scholarly journals Exon skipping induced by nonsense/frameshift mutations in DMD gene results in Becker muscular dystrophy

2020 ◽  
Vol 139 (2) ◽  
pp. 247-255 ◽  
Author(s):  
Mariko Okubo ◽  
Satoru Noguchi ◽  
Shinichiro Hayashi ◽  
Harumasa Nakamura ◽  
Hirofumi Komaki ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Nonsense Mutation ◽  
Frameshift Mutation ◽  
Exon Skipping ◽  
Becker Muscular Dystrophy ◽  
Intronic Sequence ◽  
Frameshift Mutations ◽  
Dmd Gene ◽  
Accurate Quantification

AbstractDuchenne muscular dystrophy (DMD) is caused by a nonsense or frameshift mutation in the DMD gene, while its milder form, Becker muscular dystrophy (BMD) is caused by an in-frame deletion/duplication or a missense mutation. Interestingly, however, some patients with a nonsense mutation exhibit BMD phenotype, which is mostly attributed to the skipping of the exon containing the nonsense mutation, resulting in in-frame deletion. This study aims to find BMD cases with nonsense/frameshift mutations in DMD and to investigate the exon skipping rate of those nonsense/frameshift mutations. We searched for BMD cases with nonsense/frameshift mutations in DMD in the Japanese Registry of Muscular Dystrophy. For each DMD mutation identified, we constructed minigene plasmids containing one exon with/without a mutation and its flanking intronic sequence. We then introduced them into HeLa cells and measured the skipping rate of transcripts of the minigene by RT-qPCR. We found 363 cases with a nonsense/frameshift mutation in DMD gene from a total of 1497 dystrophinopathy cases in the registry. Among them, 14 had BMD phenotype. Exon skipping rates were well correlated with presence or absence of dystrophin, suggesting that 5% exon skipping rate is critical for the presence of dystrophin in the sarcolemma, leading to milder phenotypes. Accurate quantification of the skipping rate is important in understanding the exact functions of the nonsense/frameshift mutations in DMD and for interpreting the phenotypes of the BMD patients.

scholarly journals Becker muscular dystrophy caused by exon 2-truncating mutation of DMD

2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Tetsuhiko Ikeda ◽  
Hidehiko Fujinaka ◽  
Kiyoe Goto ◽  
Takashi Nakajima ◽  
Tetsuo Ozawa
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Frameshift Mutation ◽  
Clinical Course ◽  
Becker Muscular Dystrophy ◽  
Exon 2 ◽  
Mild Phenotype ◽  
Frameshift Mutations ◽  
Stop Codons ◽  
Truncating Mutation

AbstractNonsense and frameshift mutations of the dystrophin (DMD) gene usually cause severe Duchenne muscular dystrophy (DMD). Interestingly, however, premature stop codons in exons 1 and 2 result in relatively mild Becker muscular dystrophy (BMD). Herein, we report the clinical course of a patient with a very mild phenotype of BMD caused by a frameshift mutation, NM_004006.2: c.40_41del GA/p.(Glu14ArgfsX17), in exon 2 of the DMD gene.

scholarly journals Multiple Exon Skipping in the Duchenne Muscular Dystrophy Hot Spots: Prospects and Challenges

2018 ◽  
Vol 8 (4) ◽  
pp. 41 ◽  
Author(s):  
Yusuke Echigoya ◽  
Kenji Rowel Q. Lim ◽  
Akinori Nakamura ◽  
Toshifumi Yokota
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Exon Skipping ◽  
Becker Muscular Dystrophy ◽  
Therapeutic Modality ◽  
Therapeutic Concept ◽  
Patient Registration ◽  
Potential Therapeutic Application ◽  
Dmd Gene ◽  
Retrospective Database

Duchenne muscular dystrophy (DMD), a fatal X-linked recessive disorder, is caused mostly by frame-disrupting, out-of-frame deletions in the dystrophin (DMD) gene. Antisense oligonucleotide-mediated exon skipping is a promising therapy for DMD. Exon skipping aims to convert out-of-frame mRNA to in-frame mRNA and induce the production of internally-deleted dystrophin as seen in the less severe Becker muscular dystrophy. Currently, multiple exon skipping has gained special interest as a new therapeutic modality for this approach. Previous retrospective database studies represented a potential therapeutic application of multiple exon skipping. Since then, public DMD databases have become more useful with an increase in patient registration and advances in molecular diagnosis. Here, we provide an update on DMD genotype-phenotype associations using a global DMD database and further provide the rationale for multiple exon skipping development, particularly for exons 45–55 skipping and an emerging therapeutic concept, exons 3–9 skipping. Importantly, this review highlights the potential of multiple exon skipping for enabling the production of functionally-corrected dystrophin and for treating symptomatic patients not only with out-of-frame deletions but also those with in-frame deletions. We will also discuss prospects and challenges in multiple exon skipping therapy, referring to recent progress in antisense chemistry and design, as well as disease models.

Dystrophinopathy in a Family Due to a Rare Nonsense Mutation Causing Predominant Behavioral Phenotype

2019 ◽  
Vol 18 (04) ◽  
pp. 210-213
Author(s):  
Yohei Harada ◽  
Seth T. Sorensen ◽  
Akilandeswari Aravindhan ◽  
Vikki Stefans ◽  
Aravindhan Veerapandiyan
Keyword(s):  
Intellectual Disability ◽  
Muscular Dystrophy ◽  
Behavioral Problems ◽  
Nonsense Mutation ◽  
Neuromuscular Disorders ◽  
Elevated Serum ◽  
Becker Muscular Dystrophy ◽  
Genetic Changes ◽  
Dmd Gene ◽  
Neurobehavioral Deficits

AbstractDystrophinopathies are a group of X-linked neuromuscular disorders resulting from mutations in DMD gene that encodes dystrophin. The clinical spectrum includes Duchenne muscular dystrophy, Becker muscular dystrophy, X-linked cardiomyopathy, and intellectual disability without involvement of skeletal muscle. Cognitive and behavioral problems are commonly seen among patients with dystrophinopathy. DMD gene is the largest human gene, consisting of 79 exons that produce dystrophin protein. Patients with genetic changes involving shorter dystrophin isoforms such as Dp140 and Dp71 are suggested to have higher rates of intellectual disability, attention-deficit/hyperactivity disorder, and other neuropsychiatric comorbidities. We describe three brothers who presented with prominent neurobehavioral deficits of varying degree, mild proximal weakness, and elevated serum creatine kinase due to a rare nonsense mutation, c.1702C > T; p.Gln568X, in exon 14 of DMD gene. Further studies are needed to better understand the effects of this rare mutation.

scholarly journals Accurate quantification of dystrophin mRNA and exon skipping levels in Duchenne Muscular Dystrophy

2010 ◽  
Vol 90 (9) ◽  
pp. 1396-1402 ◽  
Author(s):  
Pietro Spitali ◽  
Hans Heemskerk ◽  
Rolf HAM Vossen ◽  
Alessandra Ferlini ◽  
Johan T den Dunnen ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Exon Skipping ◽  
Accurate Quantification

scholarly journals Comparison of Long-term Ambulatory Function in Patients with Duchenne Muscular Dystrophy Treated with Eteplirsen and Matched Natural History Controls

2021 ◽  
pp. 1-11
Author(s):  
Jerry R. Mendell ◽  
Navid Khan ◽  
Nanshi Sha ◽  
Helen Eliopoulos ◽  
Craig M. McDonald ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Gene Mutations ◽  
Exon Skipping ◽  
Term Treatment ◽  
Long Term Treatment ◽  
The Difference ◽  
Dmd Gene ◽  
6 Minute Walk Test

Background: Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal, degenerative neuromuscular disease caused by DMD gene mutations. A relationship between exon skipping and dystrophin production in exon 51-amenable patients treated with eteplirsen (EXONDYS 51 ®) is established. Once-weekly eteplirsen significantly increased dystrophin, with slower decline in ambulatory function compared to baseline. Long-term treatment with eteplirsen leads to accumulation of dystrophin over time and observed functional benefits in patients with DMD. Objective: Compare long-term ambulatory function in eteplirsen-treated patients versus controls. Methods: Study 201/202 included 12 eteplirsen-treated patients assessed twice/year for ambulatory function over 4 years. Ambulatory evaluations (6-minute walk test [6MWT], loss of ambulation, and North Star Ambulatory Assessment [NSAA]) were compared with matched controls from Italian Telethon and Leuven registries. Results: At Years 3 and 4, eteplirsen-treated patients demonstrated markedly greater mean 6MWT than controls (difference in change from baseline of 132 m [95%CI (29, 235), p = 0.015] at Year 3 and 159 m [95%CI (66, 253), p = 0.002] at Year 4). At Year 4, a significantly greater proportion of eteplirsen-treated patients were still ambulant versus controls (10/12 vs 3/11; p = 0.020). At Year 3, eteplirsen-treated patients had milder NSAA decline than controls (difference in change from baseline of 2.6, 95%CI [-6, 11]), however, the difference was not statistically significant; Year 4 control NSAA data were not available. Conclusion: In this retrospective matched control study, eteplirsen treatment resulted in attenuation of ambulatory decline over a 4-year observation period, supporting long-term benefit in patients with DMD.

Comprehensive analysis: Nonsense mutation induced exon skipping in Becker muscular dystrophy

2017 ◽  
Vol 27 ◽  
pp. S104 ◽  
Author(s):  
M. Okubo ◽  
S. Noguchi ◽  
E. Kimura ◽  
S. Mitsuhashi ◽  
I. Nishino
Keyword(s):  
Muscular Dystrophy ◽  
Nonsense Mutation ◽  
Exon Skipping ◽  
Becker Muscular Dystrophy ◽  
Comprehensive Analysis

scholarly journals The lncRNA 44s2 Study Applicability to the Design of 45-55 Exon Skipping Therapeutic Strategy for DMD

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 219
Author(s):  
Elena Gargaun ◽  
Sestina Falcone ◽  
Guilhem Solé ◽  
Julien Durigneux ◽  
Andoni Urtizberea ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Gene Mutations ◽  
Exon Skipping ◽  
Becker Muscular Dystrophy ◽  
Protein Stabilization ◽  
Progressive Muscular Dystrophy ◽  
Dilatative Cardiomyopathy ◽  
Proliferation And Differentiation ◽  
Dmd Gene ◽  
Dystrophin Protein

In skeletal muscle, long noncoding RNAs (lncRNAs) are involved in dystrophin protein stabilization but also in the regulation of myocytes proliferation and differentiation. Hence, they could represent promising therapeutic targets and/or biomarkers for Duchenne and Becker muscular dystrophy (DMD/BMD). DMD and BMD are X-linked myopathies characterized by a progressive muscular dystrophy with or without dilatative cardiomyopathy. Two-thirds of DMD gene mutations are represented by deletions, and 63% of patients carrying DMD deletions are eligible for 45 to 55 multi-exons skipping (MES), becoming BMD patients (BMDΔ45-55). We analyzed the genomic lncRNA presence in 38 BMDΔ45-55 patients and characterized the lncRNA localized in introns 44 and 55 of the DMD gene. We highlighted that all four lncRNA are differentially expressed during myogenesis in immortalized and primary human myoblasts. In addition, the lncRNA44s2 was pointed out as a possible accelerator of differentiation. Interestingly, lncRNA44s expression was associated with a favorable clinical phenotype. These findings suggest that lncRNA44s2 could be involved in muscle differentiation process and become a potential disease progression biomarker. Based on these results, we support MES45-55 therapy and propose that the design of the CRISPR/Cas9 MES45-55 assay consider the lncRNA sequences bordering the exonic 45 to 55 deletion.

scholarly journals Single Exon Skipping Can Address a Multi-Exon Duplication in the Dystrophin Gene

2020 ◽  
Vol 21 (12) ◽  
pp. 4511 ◽  
Author(s):  
Kane Greer ◽  
Russell Johnsen ◽  
Yoram Nevo ◽  
Yakov Fellig ◽  
Susan Fletcher ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Exon Skipping ◽  
Dystrophin Gene ◽  
Duchenne Muscular Dystrophy Patient ◽  
Exon Duplication ◽  
Dmd Gene ◽  
Muscle Wasting Disease ◽  
Phosphorodiamidate Morpholino Oligomers

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease typically caused by protein-truncating mutations that preclude synthesis of a functional dystrophin. Exonic deletions are the most common type of DMD lesion, however, whole exon duplications account for between 10–15% of all reported mutations. Here, we describe in vitro evaluation of antisense oligonucleotide-induced splice switching strategies to re-frame the transcript disrupted by a multi-exon duplication within the DMD gene. Phosphorodiamidate morpholino oligomers and phosphorodiamidate morpholino oligomers coupled to a cell penetrating peptide were evaluated in a Duchenne muscular dystrophy patient cell strain carrying an exon 14–17 duplication. Two strategies were employed; the conventional approach was to remove both copies of exon 17 in addition to exon 18, and the second strategy was to remove only the first copy of exon 17. Both approaches result in a larger than normal but in-frame DMD transcript, but surprisingly, the removal of only the first exon 17 appeared to be more efficient in restoring dystrophin, as determined using western blotting. The emergence of a normal sized DMD mRNA transcript that was not apparent in untreated samples may have arisen from back splicing and could also account for some of the dystrophin protein being produced.

scholarly journals New Approach for Antisense Oligonucleotide-Mediated Exon Skipping in Duchenne Muscular Dystrophy

2012 ◽  
Vol 16 (4) ◽  
pp. 521-526
Author(s):  
Yoshitsugu Aoki ◽  
◽  
Tetsuya Nagata ◽  
Shin’ichi Takeda
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Antisense Oligonucleotide ◽  
Antisense Oligonucleotides ◽  
Exon Skipping ◽  
New Approach ◽  
Reading Frame ◽  
Promising Therapeutic Approach ◽  
Dmd Gene ◽  
Dystrophin Protein

Duchenne Muscular Dystrophy (DMD) is a lethalmuscle disorder characterized by mutations in the DMD gene. These mutations primarily disrupt the reading frame, resulting in the absence of functional dystrophin protein. Exon skipping, which involves the use of antisense oligonucleotides is a promising therapeutic approach for DMD, and clinical trials on exon skipping are currently underway in DMD patients. Recently, stable and less-toxic antisense oligonucleotides with higher efficacy have been developed in mouse and dog models of DMD. This review highlights a new approach for antisense oligonucleotide-based therapeutics for DMD, particularly for exon skipping-based methods.

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