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Disrupted minor intron splicing is prevalent in Mendelian disorders

BACKGROUND: Splicing is crucial for proper gene expression, and is predominately executed by the major spliceosome. Conversely, 722 introns in 699 human minor intron‐containing genes (MIGs) are spliced by the minor spliceosome. Splicing of these minor introns is disrupted in diseases caused by patho...

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Autores principales: Olthof, Anouk M., Rasmussen, Jeffrey S., Campeau, Philippe M., Kanadia, Rahul N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507305/
https://www.ncbi.nlm.nih.gov/pubmed/32573973
http://dx.doi.org/10.1002/mgg3.1374
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author Olthof, Anouk M.
Rasmussen, Jeffrey S.
Campeau, Philippe M.
Kanadia, Rahul N.
author_facet Olthof, Anouk M.
Rasmussen, Jeffrey S.
Campeau, Philippe M.
Kanadia, Rahul N.
author_sort Olthof, Anouk M.
collection PubMed
description BACKGROUND: Splicing is crucial for proper gene expression, and is predominately executed by the major spliceosome. Conversely, 722 introns in 699 human minor intron‐containing genes (MIGs) are spliced by the minor spliceosome. Splicing of these minor introns is disrupted in diseases caused by pathogenic variants in the minor spliceosome, ultimately leading to the aberrant expression of a subset of these MIGs. However, the effect of variants in minor introns and MIGs on diseases remains unexplored. METHODS: Variants in MIGs and associated clinical manifestations were identified using ClinVar. The HPO database was then used to curate the related symptoms and affected organ systems. Results: We found pathogenic variants in 211 MIGs, which commonly resulted in intellectual disability, seizures and microcephaly. This revealed a subset of MIGs whose aberrant splicing may contribute to the pathogenesis of minor spliceosome‐related diseases. Moreover, we identified 51 pathogenic variants in minor intron splice sites that reduce the splice site strength and can induce alternative splicing. CONCLUSION: These findings highlight that disrupted minor intron splicing has a broader impact on human diseases than previously appreciated. The hope is that this knowledge will aid in the development of therapeutic strategies that incorporate the minor intron splicing pathway.
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spelling pubmed-75073052020-09-28 Disrupted minor intron splicing is prevalent in Mendelian disorders Olthof, Anouk M. Rasmussen, Jeffrey S. Campeau, Philippe M. Kanadia, Rahul N. Mol Genet Genomic Med Original Articles BACKGROUND: Splicing is crucial for proper gene expression, and is predominately executed by the major spliceosome. Conversely, 722 introns in 699 human minor intron‐containing genes (MIGs) are spliced by the minor spliceosome. Splicing of these minor introns is disrupted in diseases caused by pathogenic variants in the minor spliceosome, ultimately leading to the aberrant expression of a subset of these MIGs. However, the effect of variants in minor introns and MIGs on diseases remains unexplored. METHODS: Variants in MIGs and associated clinical manifestations were identified using ClinVar. The HPO database was then used to curate the related symptoms and affected organ systems. Results: We found pathogenic variants in 211 MIGs, which commonly resulted in intellectual disability, seizures and microcephaly. This revealed a subset of MIGs whose aberrant splicing may contribute to the pathogenesis of minor spliceosome‐related diseases. Moreover, we identified 51 pathogenic variants in minor intron splice sites that reduce the splice site strength and can induce alternative splicing. CONCLUSION: These findings highlight that disrupted minor intron splicing has a broader impact on human diseases than previously appreciated. The hope is that this knowledge will aid in the development of therapeutic strategies that incorporate the minor intron splicing pathway. John Wiley and Sons Inc. 2020-06-23 /pmc/articles/PMC7507305/ /pubmed/32573973 http://dx.doi.org/10.1002/mgg3.1374 Text en © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Olthof, Anouk M.
Rasmussen, Jeffrey S.
Campeau, Philippe M.
Kanadia, Rahul N.
Disrupted minor intron splicing is prevalent in Mendelian disorders
title Disrupted minor intron splicing is prevalent in Mendelian disorders
title_full Disrupted minor intron splicing is prevalent in Mendelian disorders
title_fullStr Disrupted minor intron splicing is prevalent in Mendelian disorders
title_full_unstemmed Disrupted minor intron splicing is prevalent in Mendelian disorders
title_short Disrupted minor intron splicing is prevalent in Mendelian disorders
title_sort disrupted minor intron splicing is prevalent in mendelian disorders
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507305/
https://www.ncbi.nlm.nih.gov/pubmed/32573973
http://dx.doi.org/10.1002/mgg3.1374
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