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Different Niemann-Pick C1 Genotypes Generate Protein Phenotypes that Vary in their Intracellular Processing, Trafficking and Localization

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dc.contributor.author Shammas, Hadeel
dc.contributor.author Kuech, Eva-Maria
dc.contributor.author Rizk, Sandra
dc.contributor.author Das, Anibh M.
dc.contributor.author Naim, Hassan Y.
dc.date.accessioned 2019-09-20T10:22:13Z
dc.date.available 2019-09-20T10:22:13Z
dc.date.copyright 2019 en_US
dc.identifier.issn 2045-2322 en_US
dc.identifier.uri http://hdl.handle.net/10725/11322
dc.description.abstract Niemann-Pick Type C (NP-C) is an inherited neurovisceral lysosomal storage disease characterized by a defect in the trafficking of endocytosed cholesterol. In 95% of patients the gene encoding NPC1 is affected. The correlation of the genetic background in NP-C with the clinical phenotype such as, severity and onset of liver dysfunction, ataxia, dystonia and vertical gaze palsy, has not been elucidated at the molecular level. We have designed strategies to investigate the effect of different mutations in the NPC1 gene at the protein and cellular levels. The NPC1 mutants were expressed in mammalian cells and their structural features, maturation pathways and subcellular localization elucidated. Interestingly, three classes of NPC1 mutants could be identified and further characterized. The first group comprised mutants in which the NPC1 protein revealed virtually similar structural features to the wild type species. It was trafficked to the lysosomes and colocalized with the lysosomal protein marker Lamp2. The second class of NPC1 mutants was only partially trafficked to the lysosomes, but predominantly localized to the endoplasmic reticulum (ER). In the third group with the most severe phenotype, NPC1 mutants were entirely retained in the ER, colocalizing with the ER-protein marker calnexin. In conclusion, this study relates NPC1 mutations to the trafficking behavior of the NPC1 mutants along the secretory pathway. The findings are essential for a comprehensive understanding of the pathogenesis of NP-C and propose a mutation-based personalized therapeutical approach. en_US
dc.language.iso en en_US
dc.title Different Niemann-Pick C1 Genotypes Generate Protein Phenotypes that Vary in their Intracellular Processing, Trafficking and Localization en_US
dc.type Article en_US
dc.description.version Published en_US
dc.author.school SAS en_US
dc.author.idnumber 199829370 en_US
dc.author.department Natural Sciences en_US
dc.description.embargo N/A en_US
dc.relation.journal Scientific Reports en_US
dc.journal.volume 9 en_US
dc.journal.issue 1 en_US
dc.article.pages 1-12 en_US
dc.identifier.doi https://doi.org/10.1038/s41598-019-41707-y en_US
dc.identifier.ctation Shammas, H., Kuech, E. M., Rizk, S., Das, A. M., & Naim, H. Y. (2019). Different Niemann-Pick C1 Genotypes Generate Protein Phenotypes that Vary in their Intracellular Processing, Trafficking and Localization. Scientific reports, 9(1), 1-12 en_US
dc.author.email sandra.rizk@lau.edu.lb en_US
dc.identifier.tou http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php en_US
dc.identifier.url https://www.nature.com/articles/s41598-019-41707-y en_US
dc.orcid.id https://orcid.org/0000-0002-4405-5703 en_US
dc.author.affiliation Lebanese American University en_US


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