Browsing by Author "Buratti, Emanuele"

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    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.
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    Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine
    (Nature Research, 2023) De Las Heras Barros, Macarena Cruz; Szenfeld, Benjamín; Ballout, Rami; Buratti, Emanuele; Zanlungo Matsuhiro, Silvana; Dardis, Andrea; Klein Posternack, Andrés David
    © 2023, Springer Nature Limited and Centre of Excellence in Genomic Medicine Research, King Abdulaziz University.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.