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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Autores principales:	Christopher J. Minnis, StJohn Townsend, Julia Petschnigg, Elisa Tinelli, Jürg Bähler, Claire Russell, Sara E. Mole
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6527e4bac2b54420a484033fbe621105
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spelling	oai:doaj.org-article:6527e4bac2b54420a484033fbe6211052021-12-02T13:17:41ZGlobal network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease10.1038/s41598-021-85471-42045-2322https://doaj.org/article/6527e4bac2b54420a484033fbe6211052021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85471-4https://doaj.org/toc/2045-2322Abstract 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.Christopher J. MinnisStJohn TownsendJulia PetschniggElisa TinelliJürg BählerClaire RussellSara E. MoleNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
author	Christopher J. Minnis StJohn Townsend Julia Petschnigg Elisa Tinelli Jürg Bähler Claire Russell Sara E. Mole
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 Portfolio
publishDate	2021
url	https://doaj.org/article/6527e4bac2b54420a484033fbe621105
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Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease

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