Browsing by Author "Calderon, Juan F."

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    A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids
    (2023) Duran, Anyelo; Priestman, David A.; Las Heras, Macarena; Rebolledo-Jaramillo, Boris; Olguin, Valeria; Calderon, Juan F.; Zanlungo, Silvana; Gutierrez, Jaime; Platt, Frances M.; Klein, Andres D.
    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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    Dynamics of the MRSA Population in a Chilean Hospital: a Phylogenomic Analysis (2000-2016)
    (2023) Martinez, Jose R. W.; Planet, Paul J.; Spencer-Sandino, Maria; Rivas, Lina; Diaz, Lorena; Moustafa, Ahmed M.; Quesille-Villalobos, Ana; Riquelme-Neira, Roberto; Alcalde-Rico, Manuel; Hanson, Blake; Carvajal, Lina P.; Rincon, Sandra; Reyes, Jinnethe; Lam, Marusella; Calderon, Juan F.; Araos, Rafael; Garcia, Patricia; Arias, Cesar A.; Munita, Jose M.
    Methicillin-resistant Staphylococcus aureus (MRSA) is a major public health pathogen that disseminates through the emergence of successful dominant clones in specific geographic regions. Knowledge of the dissemination and molecular epidemiology of MRSA in Latin America is scarce and is largely based on small studies or more limited typing techniques that lack the resolution to represent an accurate description of the genomic landscape.
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    Exome Sequencing Identifies Genetic Variants Associated with Extreme Manifestations of the Cardiovascular Phenotype in Marfan Syndrome.
    (2022) Jimenez, Yanireth; Paulsen, César; Turner, Eduardo; Iturra, Sebastián; Cuevas, Óscar; Lay-son, Guillermo; Repetto, Gabriela M.; Rojas, Marcelo; Calderon, Juan F.
    Marfan Syndrome (MFS) is an autosomal dominant condition caused by variants in the fibrillin-1 (FBN1) gene. Cardinal features of MFS include ectopia lentis (EL), musculoskeletal features and aortic root aneurysm and dissection. Although dissection of the ascending aorta is the main cause of mortality in MFS, the clinical course differs considerably in age of onset and severity, even among individuals who share the same causative variant, suggesting the existence of additional genetic variants that modify the severity of the cardiovascular phenotype in MFS. We recruited MFS patients and classified them into severe (n = 8) or mild aortic phenotype (n = 14) according to age of presentation of the first aorta-related incident. We used Exome Sequencing to identify the genetic variants associated with the severity of aortic manifestations and we performed linkage analysis where suitable. We found five genes associated with severe aortic phenotype and three genes that could be protective for this phenotype in MFS. These genes regulate components of the extracellular matrix, TGFβ pathway and other signaling pathways that are involved in the maintenance of the ECM or angiogenesis. Further studies will be required to understand the functional effect of these variants and explore novel, personalized risk management and, potentially, therapies for these patients.
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    Identification of genetic modifiers of murine hepatic β-glucocerebrosidase activity
    (2021) Duran, Anyelo; Rebolledo-Jaramillo, Boris; Olguin, Valeria; Rojas-Herrera, Marcelo; Heras, Macarena Las; Calderon, Juan F.; Zanlungo, Silvana; Priestman, David A.; Platt, Frances M.; Klein, Andres D.
    The acid beta-glucocerebrosidase (GCase) enzyme cleaves glucosylceramide into glucose and ceramide. Loss of function variants in the gene encoding for GCase can lead to Gaucher disease and Parkinson's disease. Therapeutic strategies aimed at increasing GCase activity by targeting a modulating factor are attractive and poorly explored. To identify genetic modifiers, we measured hepatic GCase activity in 27 inbred mouse strains. A genome-wide association study (GWAS) using GCase activity as a trait identified several candidate modifier genes, including Dmrtc2 and Arhgef1 (p=2.1x10(-7)), and Grik5 (p=2.1x10(-7)). Bayesian integration of the gene mapping with transcriptomics was used to build integrative networks. The analysis uncovered additional candidate GCase regulators, highlighting modules of the acute phase response (p=1.01x10(-8)), acute inflammatory response (p=1.01x10(-8)), fatty acid beta-oxidation (p=7.43x10(-5)), among others. Our study revealed previously unknown candidate modulators of GCase activity, which may facilitate the design of therapies for diseases with GCase dysfunction.