Browsing by Author "Jimenez, Yanireth"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    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.
  • Thumbnail Image
    Item
    Genomic Modifiers of Neurological Resilience in a Niemann-Pick C family
    (2025) Las Heras, Macarena; Szenfeld, Benjamín; Olguín, Valeria; Rubilar, Juan Carlos; Calderón, Juan Francisco; Jimenez, Yanireth; Zanlungo Matsuhiro, Silvana; Buratti, Emanuele; Dardis, Andrea; Cubillos, Francisco A.; Klein, Andrés D.
    Niemann-Pick type C (NPC) disease, caused by pathogenic variants in the NPC1 or NPC2 genes, disrupts cellular cholesterol and glycolipids trafficking. Patients exhibit a wide spectrum of visceral and neurological manifestations, suggesting a role for genomic modifiers. To uncover the genetic basis of NPC neurological resilience, we analyzed the exomes of an NPC family with diverse phenotypes, from very mild to severe neurological involvement. Linkage analysis revealed loss-of-function (LOF) variants in CCDC115, SLC4A5, DEPDC5, ETFDH, SNRNP200, and DOCK1 that co-segregated with resistance to severe neurological signs. Biomarkers of severity are lacking in NPC. Based on LOF variants in the yeast orthologs of these genes, we successfully predicted NPC-like severity in Saccharomyces cerevisiae of different genetic backgrounds. Complementary, to associate pathways with severity, we performed RNA-seq, uncovering positive correlations between mitochondrial transcripts with cellular fitness. Finally, we modeled NPC disease in yeast lacking the sodium bicarbonate cotransporter bor1, the SLC4A5 ortholog. Deletion of bor1 enhanced cellular fitness, prevented vacuolar fragmentation, reduced sterols buildup, and improved mitochondrial function. Our study revealed modifiers/biomarkers of NPC severity, and highlighted SLC4A5 as a promising therapeutic target for this devastating disease.