Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease
| Autor: | Claire Russell, Jürg Bähler, Elisa Tinelli, StJohn Townsend, Sara E. Mole, Julia Petschnigg, Christopher J. Minnis |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Science Metabolic disorders Disease Biology medicine.disease_cause Article 03 medical and health sciences 0302 clinical medicine Fungal genetics Neuronal Ceroid-Lipofuscinoses Schizosaccharomyces medicine Humans Fungal genomics Lipid-storage diseases Neurodegeneration Author Correction Gene Eye diseases Genetic Association Studies Genetics Mutation Multidisciplinary Membrane Glycoproteins Models Genetic Disease genetics Genetic interaction Homozygote High-throughput screening Membrane Proteins Functional genomics Synthetic genetic array biology.organism_classification 030104 developmental biology CLN3 Schizosaccharomyces pombe Medicine Schizosaccharomyces pombe Proteins 030217 neurology & neurosurgery Gene Deletion Neurological disorders Molecular Chaperones |
| Zdroj: | Scientific Reports Scientific Reports, Vol 11, Iss 1, Pp 1-14 (2021) |
| ISSN: | 2045-2322 |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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