A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids
Journal
International Journal of Molecular Sciences
ISSN
1422-0067
Date Issued
2023
Author(s)
David A. Priestman
Macarena Las Las Heras
Boris Rebolledo-Jaramillo
Silvana Zanlungo
Jaime Gutiérrez
Frances M. Platt
Andrés D. Klein
Type
Resource Types::text::journal::journal article
URL Institutional Repository
Abstract
<jats:p>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.</jats:p>
Cite this document
Durán, A., Priestman, D. A., Las Heras, M. L., Rebolledo-Jaramillo, B., Olguín, V., Calderón, J. F., Zanlungo, S., Gutiérrez, J., Platt, F. M., & Klein, A. D. (2023). A mouse systems genetics approach reveals common and uncommon genetic modifiers of hepatic lysosomal enzyme activities and glycosphingolipids. International Journal of Molecular Sciences, 24(5), 4915. https://doi.org/10.3390/ijms24054915
Project(s)
Subjects
glycosphingolipids
;
lysosomal enzymes
;
metabolism
;
modifier genes
;
systems genetics
;
animals
;
glycosphingolipids
;
hydrolases
;
lysosomal storage diseases
;
lysosomes
;
mice
;
acid phosphatase
;
acid phosphatase tartrate resistant isoenzyme
;
alpha galactosidase
;
alpha glucosidase
;
alpha levo fucosidase
;
beta galactosidase
;
beta n acetylhexosaminidase
;
beta n acetylhexosaminidase a
;
chitotriosidase
;
glycosphingolipid
;
lysosome enzyme
;
messenger rna
;
microrna
;
microrna 340p
;
sialidase
;
transcription factor
;
unclassified drug
;
glycosphingolipid
;
hydrolase
;
animal tissue
;
article
;
catabolism
;
controlled study
;
enzyme activity
;
gene mapping
;
genome-wide association study
;
male
;
metabolic regulation
;
modifier gene
;
mouse
;
nonhuman
;
systems genetics
;
transcriptomics
;
animal
;
lysosome
;
lysosome storage disease
;
metabolism