Dystrophin Dp116: A yet to Be Investigated Product of the Duchenne Muscular Dystrophy Gene

Matsuo, Masafumi; Awano, Hiroyuki; Matsumoto, Masaaki; Nagai, Masashi; Kawaguchi, Tatsuya; Zhang, Zhujun; Nishio, Hisahide

doi:10.3390/8100251

Cited by 8 publications

(11 citation statements)

References 32 publications

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“…This suggests that other parameters should be considered when evaluating the consequences of in-frame mutations on dystrophin structure, such as effects on overall protein flexibility or intra-protein interactions between residues. However, it is important to point out that knowing this information would still not be sufficient to explain certain cases, such as why the same in-frame deletion leads to a mix of DMD and BMD patients (e.g., deletions of exons [45][46][47][45][46][47][48][49]48,[48][49][49][50][51]Figure 4c and Figure S1b). In these cases, genetic modifiers [31,32] or spontaneous exon skipping events (as discussed in the next paragraph) may play a role in determining patient phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Genotype–Phenotype Correlations in Duchenne and Becker Muscular Dystrophy Patients from the Canadian Neuromuscular Disease Registry

Lim

Nguyen

Yokota

2020

JPM

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Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder generally caused by out-of-frame mutations in the DMD gene. In contrast, in-frame mutations usually give rise to the milder Becker muscular dystrophy (BMD). However, this reading frame rule does not always hold true. Therefore, an understanding of the relationships between genotype and phenotype is important for informing diagnosis and disease management, as well as the development of genetic therapies. Here, we evaluated genotype–phenotype correlations in DMD and BMD patients enrolled in the Canadian Neuromuscular Disease Registry from 2012 to 2019. Data from 342 DMD and 60 BMD patients with genetic test results were analyzed. The majority of patients had deletions (71%), followed by small mutations (17%) and duplications (10%); 2% had negative results. Two deletion hotspots were identified, exons 3–20 and exons 45–55, harboring 86% of deletions. Exceptions to the reading frame rule were found in 13% of patients with deletions. Surprisingly, C-terminal domain mutations were associated with decreased wheelchair use and increased forced vital capacity. Dp116 and Dp71 mutations were also linked with decreased wheelchair use, while Dp140 mutations significantly predicted cardiomyopathy. Finally, we found that 12.3% and 7% of DMD patients in the registry could be treated with FDA-approved exon 51- and 53-skipping therapies, respectively.

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Section: Discussionmentioning

confidence: 99%

Genotype–Phenotype Correlations in Duchenne and Becker Muscular Dystrophy Patients from the Canadian Neuromuscular Disease Registry

Lim

Nguyen

Yokota

2020

JPM

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“…In our study, we also observed additional protein bands, especially in the bladder samples of 6‐month‐old rats in the 71–140 kDa range. Next to multiple splice variants of Dp140, an isoform with a size of 116 kDa is known to exist . Moreover, a protein band appeared about the size of 40 kDa.…”

Section: Discussionmentioning

confidence: 99%

Dystrophin is expressed in smooth muscle and afferent nerve fibers in the rat urinary bladder

et al. 2019

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Introduction With increasing life expectancy, comorbidities become overt in Duchenne muscular dystrophy (DMD). Although micturition problems are common, bladder function is poorly understood in DMD. We studied dystrophin expression and multiple isoform involvement in the bladder during maturation to gain insights into their roles in micturition. Methods Dystrophin distribution was evaluated in rat bladders by immunohistochemical colocalization with smooth muscle, interstitial, urothelial, and neuronal markers. Protein levels of Dp140, Dp71, and smooth muscle were quantitated by Western blotting of neonatal to adult rat bladders. Results Dystrophin colocalized with smooth muscle cells and afferent nerve fibers. Dp71 was expressed two‐ to threefold higher compared with Dp140, independently of age. Age‐related muscle mass changes did not influence isoform expression levels. Discussion Dystrophin is expressed in smooth muscle cells and afferent nerve fibers in the urinary bladder, which underscores that micturition problems in DMD may have not solely a myogenic but also a neurogenic origin. Muscle Nerve 60: 202–210, 2019

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“…Although Dp116 is expressed in a Schwann cell-specific manner [7], its expression was analyzed in U-251 glioblastoma cells. To assess its expression, it was necessary to amplify full-length Dp116 cDNA as a single product.…”

Section: Resultsmentioning

confidence: 99%

“…Dp116, the second shortest isoform of the DMD gene, is transcribed from the Dp116 promoter in intron 55. Dp116 transcript is 5.2 kb long and consists of the Dp116-specific exon S1 joined to DMD exons 56–79 [6,7]. The Dp116 promoter is characterized by its very specific activation in Schwann cells [2].…”

Section: Introductionmentioning

confidence: 99%

“…The Dp116 promoter is characterized by its very specific activation in Schwann cells [2]. Due to its limited expression and large size, the pathophysiological roles of Dp116 are largely unknown [7]. We recently reported that Dp116 plays a role in the development of cardiac dysfunction in DMD patients [8], suggesting that Dp116 expression is not limited to Schwann cells.…”

Section: Introductionmentioning

confidence: 99%

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Schwann cell-specific Dp116 is expressed in glioblastoma cells, revealing two novel DMD gene splicing patterns

Rani

Maeta

Kawaguchi

et al. 2019

Biochemistry and Biophysics Reports

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BackgroundThe DMD gene is one of the largest human genes, being composed of 79 exons. Dystrophin Dp116 expressed from the promoter in intron 55 is a Schwann cell-specific isoform. The pathophysiological roles of Dp116 are largely unknown, because of its limited expression. This study assessed the expression of Dp116 in glioblastoma cells and evaluated the splicing patterns of the DMD gene in these cells.MethodsFull-length Dp116 cDNA was PCR amplified from U-251 glioblastoma cells. Dp116 protein was analyzed by Western blotting.ResultsFull-length Dp116 cDNA, extending from exon S1 to exon 79, was PCR amplified to avoid confusion with other DMD isoforms. The full-length Dp116 transcript was amplified as nearly 3 kb in size. Western blotting of U-251 cell lysates revealed a signal at a position corresponding to vector-expressed Dp116 protein, indicating that Dp116 is expressed in glioblastoma cells. Sequencing of the amplified product revealed five splice variants, all skipping exon 78. The most abundant transcript lacked only exon 78 (Dp116b), whereas the second most abundant transcript lacked both exons 71 and 78 (Dp116ab). A third transcript lacking exons 71–74 and 78 was also identified (Dp116bc). Two novel splicing patterns were also observed, one with a deletion of exons 68 and 69 (Dp116bΔ68-69) and the other with a 100 bp deletion in the 5’ terminal end of exon 75 (75s), which was produced by the activation of a cryptic splice acceptor site (Dp116b75s). However, the splicing patterns in glioblastoma cells of DMD exons in Dp116 and Dp71 showed no significant differences.ConclusionsDp116 is expressed in glioblastoma cells as five splicing variants, with Dp116b being the most abundant. Two novel splicing patterns of DMD exons were observed.

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Dystrophin Dp116: A yet to Be Investigated Product of the Duchenne Muscular Dystrophy Gene

Cited by 8 publications

References 32 publications

Genotype–Phenotype Correlations in Duchenne and Becker Muscular Dystrophy Patients from the Canadian Neuromuscular Disease Registry

Genotype–Phenotype Correlations in Duchenne and Becker Muscular Dystrophy Patients from the Canadian Neuromuscular Disease Registry

Dystrophin is expressed in smooth muscle and afferent nerve fibers in the rat urinary bladder

Schwann cell-specific Dp116 is expressed in glioblastoma cells, revealing two novel DMD gene splicing patterns

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