serving only as a featureless scaffold. We undertook structural studies combining small-angle X-ray scattering and molecular modeling in an effort to uncover the structure of the central domain as dystrophin has been refractory to characterization. We show that this domain appears to be a tortuous and complex filament that is profoundly disorganized by the most severe BMD deletion (loss of exon 45-47). Despite the preservation of large parts of the binding site for neuronal nitric oxide synthase (nNOS) in this deletion, computational approaches failed to recreate the association of dystrophin with nNOS. This observation is in agreement with a strong decrease of nNOS immunolocalization in muscle biopsies, a parameter related to the severity of BMD phenotypes. The structural description of the whole dystrophin central domain we present here is a first necessary step to improve the design of microdystrophin constructs in the goal of a successful gene therapy for DMD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dystrophin's central domain forms a complex filament that becomes disorganized by in-frame deletions

Delalande

Molza

Morais

et al. 2018

Journal of Biological Chemistry

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“…The proof of concept has been largely demonstrated [60][61][62][63][64][65][66] [67] and there are now human trials in progress using oligonucleotides injection using AAV [68][69][70][71][72](see the excellent reviews about therapy [56,[73][74]). For example, the deletions of exon 46 or 44 both shift the reading frame and result in no dystrophin production.…”

Section: Dystrophin and Dmd Therapymentioning

confidence: 99%

Dystrophin and the two related genetic diseases, Duchenne and Becker muscular dystrophies

Rumeur¹

2015

Biomol Biomed

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Mutations of the dystrophin DMD gene, essentially deletions of one or several exons, are the cause of two devastating and to date incurable diseases, Duchenne (DMD) and Becker (BMD) muscular dystrophies. Depending upon the preservation or not of the reading frame, dystrophin is completely absent in DMD, or present in either a mutated or a truncated form in BMD. DMD is a severe disease which leads to a premature death of the patients. Therapy approaches are evolving with the aim to transform the severe DMD in the BMD form of the disease by restoring the expression of a mutated or truncated dystrophin. These therapies are based on the assumption that BMD is a mild disease. However, this is not completely true as BMD patients are more or less severely affected and no molecular basis of this heterogeneity of the BMD form of the disease is yet understood. The aim of this review is to report for the correlation between dystrophin structures in BMD deletions in view of this heterogeneity and to emphasize that examining BMD patients in details is highly relevant to anticipate for DMD therapy effects.

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“…Skipping of in-frame mutated exons and deletions by antisense oligonucleotides (AONs) has long been considered a promising therapeutic strategy for DMD. This strategy aims at artificially inducing favorable exclusion of mutated/out-of-frame exons to restore the correct reading frame 4 . The exciting prospect of an effective AON-based exon skipping therapy was raised by promising data from early clinical trials that were, however, not confirmed by double-blind, placebo-controlled phase IIb and III trials, which failed to meet efficacy endpoints 5 .…”

Section: Introductionmentioning

confidence: 99%

Correction of the Exon 2 Duplication in DMD Myoblasts by a Single CRISPR/Cas9 System

Lattanzi

Duguez

Moiani

et al. 2017

Molecular Therapy - Nucleic Acids

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Exonic duplications account for 10%–15% of all mutations in Duchenne muscular dystrophy (DMD), a severe hereditary neuromuscular disorder. We report a CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9-based strategy to correct the most frequent (exon 2) duplication in the DMD gene by targeted deletion, and tested the efficacy of such an approach in patient-derived myogenic cells. We demonstrate restoration of wild-type dystrophin expression at transcriptional and protein level in myotubes derived from genome-edited myoblasts in the absence of selection. Removal of the duplicated exon was achieved by the use of only one guide RNA (gRNA) directed against an intronic duplicated region, thereby increasing editing efficiency and reducing the risk of off-target effects. This study opens a novel therapeutic perspective for patients carrying disease-causing duplications.

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The emperor's new dystrophin: finding sense in the noise

Cited by 36 publications

References 118 publications

Dystrophin's central domain forms a complex filament that becomes disorganized by in-frame deletions

Dystrophin's central domain forms a complex filament that becomes disorganized by in-frame deletions

Dystrophin and the two related genetic diseases, Duchenne and Becker muscular dystrophies

Correction of the Exon 2 Duplication in DMD Myoblasts by a Single CRISPR/Cas9 System

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