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Author(s):  
Emma M. Wade ◽  
Zandra A. Jenkins ◽  
Tim Morgan ◽  
Gregory Gimenez ◽  
Hayley Gibson ◽  
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2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Botao Zhang ◽  
Quanyou Wu ◽  
Shujun Cheng ◽  
Wenbin Li

Despite many changes in alternative splicing events (ASEs) are frequently involved in various cancers, prognosis-related ASEs and drug treatment targets in glioblastoma multiforme (GBM) have not been well explored. ASEs participate in many biological behaviors in the initiation and progression of tumors, the aberrant ASE has been considered another hallmark of cancer, and the systematic study of alternative splicing may provide potential biomarkers for malignancies. In this study, we carried out a systematic analysis to characterize the ASE signatures in GBM cohort. Through comparing GBM tissues and nontumor tissues, a total of 48,191 differently expressed ASEs from 10,727 genes were obtained, and these aberrant ASEs play an important role in the oncogenic process. Then, we identified 514 ASEs independently associated with patient survival in GBM by univariate and multivariate Cox regression, including exon skip in CD3D, alternate acceptor site in POLD2, and exon skip in DCN. Those prognostic models built on ASEs of each splice type can accurately predict the outcome of GBM patients, and values for the area under curve were 0.97 in the predictive model based on alternate acceptor site. In addition, the splicing-regulatory network revealed an interesting correlation between survival-associated splicing factors and prognostic ASE corresponding genes. Moreover, these three hub splicing factors in splicing regulation network are the potential targets of some drugs. In conclusion, a systematic analysis of ASE signatures in GBM could serve as an indicator for identifying novel prognostic biomarkers and guiding clinical treatment.


2021 ◽  
Vol 11 (1) ◽  
pp. 46
Author(s):  
Saeed Anwar ◽  
Merry He ◽  
Kenji Rowel Q. Lim ◽  
Rika Maruyama ◽  
Toshifumi Yokota

Dystrophinopathies are caused by mutations in the DMD gene. Out-of-frame deletions represent most mutational events in severe Duchenne muscular dystrophy (DMD), while in-frame deletions typically lead to milder Becker muscular dystrophy (BMD). Antisense oligonucleotide-mediated exon skipping converts an out-of-frame transcript to an in-frame one, inducing a truncated but partially functional dystrophin protein. The reading frame rule, however, has many exceptions. We thus sought to simulate clinical outcomes of exon-skipping therapies for DMD exons from clinical data of exon skip-equivalent in-frame deletions, in which the expressed quasi-dystrophins are comparable to those resulting from exon-skipping therapies. We identified a total of 1298 unique patients with exon skip-equivalent mutations in patient registries and the existing literature. We classified them into skip-equivalent deletions of each exon and statistically compared the ratio of DMD/BMD and asymptomatic individuals across the DMD gene. Our analysis identified that five exons are associated with significantly milder phenotypes than all other exons when corresponding exon skip-equivalent in-frame deletion mutations occur. Most exon skip-equivalent in-frame deletions were associated with a significantly milder phenotype compared to corresponding exon skip-amenable out-of-frame mutations. This study indicates the importance of genotype-phenotype correlation studies in the rational design of exon-skipping therapies.


Biochemistry ◽  
2019 ◽  
Vol 58 (15) ◽  
pp. 2061-2076 ◽  
Author(s):  
Krystal Manyuan Ma ◽  
Evelyn S. Thomas ◽  
Jeff Wereszczynski ◽  
Nick Menhart

2019 ◽  
Author(s):  
Krystal Manyuan Ma ◽  
Evelyn S Thomas ◽  
Jeff Wereszczynski ◽  
Nick Menhart

AbstractDuchenne muscular dystrophy is a common and devastating genetic disease that is primarily caused by exon deletions that create a genetic frameshift in dystrophin. Exon skipping therapy seeks to correct this by masking an exon during the mRNA maturation process, which restores dystrophin expression, but creates an edited protein missing both the original defect and the therapeutically skipped region. Crucially, it is possible to correct many defects in alternative ways, by skipping an exon either before, or after the patient’s defect. This results in alternatively edited, hybrid proteins, of possibly different properties and therapeutic consequences. Here, we examined three such dystrophin exon skipped edits, comprising two pairs of alternative repairs of the same underlying DMD defect. We found that in both cases, one member of each alternative repair was more stable than the other by a variety of thermodynamic and biochemical measures. We also examined the origin of these differences by molecular dynamics simulations, which showed that these stability differences were the result of different types of structural perturbations. For example, in one edit there was partial unfolding at the edit site which caused domain-localized perturbations, while in another there was unfolding at the protein domain junctions distal to the edit site which increased molecular flexibility. These results demonstrate that alternative exon skip repairs of the same underlying defect can have very different consequences at the level of protein structure and stability, and furthermore that these can arise by different mechanisms, either locally, or by more subtle long-range perturbations.


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