Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease
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) an...
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doaj-6527e4bac2b54420a484033fbe6211052021-03-21T12:32:59ZengNature Publishing GroupScientific Reports2045-23222021-03-0111111410.1038/s41598-021-85471-4Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 diseaseChristopher J. Minnis0StJohn Townsend1Julia Petschnigg2Elisa Tinelli3Jürg Bähler4Claire Russell5Sara E. Mole6MRC Laboratory for Molecular Cell Biology and Great Ormond Street, Institute of Child Health, University College LondonInstitute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College LondonMRC Laboratory for Molecular Cell Biology and Great Ormond Street, Institute of Child Health, University College LondonMRC Laboratory for Molecular Cell Biology and Great Ormond Street, Institute of Child Health, University College LondonInstitute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College LondonDepartment of Comparative Biomedical Sciences, Royal Veterinary CollegeMRC Laboratory for Molecular Cell Biology and Great Ormond Street, Institute of Child Health, University College LondonAbstract 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 (btn1 102–208del ) shows a distinct interaction pattern. Taken together, our results imply 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.https://doi.org/10.1038/s41598-021-85471-4 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Christopher J. Minnis StJohn Townsend Julia Petschnigg Elisa Tinelli Jürg Bähler Claire Russell Sara E. Mole |
spellingShingle |
Christopher J. Minnis StJohn Townsend Julia Petschnigg Elisa Tinelli Jürg Bähler Claire Russell Sara E. Mole Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease Scientific Reports |
author_facet |
Christopher J. Minnis StJohn Townsend Julia Petschnigg Elisa Tinelli Jürg Bähler Claire Russell Sara E. Mole |
author_sort |
Christopher J. Minnis |
title |
Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease |
title_short |
Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease |
title_full |
Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease |
title_fullStr |
Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease |
title_full_unstemmed |
Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease |
title_sort |
global network analysis in schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile cln3 disease |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-03-01 |
description |
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 (btn1 102–208del ) shows a distinct interaction pattern. Taken together, our results imply 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. |
url |
https://doi.org/10.1038/s41598-021-85471-4 |
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