A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids
Abstract
:1. Introduction
2. Results
2.1. High Variability in the Hepatic Activity of Lysosomal Enzymes across Mouse Strains
2.2. Lack of Correlation between the Enzyme Activity and Its mRNA Levels
2.3. High Variability in the Hepatic Glycosphingolipid Levels across Mouse Strains
2.4. Correlations between the GSLs and the mRNA Levels of the Biosynthetic Genes
2.5. Lack of Correlation between Hepatic Lysosomal Enzyme Activity and Their Natural Substrates across Mouse Strains
2.6. Identification of Putative Modifier Genes of Lysosomal Enzyme Activity and Sphingolipids Levels
2.7. Correlations between the Traits and the mRNA Levels of Putative Modifiers
2.8. Enrichment Analysis and Common Modifier Genes between Glycosphingolipids Levels and Lysosomal Enzyme Activities
2.9. Common and Uncommon Modifiers between Hepatic Lysosomal Enzyme Activity and Sphingolipids Levels
Gene | Description | Traits | Related Functions | Associated Human Diseases | Previosly Associated with Traits | References | |||
---|---|---|---|---|---|---|---|---|---|
Enzyme | p-Value GWAS | GSLs | p-Value GWAS | ||||||
Tiam2 | T cell lymphoma invasion and metastasis 2 | α-Glucosidase | 1.89 × 10−6 | GM3-Gc | 1.51 × 10−31 | neuroplasticity | liver cancer | No | [47,54] |
Tfb1m | Dimethyladenosine transferase 1, mitochondrial | α-Glucosidase | 1.89 × 10−7 | GM3-Gc | 1.51 × 10−31 | promotion of mitochondrial biogenesis | deafness | No | [36,55] |
Dok5 | Insulin receptor substrate 6 | β-D-galactosidase | 1.43 × 10−7 | Lac | 1.38 × 10−12 | osteoblast differentiation, insulin and IGF-1 signaling | cancer, Alzheimer’s disease | No | [56,57,58,59] |
4930433b08Rik | RIKEN cDNA 4930433B08 gene | β-D-galactosidase | 2.32 × 10−8 | Lac | 1.38 × 10−12 | - | - | - | - |
A830019l24Rik | RIKEN cDNA A830019L24 gene | β-D-galactosidase | 1.43 × 10−7 | Lac | 1.38 × 10−12 | - | - | - | - |
Tmem135 | Transmembrane protein 135 | β-D-galactosidase | 1.43 × 10−7 | GM3-Gc | 1.51 × 10−31 | involved in mitochondrial dynamics | retinal diseases | No | [37,60] |
Fam181b | Family with sequence similarity 181, member B | β-D-galactosidase | 1.43 × 10−7 | GM3-Gc | 1.51 × 10−31 | increased expression during mouse development | - | No | [31] |
Tenm4 | Teneurin transmembrane protein 4 | β-D-galactosidase | 1.43 × 10−7 | GM3-Gc | 1.51 × 10−31 | cell maturation and myelination in SNC | neuropsychiatric disorders, Parkinson’s disease | No | [51,61,62,63] |
Plk2 | Serine/Threonine-protein kinase PLK2 | α-L-Fucosidase | 1.43 × 10−7 | GM3-Gc | 1.51 × 10−31 | cell proliferation, alpha-synuclein phosphorylation | pulmonary fibrosis | No | [64,65] |
Stk32a | Serine/Threonine kinase 32A | α-L-Fucosidase | 1.43 × 10−7 | GM3-Gc | 1.51 × 10−31 | kinase activity | lung cancer | No | [66,67] |
Dpysl3 | Dihydropyrimidinase like 3 | α-L-Fucosidase | 1.43 × 10−7 | GM3-Gc | 1.51 × 10−31 | cell migration, cytoskeletal dynamics and inflammation | gastric cancer, amyotrophic lateral sclerosis | No | [68,69,70] |
Prex1 | PIP3 Dependent rac exchange factor 1 | α-L-Fucosidase | 6.67 × 10−8 | GM3-Gc | 1.51 × 10−31 | contributes to the effector activity of mouse neutrophils | prostate cancer | No | [71,72] |
Fstl5 | Follistatin-related protein 5 | α-L-Fucosidase | 6.67 × 10−8 | Lac | 1.38 × 10−12 | play a role in cell proliferation | hepatocellular carcinoma | No | [38,73] |
Vps45 | Vacuolar protein sorting-associated protein 45 | α-L-Fucosidase | 1.13 × 10−1 | GM3-Gc | 1.51 × 10−31 | vesicle-mediated protein trafficking from the Golgi | neutrophil disorders | No | [42,74] |
Hist2h2be | Histone cluster 2 H2B family member E | α-L-Fucosidase | 1.13 × 10−1 | GM3-Gc | 1.51 × 10−31 | is necessary for proliferation | breast cancer | No | [75] |
Pde4dip | Phosphodiesterase 4D interacting protein | α-L-Fucosidase | 2.29 × 10−7 | GM3-Gc | 1.51 × 10−31 | cAMP-dependent pathway to Golgi and/or centrosomes | schizophrenia | No | [52] |
Tusc1 | Tumor suppressor candidate 1 | α-L-Fucosidase | 6.67 × 10−8 | GM3-Gc | 1.51 × 10−31 | reduced cell proliferation in vitro e in vivo | glioblastoma | No | [76,77] |
Fzd10 | Frizzled class receptor 10 | α-L-Fucosidase | 6.67 × 10−8 | GM3-Gc | 1.51 × 10−31 | promotes cell proliferation through Wnt1 | cancer | No | [39,48] |
Grid2 | Glutamate ionotropic receptor delta type subunit 2 | α-L-Fucosidase | 6.67 × 10−8 | Lac | 1.38 × 10−12 | receptor for glutamate | neurodevelopmental syndrome/intellectual disability | No | [78] |
Zc3h12c | Zinc finger CCCH-type containing 12C | α-L-Fucosidase | 1.64 × 10−6 | GM3-Gc | 1.51 × 10−31 | RNA stability associated with inflammatory genes | psoriasis | No | [79,80] |
Arhgap18 | Rho GTPase activating protein 18 | α-L-Fucosidase | 6.67 × 10−8 | GM3-Gc | 1.51 × 10−31 | role in migration, spreading and controls stress fiber formation | schizophrenia in Chinese population | No | [40,81] |
Cdh6 | Cadherin 6 | α-L-Fucosidase | 1.34 × 10−6 | Lac | 1.38 × 10−12 | inhibit platelet aggregation | cancer | No | [41,49] |
Fam91a1 | Family with sequence similarity 91 member A1 | α-L-Fucosidase | 6.67 × 10−8 | GM3-Gc | 1.51 × 10−31 | WDR11 complex (vesicular trafficking) | adenocarcinoma | No | [82,83] |
4933412e24Rik | RIKEN cDNA 4933412E24 gene | α-L-Fucosidase | 6.67 × 10−8 | Lac | 1.38 × 10−12 | - | - | - | - |
A1bg | Alpha−1B-Glycoprotein | α-L-Fucosidase | 6.67 × 10−8 | GM3-Gc | 1.51 × 10−31 | cell dynamics and acquired immune response | cervical and bladder carcinogenesis | No | [84,85,86] |
Pvt1 | Pvt1 Oncogene | α-L-Fucosidase | 6.67 × 10−8 | GM3-Gc | 1.51 × 10−31 | promotes cell proliferation | cancer | No | [50,87] |
Adamts5 | ADAM Metallopeptidase with thrombospondin type 1 motif 5 | α-L-Fucosidase | 6.67 × 10−8 | GM3-Gc | 1.51 × 10−31 | metalloproteinase that remoldels connective tissue | osteoarthritis | No | [88] |
Csnk1g3 | Casein kinase 1 gamma 3 | α-L-Fucosidase | 3.51 × 10−7 | Lac | 1.38 × 10−12 | wnt signaling pathway | breast, brain and colon cancer | No | [89,90] |
Chchd6 | Coiled-coil-helix-coiled-coil-helix domain containing 6 | Chitotriosidase | 1.37 × 10−6 | GA2 | 3.27 × 10−6 | mitochondrial membrane morphology | cancer | No | [29] |
Zfat | Zinc finger protein ZFAT | TRAP | 7.72 × 10−7 | Lac | 1.38 × 10−12 | immune response | hashimoto’s disease | No | [43,91] |
3. Discussion
4. Materials and Methods
4.1. Mouse Tissues
4.2. Enzyme Activity Assays
4.3. Glycosphingolipids Levels Quantification
4.4. Genome-Wide Association Studies (GWAS)
4.5. Gene Expression Array and Heat Maps
4.6. Functional Impact of Genomic Variants
4.7. Enrichment Analysis
4.8. Identification of Transcription Factors
4.9. Statistics
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Trait | Gene | Region | Chr | Position | Ref | Alt | p-Value | SNV p < 10−6 | Non-Redundant Genes | |
---|---|---|---|---|---|---|---|---|---|---|
lysosomal enzymes | α-Galactosidase A | Stard4 | intergenic | 18 | 33494519 | C | T | 2.88 × 10−6 | 1 | 1 |
α-Galactosidase B | Barhl2 | intergenic | 5 | 106880801 | T | C | 4.10 × 10−7 | 1 | 1 | |
GCase | Dmrtc2 | UTR3 | 7 | 25662483 | A | G | 7.46 × 10−7 | 2 | 2 | |
Arhgef1 | UTR3 | 7 | 25711350 | G | T | 7.46 × 10−7 | ||||
α-Glucosidase | Tiam2 | intergenic | 17 | 3338741 | T | C | 1.89 × 10−6 | 3 | 2 | |
Tfb1m | intronic | 17 | 3557483 | G | T | 1.89 × 10−6 | ||||
β-D-Galactosidase | Lyplal1 | intergenic | 1 | 188026657 | A | G | 9.09 × 10−9 | 88 | 70 | |
4930433B08Rik | intergenic | 3 | 18512557 | A | G | 2.32 × 10−8 | ||||
Peak1 | intronic | 9 | 56165236 | T | C | 2.32 × 10−8 | ||||
Imp3 | intergenic | 9 | 56793621 | A | G | 2.32 × 10−8 | ||||
Scamp2 | intronic | 9 | 57409841 | T | C | 2.32 × 10−8 | ||||
Loxl1 | intergenic | 9 | 58188292 | A | G | 2.32 × 10−8 | ||||
1700072B07Rik | intergenic | 9 | 58256079 | G | A | 2.32 × 10−8 | ||||
Arih1 | intergenic | 9 | 59348484 | C | T | 2.32 × 10−8 | ||||
Pkm | intronic | 9 | 59506197 | A | T | 2.32 × 10−8 | ||||
Iqch | intronic | 9 | 63413504 | A | G | 2.32 × 10−8 | ||||
Chitotriosidase 1 | Wdr89 | intergenic | 12 | 76773815 | T | C | 2.45 × 10−8 | 8 | 3 | |
Syne2 | intronic | 12 | 76961077 | T | C | 2.45 × 10−8 | ||||
Chchd6 | intergenic | 6 | 89566833 | A | G | 1.37 × 10−6 | ||||
α-L-Fucosidase | Myom3 | intergenic | 4 | 135400588 | C | T | 6.06 × 10−17 | 103 | 56 | |
Vps45 | intronic | 3 | 95807768 | C | T | 1.13 × 10−1 | ||||
Hist2h2be | downstream | 3 | 96027761 | G | A | 1.13 × 10−1 | ||||
Tet2 | intergenic | 3 | 133254547 | A | C | 1.13 × 10−1 | ||||
Zfp46 | UTR3 | 4 | 135847850 | A | G | 1.13 × 10−1 | ||||
Hnrnpr | intergenic | 4 | 135915162 | C | T | 1.13 × 10−1 | ||||
E2f2 | UTR3 | 4 | 135750026 | C | T | 8.13 × 10−9 | ||||
Stkld1 | intronic | 2 | 26790736 | A | C | 6.67 × 10−8 | ||||
Xkr7 | intergenic | 2 | 152887679 | G | A | 6.67 × 10−8 | ||||
Ttpal | intronic | 2 | 163432431 | A | G | 6.67 × 10−8 | ||||
TRAP | Zfat | intronic | 15 | 68115989 | A | C | 7.70 × 10−7 | 5 | 2 | |
Mir30d | intergenic | 15 | 68244382 | C | T | 7.72 × 10−7 | ||||
GSLs | GD1a | Ctnnbl1 | intronic | 2 | 157632357 | T | A | 1.46 × 10−7 | 37 | 26 |
Rap2b | intergenic | 3 | 61765728 | A | C | 1.46 × 10−7 | ||||
Arhgef26 | intronic | 3 | 62232093 | C | T | 1.46 × 10−7 | ||||
GA2 | Dars | intergenic | 1 | 130350640 | C | T | 1.09 × 10−11 | 190 | 103 | |
Abca16 | intronic | 7 | 127596308 | G | A | 1.09 × 10−11 | ||||
E130201H02Rik | intergenic | 7 | 127763574 | G | A | 1.09 × 10−11 | ||||
Vwa3a | intronic | 7 | 127887001 | G | A | 1.09 × 10−11 | ||||
Eef2k | intronic | 7 | 127993389 | A | G | 1.09 × 10−11 | ||||
LacCer | Tgs1 | intergenic | 4 | 3571870 | C | G | 1.38 × 10−12 | 1152 | 723 | |
Dtnb | intronic | 12 | 3586440 | C | T | 1.38 × 10−12 | ||||
Lyn | intronic | 4 | 3673421 | A | G | 1.38 × 10−12 | ||||
Ghr | intergenic | 15 | 3696333 | T | C | 1.38 × 10−12 | ||||
1810055G02Rik | intergenic | 19 | 3731017 | G | A | 1.38 × 10−12 | ||||
Bambi | intergenic | 18 | 3826103 | C | A | 1.38 × 10−12 | ||||
Hnf4g | intergenic | 3 | 3989664 | G | T | 1.38 × 10−12 | ||||
Dnajc27 | UTR3 | 12 | 4106955 | G | C | 1.38 × 10−12 | ||||
Mterf1b | intergenic | 5 | 4503200 | A | G | 1.38 × 10−12 | ||||
Impad1 | intergenic | 4 | 4885958 | C | G | 1.38 × 10−12 | ||||
GD1b | Ahctf1 | intergenic | 1 | 181812047 | C | A | 1.03 × 10−8 | 23 | 17 | |
Psen2 | intronic | 1 | 182170093 | C | T | 1.03 × 10−8 | ||||
Fhit | intronic | 14 | 11843484 | G | A | 1.03 × 10−8 | ||||
GM3Gc | Cdk6 | intergenic | 5 | 3011917 | T | C | 1.51 × 10−31 | 1811 | 995 | |
Insr | intergenic | 8 | 3058687 | C | T | 1.51 × 10−31 | ||||
Eif4enif1 | intronic | 11 | 3143753 | G | A | 1.51 × 10−31 | ||||
Tiam2 | intronic | 17 | 3417745 | T | C | 1.51 × 10−31 | ||||
Ppp6r3 | intronic | 19 | 3539614 | C | T | 1.51 × 10−31 | ||||
Tfb1m | intronic | 17 | 3540913 | C | A | 1.51 × 10−31 | ||||
1700102H20Rik | intergenic | 17 | 3611518 | G | A | 1.51 × 10−31 | ||||
Pex1 | intronic | 5 | 3632859 | T | G | 1.51 × 10−31 | ||||
Ankib1 | intronic | 5 | 3711311 | C | T | 1.51 × 10−31 | ||||
Ankib1 | intronic | 5 | 3778272 | C | T | 1.51 × 10−31 | ||||
GM1b | Hrasls | intergenic | 16 | 29161604 | A | C | 2.71 × 10−6 | 2 | 1 |
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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. 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
Durán A, Priestman DA, Las Heras M, Rebolledo-Jaramillo B, Olguín V, Calderón JF, Zanlungo S, Gutiérrez J, Platt FM, Klein AD. A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids. International Journal of Molecular Sciences. 2023; 24(5):4915. https://doi.org/10.3390/ijms24054915
Chicago/Turabian StyleDurán, Anyelo, David A. Priestman, Macarena Las Heras, Boris Rebolledo-Jaramillo, Valeria Olguín, Juan F. Calderón, Silvana Zanlungo, Jaime Gutiérrez, Frances M. Platt, and Andrés D. Klein. 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, no. 5: 4915. https://doi.org/10.3390/ijms24054915