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Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing
It is estimated that up to one-third of all variants causing inherited diseases affect splicing; however, their deleterious effects and roles in disease pathogenesis are often not fully characterized. Given their prevalence and the development of various antisense-based splice-modulating approaches,...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073151/ https://www.ncbi.nlm.nih.gov/pubmed/33923806 http://dx.doi.org/10.3390/ijms22084154 |
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author | Bychkov, Igor Galushkin, Artur Filatova, Alexandra Nekrasov, Andrey Kurkina, Marina Baydakova, Galina Ilyushkina, Alexandra Skoblov, Mikhail Zakharova, Ekaterina |
author_facet | Bychkov, Igor Galushkin, Artur Filatova, Alexandra Nekrasov, Andrey Kurkina, Marina Baydakova, Galina Ilyushkina, Alexandra Skoblov, Mikhail Zakharova, Ekaterina |
author_sort | Bychkov, Igor |
collection | PubMed |
description | It is estimated that up to one-third of all variants causing inherited diseases affect splicing; however, their deleterious effects and roles in disease pathogenesis are often not fully characterized. Given their prevalence and the development of various antisense-based splice-modulating approaches, pathogenic splicing variants have become an important object of genomic medicine. To improve the accuracy of variant interpretation in public mutation repositories, we applied the minigene splicing assay to study the effects of 24 variants that were predicted to affect normal splicing in the genes associated with propionic acidemia (PA)—PCCA and PCCB. As a result, 13 variants (including one missense and two synonymous variants) demonstrated a significant alteration of splicing with the predicted deleterious effect at the protein level and were characterized as spliceogenic loss-of-function variants. The analysis of the available data for the studied variants and application of the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) guidelines allowed us to precisely classify five of the variants and change the pathogenic status of nine. Using the example of the PA genes, we demonstrated the utility of the minigene splicing assay in the fast and effective assessment of the spliceogenic effect for identified variants and highlight the necessity of their standardized classification. |
format | Online Article Text |
id | pubmed-8073151 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-80731512021-04-27 Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing Bychkov, Igor Galushkin, Artur Filatova, Alexandra Nekrasov, Andrey Kurkina, Marina Baydakova, Galina Ilyushkina, Alexandra Skoblov, Mikhail Zakharova, Ekaterina Int J Mol Sci Article It is estimated that up to one-third of all variants causing inherited diseases affect splicing; however, their deleterious effects and roles in disease pathogenesis are often not fully characterized. Given their prevalence and the development of various antisense-based splice-modulating approaches, pathogenic splicing variants have become an important object of genomic medicine. To improve the accuracy of variant interpretation in public mutation repositories, we applied the minigene splicing assay to study the effects of 24 variants that were predicted to affect normal splicing in the genes associated with propionic acidemia (PA)—PCCA and PCCB. As a result, 13 variants (including one missense and two synonymous variants) demonstrated a significant alteration of splicing with the predicted deleterious effect at the protein level and were characterized as spliceogenic loss-of-function variants. The analysis of the available data for the studied variants and application of the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) guidelines allowed us to precisely classify five of the variants and change the pathogenic status of nine. Using the example of the PA genes, we demonstrated the utility of the minigene splicing assay in the fast and effective assessment of the spliceogenic effect for identified variants and highlight the necessity of their standardized classification. MDPI 2021-04-16 /pmc/articles/PMC8073151/ /pubmed/33923806 http://dx.doi.org/10.3390/ijms22084154 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Bychkov, Igor Galushkin, Artur Filatova, Alexandra Nekrasov, Andrey Kurkina, Marina Baydakova, Galina Ilyushkina, Alexandra Skoblov, Mikhail Zakharova, Ekaterina Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing |
title | Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing |
title_full | Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing |
title_fullStr | Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing |
title_full_unstemmed | Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing |
title_short | Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing |
title_sort | functional analysis of the pcca and pccb gene variants predicted to affect splicing |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073151/ https://www.ncbi.nlm.nih.gov/pubmed/33923806 http://dx.doi.org/10.3390/ijms22084154 |
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