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While cysteamine lowers the cystine levels, it does not cure the disease, suggesting that CTNS exerts additional functions besides cystine transport. This study investigated the impact of infantile and juvenile CTNS mutations with discrepant genotype\/phenotype correlations on CTNS expression, and subcellular localisation and function in clinically relevant cystinosis cell models to better understand the link between genotype and CTNS function. Using CTNS-depleted proximal tubule epithelial cells and patient-derived fibroblasts, we expressed a selection of CTNSmutants under various promoters. EF1a-driven expression led to substantial overexpression, resulting in CTNS protein levels that localised to the lysosomal compartment. All CTNSmutants tested also reversed cystine accumulation, indicating that CTNSmutants still exert transport activity, possibly due to the overexpression conditions. Surprisingly, even CTNSmutants expression driven by the less potent CTNS and EFS promoters reversed the cystine accumulation, contrary to the CTNSG339R missense mutant. Taken together, our findings shed new light on CTNS mutations, highlighting the need for robust assessment methodologies in clinically relevant cellular models and thus paving the way for better stratification of cystinosis patients, and advocating for the development of more personalized therapy.<\/jats:p>","DOI":"10.3390\/cells13070646","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T12:01:22Z","timestamp":1712577682000},"page":"646","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Residual Cystine Transport Activity for Specific Infantile and Juvenile CTNS Mutations in a PTEC-Based Addback Model"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2998-7358","authenticated-orcid":false,"given":"Louise","family":"Medaer","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, Faculty of Medicine, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4059-6326","authenticated-orcid":false,"given":"Dries","family":"David","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, Faculty of Medicine, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0997-8993","authenticated-orcid":false,"given":"Maxime","family":"Smits","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, Faculty of Medicine, KU Leuven, 3000 Leuven, Belgium"},{"name":"Leuven Viral Vector Core, Faculty of Medicine, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Levtchenko","sequence":"additional","affiliation":[{"name":"Department of Paediatric Nephrology & Development and Regeneration, University Hospitals Leuven & KU Leuven, 3000 Leuven, Belgium"},{"name":"Department of Paediatric Nephrology, Amsterdam University Medical Centre, 1081 Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2422-3757","authenticated-orcid":false,"given":"Maurilio","family":"Sampaolesi","sequence":"additional","affiliation":[{"name":"Translational Cardiology Laboratory, Department of Development and Regeneration, Stem Cell Institute, Faculty of Medicine, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0191-3904","authenticated-orcid":false,"given":"Rik","family":"Gijsbers","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, Faculty of Medicine, KU Leuven, 3000 Leuven, Belgium"},{"name":"Leuven Viral Vector Core, Faculty of Medicine, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,6]]},"reference":[{"key":"ref_1","first-page":"535","article-title":"High-Resolution Mapping of the Gene for Cystinosis, Using Combined Biochemical and Linkage Analysis","volume":"58","author":"Jean","year":"1996","journal-title":"Am. 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