Disrupted minor intron splicing is prevalent in Mendelian disorders
| Autor: | Philippe M. Campeau, Anouk M. Olthof, Rahul N. Kanadia, Jeffrey S. Rasmussen |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Spliceosome lcsh:QH426-470 030105 genetics & heredity Biology 03 medical and health sciences Gene Frequency Minor spliceosome Gene expression Genetics Humans splice Molecular Biology Gene Genetics (clinical) disease nervous system Alternative splicing Genetic Diseases Inborn Intron Original Articles splice site Introns minor spliceosome Alternative Splicing lcsh:Genetics 030104 developmental biology variant RNA splicing Original Article RNA Splice Sites |
| Zdroj: | Molecular Genetics & Genomic Medicine, Vol 8, Iss 9, Pp n/a-n/a (2020) Molecular Genetics & Genomic Medicine |
| ISSN: | 2324-9269 |
| DOI: | 10.1002/mgg3.1374 |
| Popis: | 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. Pathogenic variants in minor spliceosome components result in disrupted splicing of minor introns and a wide range of symptoms affecting many organ systems. Here, we identified a subset of minor intron‐containing genes that may play a role in the pathogenesis of these minor spliceosome‐related diseases. Moreover, we report the presence of 51 pathogenic variants in minor intron splice sites that result in a reduced splice site strength. |
| Databáze: | OpenAIRE |
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