A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids
Date
2023
Type:
Article
item.page.extent
item.page.accessRights
Acceso abierto
item.contributor.advisor
ORCID:
Journal Title
Journal ISSN
Volume Title
Publisher
item.page.isbn
item.page.issn
item.page.issne
item.page.doiurl
item.page.other
item.page.references
Abstract
Identification of genetic modulators of lysosomal enzyme activities and glycosphingolipids (GSLs) may facilitate the development of therapeutics for diseases in which they participate, including Lysosomal Storage Disorders (LSDs). To this end, we used a systems genetics approach: we measured 11 hepatic lysosomal enzymes and many of their natural substrates (GSLs), followed by modifier gene mapping by GWAS and transcriptomics associations in a panel of inbred strains. Unexpectedly, most GSLs showed no association between their levels and the enzyme activity that catabolizes them. Genomic mapping identified 30 shared predicted modifier genes between the enzymes and GSLs, which are clustered in three pathways and are associated with other diseases. Surprisingly, they are regulated by ten common transcription factors, and their majority by miRNA-340p. In conclusion, we have identified novel regulators of GSL metabolism, which may serve as therapeutic targets for LSDs and may suggest the involvement of GSL metabolism in other pathologies.
Description
item.page.coverage.spatial
item.page.sponsorship
Citation
Durán, A.; Priestman, D.A.; Las Heras, M.; Rebolledo-Jaramillo, B.; Olguín, V.; Calderón, J.F.; Zanlungo, S.; Gutiérrez, J.; Platt, F.M.; Klein, A.D. A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids. Int. J. Mol. Sci. 2023, 24, 4915. https://doi.org/10.3390/ijms24054915
Keywords
Metabolism, Lysosomal enzymes, Glycosphingolipids, Systems genetics, Modifier genes