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

Anyelo Durán; David A. Priestman; Macarena Las Heras; Boris Rebolledo-Jaramillo; Valeria Olguín; Juan F. Calderón; Silvana Zanlungo; Jaime Gutiérrez; Frances M. Platt; Andrés D. Klein

doi:10.3390/ijms24054915

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

Anyelo Durán, David A. Priestman, Macarena Las Heras, Boris Rebolledo-Jaramillo, Valeria Olguín, Juan F. Calderón, Silvana Zanlungo, Jaime Gutiérrez, Frances M. Platt, Andrés D. Klein^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English
Article number	4915
Journal	International Journal of Molecular Sciences
Volume	24
Issue number	5
DOIs	https://doi.org/10.3390/ijms24054915
State	Published - 2023

Bibliographical note

Funding Information:
This work was supported by ANID-CHILE: Fondecyt grant No 1180337 (A.D.K.) (2018–2022), 1190334 (S.Z.) (2019–2023), EQM190110 and ACT210012 (J.F.C.), EQM150093 (B.R.-J.) and 1221362 (J.G.) (2022–2025). LysoMod, funded by the European Union’s Horizon 2020 research and innovation programme (RISE) under the Marie Sklodowska-Curie grant agreement No 734825 (S.Z., F.M.P., A.D.K.) (2017–2022), and the Mizutani Foundation for Glycoscience, grant No: 200133 (F.M.P., D.A.P., A.D.K.) (2020). F.M.P. is a Wolfson Royal Society Merit Award Holder and a Wellcome Trust Investigator in science.

Publisher Copyright:
© 2023 by the authors.

ASJC Scopus subject areas

Catalysis
Molecular Biology
Spectroscopy
Computer Science Applications
Physical and Theoretical Chemistry
Organic Chemistry
Inorganic Chemistry

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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. (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), Article 4915. https://doi.org/10.3390/ijms24054915

@article{dd1a364f32a049ae84fd00bcb469bac2,

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

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.",

keywords = "glycosphingolipids, lysosomal enzymes, metabolism, modifier genes, systems genetics",

author = "Anyelo Dur{\'a}n and Priestman, {David A.} and {Las Heras}, Macarena and Boris Rebolledo-Jaramillo and Valeria Olgu{\'i}n and Calder{\'o}n, {Juan F.} and Silvana Zanlungo and Jaime Guti{\'e}rrez and Platt, {Frances M.} and Klein, {Andr{\'e}s D.}",

note = "Funding Information: This work was supported by ANID-CHILE: Fondecyt grant No 1180337 (A.D.K.) (2018–2022), 1190334 (S.Z.) (2019–2023), EQM190110 and ACT210012 (J.F.C.), EQM150093 (B.R.-J.) and 1221362 (J.G.) (2022–2025). LysoMod, funded by the European Union{\textquoteright}s Horizon 2020 research and innovation programme (RISE) under the Marie Sklodowska-Curie grant agreement No 734825 (S.Z., F.M.P., A.D.K.) (2017–2022), and the Mizutani Foundation for Glycoscience, grant No: 200133 (F.M.P., D.A.P., A.D.K.) (2020). F.M.P. is a Wolfson Royal Society Merit Award Holder and a Wellcome Trust Investigator in science. Publisher Copyright: {\textcopyright} 2023 by the authors.",

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journal = "International Journal of Molecular Sciences",

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Durán, A, Priestman, DA, Las Heras, M, Rebolledo-Jaramillo, B, Olguín, V, Calderón, JF, Zanlungo, S, Gutiérrez, J, Platt, FM & Klein, AD 2023, 'A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids', International Journal of Molecular Sciences, vol. 24, no. 5, 4915. https://doi.org/10.3390/ijms24054915

TY - JOUR

T1 - A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids

AU - Durán, Anyelo

AU - Priestman, David A.

AU - Las Heras, Macarena

AU - Rebolledo-Jaramillo, Boris

AU - Olguín, Valeria

AU - Calderón, Juan F.

AU - Zanlungo, Silvana

AU - Gutiérrez, Jaime

AU - Platt, Frances M.

AU - Klein, Andrés D.

N1 - Funding Information: This work was supported by ANID-CHILE: Fondecyt grant No 1180337 (A.D.K.) (2018–2022), 1190334 (S.Z.) (2019–2023), EQM190110 and ACT210012 (J.F.C.), EQM150093 (B.R.-J.) and 1221362 (J.G.) (2022–2025). LysoMod, funded by the European Union’s Horizon 2020 research and innovation programme (RISE) under the Marie Sklodowska-Curie grant agreement No 734825 (S.Z., F.M.P., A.D.K.) (2017–2022), and the Mizutani Foundation for Glycoscience, grant No: 200133 (F.M.P., D.A.P., A.D.K.) (2020). F.M.P. is a Wolfson Royal Society Merit Award Holder and a Wellcome Trust Investigator in science. Publisher Copyright: © 2023 by the authors.

PY - 2023/3

Y1 - 2023/3

N2 - 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.

AB - 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.

KW - glycosphingolipids

KW - lysosomal enzymes

KW - metabolism

KW - modifier genes

KW - systems genetics

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U2 - 10.3390/ijms24054915

DO - 10.3390/ijms24054915

M3 - Article

C2 - 36902345

AN - SCOPUS:85149896115

SN - 1661-6596

VL - 24

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 5

M1 - 4915

ER -

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

Abstract

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