A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids

• Published in: International journal of molecular sciences Vol. 24; no. 5; p. 4915
• Main Authors: Durán, Anyelo, Priestman, David A, Las Heras, Macarena, Rebolledo-Jaramillo, Boris, Olguín, Valeria, Calderón, Juan F, Zanlungo, Silvana, Gutiérrez, Jaime, Platt, Frances M, Klein, Andrés D
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.03.2023; MDPI
• Subjects: Acids; Animals; Biosynthesis; Disease; DNA binding proteins; Drug development; Enzymatic activity; Enzyme activity; Enzymes; Gene mapping; Genes; Genetics; Genomes; Genomics; Glycosphingolipids; Glycosphingolipids - metabolism; Homeopathy; Hydrolases - metabolism; Inbreeding; Lipids; Liver; Lysosomal enzymes; Lysosomal storage diseases; Lysosomal Storage Diseases - metabolism; Lysosomes - metabolism; Mapping; Materia medica and therapeutics; Metabolism; Mice; miRNA; modifier genes; Phosphatase; Physiological aspects; systems genetics; Therapeutic targets; Therapeutics; Transcription factors; Transcriptomics; United Kingdom; systems genetics; lysosomal enzymes; metabolism; modifier genes; glycosphingolipids
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24054915

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.