Claire Russell
Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease
Russell, Claire; Minnis, Christopher J.; Townsend, StJohn; Petschnigg, Julia; Tinelli, Elisa; Bähler, Jürg; Russell, Claire; Mole, Sara E.
Authors
Christopher J. Minnis
StJohn Townsend
Julia Petschnigg
Elisa Tinelli
Jürg Bähler
Claire Russell
Sara E. Mole
Abstract
Juvenile CLN3 disease is a recessively inherited paediatric neurodegenerative disorder, with most patients homozygous for a 1-kb intragenic deletion in CLN3. The btn1 gene is the Schizosaccharomyces pombe orthologue of CLN3. Here, we have extended the use of synthetic genetic array (SGA) analyses to delineate functional signatures for two different disease-causing mutations in addition to complete deletion of btn1. We show that genetic-interaction signatures can differ for mutations in the same gene, which helps to dissect their distinct functional effects. The mutation equivalent to the minor transcript arising from the 1-kb deletion (btn1102-208del) shows a distinct interaction pattern. Taken together, our results infer that the minor 1-kb deletion transcript has three consequences for CLN3: to both lose and retain some inherent functions and to acquire abnormal characteristics. This has particular implications for the therapeutic development of juvenile CLN3 disease. In addition, this proof of concept could be applied to conserved genes for other mendelian disorders or any gene of interest, aiding in the dissection of their functional domains, unpacking the global consequences of disease pathogenesis, and clarifying genotype-phenotype correlations. In doing so, this detail will enhance the goals of personalised medicine to improve treatment outcomes and reduce adverse events.
Citation
Russell, C., Minnis, C. J., Townsend, S., Petschnigg, J., Tinelli, E., Bähler, J., …Mole, S. E. (2021). Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease. Scientific Reports,
Journal Article Type | Article |
---|---|
Acceptance Date | Feb 23, 2021 |
Publication Date | Mar 18, 2021 |
Deposit Date | Nov 4, 2021 |
Publicly Available Date | Nov 4, 2021 |
Journal | Scientific Reports |
Publisher | Nature Research |
Peer Reviewed | Peer Reviewed |
Public URL | https://rvc-repository.worktribe.com/output/1444082 |
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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/
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