Disrupted minor intron splicing is prevalent in Mendelian disorders

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 pathog...

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Bibliographic Details
Published in:Molecular genetics & genomic medicine Vol. 8; no. 9; pp. e1374 - n/a
Main Authors: Olthof, Anouk M., Rasmussen, Jeffrey S., Campeau, Philippe M., Kanadia, Rahul N.
Format: Journal Article
Language:English
Published: Bognor Regis John Wiley & Sons, Inc 01-09-2020
John Wiley and Sons Inc
Wiley
Subjects:
Alternative splicing
Ataxia
Disease
Diseases
Gene expression
Identification methods
Intellectual disabilities
Introns
Microencephaly
minor spliceosome
Mutation
Nervous system
Ontology
Original
Pathogenesis
Seizures
Signs and symptoms
splice site
Splicing
variant
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Summary: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.
Bibliography:Funding information
This study was supported by National Institute of Health (grant number R01NS102538 and R21NS101616), awarded to RNK.
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ISSN:2324-9269
2324-9269
DOI:10.1002/mgg3.1374