Genetic Background Matters: Population-Based Studies in Model Organisms for Translational Research

Olguín, Valeria; Durán, Anyelo; Heras, Macarena Las; Rubilar, Juan Carlos; Cubillos, Francisco A.; Olguı́n, Patricio; Klein, Andrés D.

doi:10.3390/ijms23147570

Cited by 7 publications

(4 citation statements)

References 110 publications

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“…One exception is -D-galactosidase, for which we found a positive correlation between its transcript levels and activity. Furthermore, the GWAS for this enzyme identified Glb1, the gene encoding for -D-galactosidase, as a putative modifier of its activity, validating the power of discovery of our population-based strategy 60 .…”

Section: Discussionmentioning

confidence: 54%

A mouse systems genetics approach reveals common and uncommon genetic modifiers of hepatic lysosomal enzyme activities and glycosphingolipids

Durán

Priestman

Heras

et al. 2022

Preprint

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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.

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Section: Discussionmentioning

confidence: 54%

A mouse systems genetics approach reveals common and uncommon genetic modifiers of hepatic lysosomal enzyme activities and glycosphingolipids

Durán

Priestman

Heras

et al. 2022

Preprint

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“…In conclusion, several NPC mouse models have been described in different genetic backgrounds. With the current advances in genetics and genomics, it is expected that they will represent very valuable resources for dissecting the genomic architecture underlying disease severity and progression of NPC 73 . Once identified, it is hoped that these modifier genes will facilitate the development of severity biomarkers and customized therapeutic approaches for subsets of patients.…”

Section: Npc Mouse Models Of Different Genetic Backgrounds For Modifi...mentioning

confidence: 99%

Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine

Las Heras,

Szenfeld,

Ballout

et al. 2023

npj Genom. Med.

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Niemann-Pick type C (NPC) disease is a lysosomal storage disease (LSD) characterized by the buildup of endo-lysosomal cholesterol and glycosphingolipids due to loss of function mutations in the NPC1 and NPC2 genes. NPC patients can present with a broad phenotypic spectrum, with differences at the age of onset, rate of progression, severity, organs involved, effects on the central nervous system, and even response to pharmacological treatments. This article reviews the phenotypic variation of NPC and discusses its possible causes, such as the remaining function of the defective protein, modifier genes, sex, environmental cues, and splicing factors, among others. We propose that these factors should be considered when designing or repurposing treatments for this disease. Despite its seeming complexity, this proposition is not far-fetched, considering the expanding interest in precision medicine and easier access to multi-omics technologies.

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“…Alternately, 129 may differ in outer segment renewal rhythmicity from C57 mice inherently due to genetic differences. Indeed, numerous phenotypic, physiological, and behavioral differences exist among inbred mouse strains in general [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Differences in Diurnal Rhythm of Rod Outer Segment Renewal between 129T2/SvEmsJ and C57BL/6J Mice

Vargas

Finnemann

2022

IJMS

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In all mammalian species tested to date, rod photoreceptor outer segment renewal is a circadian process synchronized by light with a burst of outer segment fragment (POS) shedding and POS phagocytosis by the adjacent retinal pigment epithelium (RPE) every morning at light onset. Recent reports show that RPE phagocytosis also increases shortly after dark onset in C57BL/6 (C57) mice. Genetic differences between C57 mice and 129T2/SvEmsJ (129) mice may affect regulation of outer segment renewal. Here, we used quantitative methods to directly compare outer segment renewal in C57 and 129 mouse retina. Quantification of rhodopsin-positive phagosomes in the RPE showed that in 129 mice, rod POS phagocytosis after light onset was significantly increased compared to C57 mice, but that 129 mice did not show a second peak after dark onset. Cone POS phagosome content of RPE cells did not differ by mouse strain with higher phagosome numbers after light than after dark. We further quantified externalization of the “eat me” signal phosphatidylserine by outer segment tips, which precedes POS phagocytosis. Live imaging of retina ex vivo showed that rod outer segments extended PS exposure in both strains but that frequency of outer segments with exposed PS after light onset was lower in C57 than in 129 retina. Taken together, 129 mice lacked a burst of rod outer segment renewal after dark onset. The increases in rod outer segment renewal after light and after dark onset in C57 mice were attenuated compared to the peak after light onset in 129 mice, suggesting an impairment in rhythmicity in C57 mice.

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Genetic Background Matters: Population-Based Studies in Model Organisms for Translational Research

Cited by 7 publications

References 110 publications

A mouse systems genetics approach reveals common and uncommon genetic modifiers of hepatic lysosomal enzyme activities and glycosphingolipids

A mouse systems genetics approach reveals common and uncommon genetic modifiers of hepatic lysosomal enzyme activities and glycosphingolipids

Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine

Differences in Diurnal Rhythm of Rod Outer Segment Renewal between 129T2/SvEmsJ and C57BL/6J Mice

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