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Mutations of Pre-mRNA Splicing Regulatory Elements: Are Predictions Moving Forward to Clinical Diagnostics?

For more than three decades, researchers have known that consensus splice sites alone are not sufficient regulatory elements to provide complex splicing regulation. Other regulators, so-called splicing regulatory elements (SREs) are needed. Most importantly, their sequence variants often underlie th...

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Detalles Bibliográficos
Autores principales: Grodecká, Lucie, Buratti, Emanuele, Freiberger, Tomáš
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578058/
https://www.ncbi.nlm.nih.gov/pubmed/28758972
http://dx.doi.org/10.3390/ijms18081668
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author Grodecká, Lucie
Buratti, Emanuele
Freiberger, Tomáš
author_facet Grodecká, Lucie
Buratti, Emanuele
Freiberger, Tomáš
author_sort Grodecká, Lucie
collection PubMed
description For more than three decades, researchers have known that consensus splice sites alone are not sufficient regulatory elements to provide complex splicing regulation. Other regulators, so-called splicing regulatory elements (SREs) are needed. Most importantly, their sequence variants often underlie the development of various human disorders. However, due to their variable location and high degeneracy, these regulatory sequences are also very difficult to recognize and predict. Many different approaches aiming to identify SREs have been tried, often leading to the development of in silico prediction tools. While these tools were initially expected to be helpful to identify splicing-affecting mutations in genetic diagnostics, we are still quite far from meeting this goal. In fact, most of these tools are not able to accurately discern the SRE-affecting pathological variants from those not affecting splicing. Nonetheless, several recent evaluations have given appealing results (namely for EX-SKIP, ESRseq and Hexplorer predictors). In this review, we aim to summarize the history of the different approaches to SRE prediction, and provide additional validation of these tools based on patients’ clinical data. Finally, we evaluate their usefulness for diagnostic settings and discuss the challenges that have yet to be met.
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spelling pubmed-55780582017-09-05 Mutations of Pre-mRNA Splicing Regulatory Elements: Are Predictions Moving Forward to Clinical Diagnostics? Grodecká, Lucie Buratti, Emanuele Freiberger, Tomáš Int J Mol Sci Review For more than three decades, researchers have known that consensus splice sites alone are not sufficient regulatory elements to provide complex splicing regulation. Other regulators, so-called splicing regulatory elements (SREs) are needed. Most importantly, their sequence variants often underlie the development of various human disorders. However, due to their variable location and high degeneracy, these regulatory sequences are also very difficult to recognize and predict. Many different approaches aiming to identify SREs have been tried, often leading to the development of in silico prediction tools. While these tools were initially expected to be helpful to identify splicing-affecting mutations in genetic diagnostics, we are still quite far from meeting this goal. In fact, most of these tools are not able to accurately discern the SRE-affecting pathological variants from those not affecting splicing. Nonetheless, several recent evaluations have given appealing results (namely for EX-SKIP, ESRseq and Hexplorer predictors). In this review, we aim to summarize the history of the different approaches to SRE prediction, and provide additional validation of these tools based on patients’ clinical data. Finally, we evaluate their usefulness for diagnostic settings and discuss the challenges that have yet to be met. MDPI 2017-07-31 /pmc/articles/PMC5578058/ /pubmed/28758972 http://dx.doi.org/10.3390/ijms18081668 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Grodecká, Lucie
Buratti, Emanuele
Freiberger, Tomáš
Mutations of Pre-mRNA Splicing Regulatory Elements: Are Predictions Moving Forward to Clinical Diagnostics?
title Mutations of Pre-mRNA Splicing Regulatory Elements: Are Predictions Moving Forward to Clinical Diagnostics?
title_full Mutations of Pre-mRNA Splicing Regulatory Elements: Are Predictions Moving Forward to Clinical Diagnostics?
title_fullStr Mutations of Pre-mRNA Splicing Regulatory Elements: Are Predictions Moving Forward to Clinical Diagnostics?
title_full_unstemmed Mutations of Pre-mRNA Splicing Regulatory Elements: Are Predictions Moving Forward to Clinical Diagnostics?
title_short Mutations of Pre-mRNA Splicing Regulatory Elements: Are Predictions Moving Forward to Clinical Diagnostics?
title_sort mutations of pre-mrna splicing regulatory elements: are predictions moving forward to clinical diagnostics?
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578058/
https://www.ncbi.nlm.nih.gov/pubmed/28758972
http://dx.doi.org/10.3390/ijms18081668
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