Splicing Characteristics of Dystrophin Pseudoexons and Identification of a Novel Pathogenic Intronic Variant in the DMD Gene

Xie, Zhiying; Tang, Liuqin; Xie, Zhenghua; Sun, Chengyue; Shuai, Haoyue; Zhou, Chao; Liu, Yilin; Yu, Meng; Zheng, Yiming; Meng, Lingchao; Zhang, Wei; Leal, Suzanne M.; Wang, Zhaoxia; Schrauwen, Isabelle; Yuan, Yun

doi:10.3390/genes11101180

Cited by 10 publications

(13 citation statements)

References 37 publications

(82 reference statements)

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“…Instead, we collected 133 pseudoexons from literature, experimentally confirmed using patient, mini, or midigene-derived RNA. Notably, similar findings to our results using approaches other than ESRseq tools have been recently reported, in 42 pseudoexons experimentally validated in the DMD gene, showing a smaller density of exonic splicing enhancers (ESEs) together with a higher density of exonic splicing silencers (ESSs) compared to canonical exons, which suggested that the pseudoexons presented a weaker exon profile in terms of SREs [30]. Interestingly, these differences have also been observed between alternative and canonical exons.…”

Section: Discussionsupporting

confidence: 90%

“…Moreover, the arrangement of cis splicing elements in deep intronic regions, especially those corresponding to regulatory elements, would configure sequences with structures similar to those of canonical exons [30,31]. This landscape of regulatory zones would favor the generation of pseudoexons if a new deep intronic variant helps to define these structures.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, in this study we also compare the SRE presence between canonical exons of HBOC genes and published pseudoexons in order to characterize an "exon-like landscape" across introns which would help to identify potentially "exonizable" intronic regions. Moreover, the arrangement of cis splicing elements in deep intronic regions, especially those corresponding to regulatory elements, would configure sequences with structures similar to those of canonical exons [30,31]. This landscape of regulatory zones would favor the generation of pseudoexons if a new deep intronic variant helps to define these structures.…”

Section: Introductionmentioning

confidence: 99%

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Role of Splicing Regulatory Elements and In Silico Tools Usage in the Identification of Deep Intronic Splicing Variants in Hereditary Breast/Ovarian Cancer Genes

Moles‐Fernández¹,

Domènech-Vivó²,

Tenés

et al. 2021

Cancers

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The contribution of deep intronic splice-altering variants to hereditary breast and ovarian cancer (HBOC) is unknown. Current computational in silico tools to predict spliceogenic variants leading to pseudoexons have limited efficiency. We assessed the performance of the SpliceAI tool combined with ESRseq scores to identify spliceogenic deep intronic variants by affecting cryptic sites or splicing regulatory elements (SREs) using literature and experimental datasets. Our results with 233 published deep intronic variants showed that SpliceAI, with a 0.05 threshold, predicts spliceogenic deep intronic variants affecting cryptic splice sites, but is less effective in detecting those affecting SREs. Next, we characterized the SRE profiles using ESRseq, showing that pseudoexons are significantly enriched in SRE-enhancers compared to adjacent intronic regions. Although the combination of SpliceAI with ESRseq scores (considering ∆ESRseq and SRE landscape) showed higher sensitivity, the global performance did not improve because of the higher number of false positives. The combination of both tools was tested in a tumor RNA dataset with 207 intronic variants disrupting splicing, showing a sensitivity of 86%. Following the pipeline, five spliceogenic deep intronic variants were experimentally identified from 33 variants in HBOC genes. Overall, our results provide a framework to detect deep intronic variants disrupting splicing.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of Splicing Regulatory Elements and In Silico Tools Usage in the Identification of Deep Intronic Splicing Variants in Hereditary Breast/Ovarian Cancer Genes

Moles‐Fernández¹,

Domènech-Vivó²,

Tenés

et al. 2021

Cancers

View full text Add to dashboard Cite

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“…DMD is one of the largest genes within the human genome, containing 79 protein-coding exons and 42 putative PEs. Importantly, an intronic pathogenic variant of the DMD gene may activate the inclusion of PEs, resulting in disease manifestation ( Xie et al, 2020 ). While PE usage is implicated in dystrophinopathies, the pathophysiology of both myotonic dystrophy type 1 (DM1) and type 2 (DM2) is also associated with the sequestration of Muscleblind-like (MBNL) proteins to RNAs containing CUG or CCUG repeats ( Sznajder and Swanson, 2019 ).…”

Section: Aberrant Pe Regulation Is Implicated In Neurological Disordersmentioning

confidence: 99%

Exploring the Diverse Functional and Regulatory Consequences of Alternative Splicing in Development and Disease

2021

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Alternative splicing is a fundamental mechanism of eukaryotic RNA regulation that increases the transcriptomic and proteomic complexity within an organism. Moreover, alternative splicing provides a framework for generating unique yet complex tissue- and cell type-specific gene expression profiles, despite using a limited number of genes. Recent efforts to understand the negative consequences of aberrant splicing have increased our understanding of developmental and neurodegenerative diseases such as spinal muscular atrophy, frontotemporal dementia and Parkinsonism linked to chromosome 17, myotonic dystrophy, and amyotrophic lateral sclerosis. Moreover, these studies have led to the development of innovative therapeutic treatments for diseases caused by aberrant splicing, also known as spliceopathies. Despite this, a paucity of information exists on the physiological roles and specific functions of distinct transcript spliceforms for a given gene. Here, we will highlight work that has specifically explored the distinct functions of protein-coding spliceforms during development. Moreover, we will discuss the use of alternative splicing of noncoding exons to regulate the stability and localization of RNA transcripts.

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“…PEs have been extensively studied in the context of RBPs, and, in particular, SR proteins, and the presence of pathogenic variants within and around PEs in SR genes and also in functionally unrelated genes has been linked to neurodevelopmental disorders (NDDs) [5]. Finally, the misregulation of PE splicing has also been identified in individuals with Duchenne muscular dystrophy, Ewing sarcoma, and other types of cancer [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Targeting Poison Exons to Treat Developmental and Epileptic Encephalopathy

2021

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Developmental and epileptic encephalopathies (DEEs) describe a subset of neurodevelopmental disorders categorized by refractory epilepsy that is often associated with intellectual disability and autism spectrum disorder. The majority of DEEs are now known to have a genetic basis with de novo coding variants accounting for the majority of cases. More recently, a small number of individuals have been identified with intronic <i>SCN1A</i> variants that result in alternative splicing events that lead to ectopic inclusion of poison exons (PEs). PEs are short highly conserved exons that contain a premature truncation codon, and when spliced into the transcript, lead to premature truncation and subsequent degradation by nonsense-mediated decay. The reason for the inclusion/exclusion of these PEs is not entirely clear, but research suggests an autoregulatory role in gene expression and protein abundance. This is seen in proteins such as RNA-binding proteins and serine/arginine-rich proteins. Recent studies have focused on targeting these PEs as a method for therapeutic intervention. Targeting PEs using antisense oligonucleotides (ASOs) has shown to be effective in modulating alternative splicing events by decreasing the amount of transcripts harboring PEs, thus increasing the abundance of full-length transcripts and thereby the amount of protein in haploinsufficient genes implicated in DEE. In the age of personalized medicine, cellular and animal models of the genetic epilepsies have become essential in developing and testing novel precision therapeutics, including PE-targeting ASOs in a subset of DEEs.

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Splicing Characteristics of Dystrophin Pseudoexons and Identification of a Novel Pathogenic Intronic Variant in the DMD Gene

Cited by 10 publications

References 37 publications

Role of Splicing Regulatory Elements and In Silico Tools Usage in the Identification of Deep Intronic Splicing Variants in Hereditary Breast/Ovarian Cancer Genes

Role of Splicing Regulatory Elements and In Silico Tools Usage in the Identification of Deep Intronic Splicing Variants in Hereditary Breast/Ovarian Cancer Genes

Exploring the Diverse Functional and Regulatory Consequences of Alternative Splicing in Development and Disease

Targeting Poison Exons to Treat Developmental and Epileptic Encephalopathy

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