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Alternative Splicing and Human Disease
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Alternative Splicing and Human Disease

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 11728

Special Issue Editors

Dr. Monica Rienzo

E-Mail Website
Guest Editor
Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
Interests: PRDM genes; cancer; transcriptional regulation
Special Issues, Collections and Topics in MDPI journals
Dr. Erika Zazzo

E-Mail Website
Guest Editor
Department of Medicine and Health Science, University of Molise, Campobasso, Italy
Interests: PRDM genes; cancers; signal transduction; cancer; cell cycle; apoptosis; androgens; estrogens; prostate cancer; breast cancer; oxidative stress; steroid receptors; testicular germ cell tumors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Transcriptomics is a reference research field, especially in the study of human diseases. The transcriptome includes full information about all RNAs transcribed from the genome in a specific tissue or cell type, at a precise developmental stage, and under a definite physiological or pathological condition. Thus, transcriptome analysis not only allows an understanding of the human genome at the transcription level but also provides a comprehension of gene structure and function, gene expression regulation, and genome plasticity. Several mechanisms are responsible for the formation of protein isoforms, increasing transcriptomic and proteomic diversity, such as genetic variations, somatic recombination, post-translational and proteolytic modifications, and alternative splicing.

Alternative splicing is an evolutionarily conserved mechanism that contributes to the complexity of an organism by allowing the generation of more mRNA products from a single gene. In the last decade, RNA-Seq studies have revealed the close link between splicing deregulation and many human diseases, so that also therapeutic strategies specifically targeting splicing defects are currently under investigation. Human diseases showing aberrant RNA splicing range from neurological pathologies to immunohematology disorders and malignancies. Splicing mechanism and the regulation of alternative splicing can be disrupted both by mutations within cis‐acting elements needed for correct pre‐mRNA processing and by mutations that affect trans‐acting components that are required for splicing regulation. Effects on splicing can be direct causative agents of disease, contributors to the susceptibility to disease, or modulators of disease severity.

In this Special Issue, we are inviting reviews, perspectives, and original research articles to address the identification and characterization of novel splicing events in human disease. Topics include, but not limited to, novel isoforms by alternative events, clinical applications, isoforms as possible biomarkers, signaling pathways, and preclinical models.

Dr. Monica Rienzo
Dr. Erica di Zazzo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • alternative splicing
  • alternative transcripts
  • gene expression analysis
  • next-generation sequencing
  • RNA structure
  • genome structure
  • human health and diseases
  • RNA structure
  • transcription machinery
  • transcriptomics

Published Papers (3 papers)

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Research

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17 pages, 2687 KiB  
Article
Prognostic Value and Potential Regulatory Mechanism of Alternative Splicing in Geriatric Breast Cancer
by Xin Li, Yaxuan Wang, Bingjie Li and Wang Ma
Genes 2020, 11(2), 200; https://doi.org/10.3390/genes11020200 - 16 Feb 2020
Cited by 5 | Viewed by 2302
Abstract
Breast cancer has the highest mortality and morbidity among women, especially in elderly women over 60 years old. Abnormal alternative splicing (AS) events are associated with the occurrence and development of geriatric breast cancer (GBC), yet strong evidence is lacking for the prognostic [...] Read more.
Breast cancer has the highest mortality and morbidity among women, especially in elderly women over 60 years old. Abnormal alternative splicing (AS) events are associated with the occurrence and development of geriatric breast cancer (GBC), yet strong evidence is lacking for the prognostic value of AS in GBC and the regulatory network of AS in GBC, which may highlight the mechanism through which AS contributes to GBC. In the present study, we obtained splicing event information (SpliceSeq) and clinical information for GBC from The Cancer Genome Atlas, and we constructed a GBC prognosis model based on AS events to predict the survival outcomes of GBC. Kaplan–Meier analysis was conducted to evaluate the predictive accuracy among different molecular subtypes of GBC. We conducted enrichment analysis and constructed a splicing network between AS and the splicing factor (SF) to examine the possible regulatory mechanisms of AS in GBC. We constructed eight prognostic signatures with very high statistical accuracy in predicting GBC survival outcomes from 45,421 AS events of 10,480 genes detected in 462 GBC patients; the prognostic model based on exon skip (ES) events had the highest accuracy, indicating its significant value in GBC prognosis. The constructed regulatory SF–AS network may explain the potential regulatory mechanism between SF and AS, which may be the mechanism through which AS events contribute to GBC survival outcomes. The findings confirm that AS events have a significant prognostic value in GBC, and we found a few effective prognostic signatures. We also hypothesized the mechanism underlying AS in GBC and discovered a potential regulatory mechanism between SF and AS. Full article
(This article belongs to the Special Issue Alternative Splicing and Human Disease)
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12 pages, 1291 KiB  
Article
Aberrant Splicing Events Associated to CDH23 Noncanonical Splice Site Mutations in a Proband with Atypical Usher Syndrome 1
by Rebeca Valero, Marta de Castro-Miró, Sofía Jiménez-Ochoa, Juan José Rodríguez-Ezcurra, Gemma Marfany and Roser Gonzàlez-Duarte
Genes 2019, 10(10), 732; https://doi.org/10.3390/genes10100732 - 21 Sep 2019
Cited by 15 | Viewed by 2803
Abstract
Aims: The aim of this study was the genetic diagnosis by next generation sequencing (NGS) of a patient diagnosed with Usher syndrome type 2 and the functional evaluation of the identified genetic variants to establish a phenotype–genotype correlation. Methods: Whole exome sequencing (WES) [...] Read more.
Aims: The aim of this study was the genetic diagnosis by next generation sequencing (NGS) of a patient diagnosed with Usher syndrome type 2 and the functional evaluation of the identified genetic variants to establish a phenotype–genotype correlation. Methods: Whole exome sequencing (WES) analysis identified two heterozygous intronic variants in CDH23, a gene responsible of Usher syndrome type 1. Evaluation of the putative splicing effects was performed in vivo, in whole blood samples, and in vitro, by transfection of midigene constructs in HEK293T cells. Results: Two intronic variants were identified in intron 45 of CDH23—one novel, c.6050-15G>A, and the other, c.6050-9G>A, already reported as a noncanonical splice site (NCSS) mutation—with partial functional characterization. In vivo and in vitro analyses showed aberrant transcripts by the addition of 13 and 7 nucleotides to exon 46, respectively. Transcript degradation by nonsense mediated decay (NMD) in blood cells could only be prevented by cycloheximide treatment. Midigene constructs showed that the two variants contributed to exon skipping and generated aberrantly spliced transcripts. Conclusions: A combination of in vivo and in vitro assays provided a comprehensive view of the physiological effects of NCSS variants, which in this case led to a clinical reassignment of the proband as affected with atypical USH1 syndrome. Full article
(This article belongs to the Special Issue Alternative Splicing and Human Disease)
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Review

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21 pages, 1576 KiB  
Review
The Emerging Role of the RBM20 and PTBP1 Ribonucleoproteins in Heart Development and Cardiovascular Diseases
by Stefania Fochi, Pamela Lorenzi, Marilisa Galasso, Chiara Stefani, Elisabetta Trabetti, Donato Zipeto and Maria Grazia Romanelli
Genes 2020, 11(4), 402; https://doi.org/10.3390/genes11040402 - 8 Apr 2020
Cited by 24 | Viewed by 6063
Abstract
Alternative splicing is a regulatory mechanism essential for cell differentiation and tissue organization. More than 90% of human genes are regulated by alternative splicing events, which participate in cell fate determination. The general mechanisms of splicing events are well known, whereas only recently [...] Read more.
Alternative splicing is a regulatory mechanism essential for cell differentiation and tissue organization. More than 90% of human genes are regulated by alternative splicing events, which participate in cell fate determination. The general mechanisms of splicing events are well known, whereas only recently have deep-sequencing, high throughput analyses and animal models provided novel information on the network of functionally coordinated, tissue-specific, alternatively spliced exons. Heart development and cardiac tissue differentiation require thoroughly regulated splicing events. The ribonucleoprotein RBM20 is a key regulator of the alternative splicing events required for functional and structural heart properties, such as the expression of TTN isoforms. Recently, the polypyrimidine tract-binding protein PTBP1 has been demonstrated to participate with RBM20 in regulating splicing events. In this review, we summarize the updated knowledge relative to RBM20 and PTBP1 structure and molecular function; their role in alternative splicing mechanisms involved in the heart development and function; RBM20 mutations associated with idiopathic dilated cardiovascular disease (DCM); and the consequences of RBM20-altered expression or dysfunction. Furthermore, we discuss the possible application of targeting RBM20 in new approaches in heart therapies. Full article
(This article belongs to the Special Issue Alternative Splicing and Human Disease)
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