{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T13:24:04Z","timestamp":1775136244844,"version":"3.50.1"},"reference-count":26,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T00:00:00Z","timestamp":1731456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["EXPL\/BTM-TEC\/1477\/2021"],"award-info":[{"award-number":["EXPL\/BTM-TEC\/1477\/2021"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/00211\/2020"],"award-info":[{"award-number":["UIDB\/00211\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"FCT\/MCTES","award":["EXPL\/BTM-TEC\/1477\/2021"],"award-info":[{"award-number":["EXPL\/BTM-TEC\/1477\/2021"]}]},{"name":"FCT\/MCTES","award":["UIDB\/00211\/2020"],"award-info":[{"award-number":["UIDB\/00211\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Niemann\u2013Pick type C (NPC) is a lysosomal storage disorder (LSD) caused by pathogenic variants in either the NPC1 or NPC2 genes, which encode proteins involved in the lysosomal export of unesterified cholesterol. In patients of Western European descent, the p.Ile1061Thr variant in NPC1 is especially prevalent. However, mounting evidence has positioned p.Ala1035Val as the most common variant in Portugal and the second most prevalent variant worldwide. By analyzing 10 Portuguese NPC patients homozygous for p.Ala1035Val, we found an SNP in cis on position 858 (p.Ile858Val), which we hypothesize could have a disease-modifying effect. To address this query, we created variant-specific in vitro models of NPC by stably transducing NPC1\u2212\/\u2212 ARPE-19 cells with constructs encoding different fluorescently-tagged variants of NPC1, which we used, alongside patient-derived skin fibroblasts, to investigate lysosomal positioning and the trafficking routes elicited by p.Ile1061Thr and p.Ala1035Val (with and without the p.Ile858Val SNP in cis). Our results corroborate the previously described decrease in p.Ile1061Thr-NPC1 trafficking to the lysosome and suggest a similar, if not worse, scenario for the p.Ala1035Val variant, especially when in cis with p.Ile858Val. This is the first reported functional study addressing the impact of the p.Ala1035Val variant at the cellular level, paving the way for novel therapeutic options.<\/jats:p>","DOI":"10.3390\/ijms252212186","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T06:23:16Z","timestamp":1731478996000},"page":"12186","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Investigating p.Ala1035Val in NPC1: New Cellular Models for Niemann\u2013Pick Type C Disease"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9623-4017","authenticated-orcid":false,"given":"Hugo","family":"David","sequence":"first","affiliation":[{"name":"Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge (INSA, I. P.), Rua Alexandre Herculano 321, 4000-055 Porto, Portugal"},{"name":"Center for the Study of Animal Science\u2014Instituto de Ci\u00eancias, Tecnologias e Agroambiente da Universidade do Porto (CECA-ICETA), University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"name":"Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), Faculdade de Medicina Veterin\u00e1ria, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}]},{"given":"Jlenia","family":"Monfregola","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Italy"}]},{"given":"Isaura","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioqu\u00edmica Gen\u00e9tica, Servi\u00e7o de Gen\u00e9tica Laboratorial, Cl\u00ednica de Gen\u00e9tica e de Patologia, Centro de Gen\u00e9tica M\u00e9dica Jacinto de Magalh\u00e3es, Unidade Local de Sa\u00fade de Santo Ant\u00f3nio, 4099-001 Porto, Portugal"},{"name":"Unidade Multidisciplinar de Investiga\u00e7\u00e3o Biom\u00e9dica (UMIB), Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS), University of Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"Laboratory for Integrative and Translational Research in Population Health (ITR), Institute of Public Health, University of Porto, Rua das Taipas 135, 4050-600 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9908-3739","authenticated-orcid":false,"given":"Maria Teresa","family":"Cardoso","sequence":"additional","affiliation":[{"name":"Reference Center for Diagnosis and Treatment, Centro Hospitalar e Universit\u00e1rio de S\u00e3o Jo\u00e3o (CHUSJ), Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3276-060X","authenticated-orcid":false,"given":"Ana Catarina","family":"Sandiares","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge (INSA, I. P.), Rua Alexandre Herculano 321, 4000-055 Porto, Portugal"},{"name":"Center for the Study of Animal Science\u2014Instituto de Ci\u00eancias, Tecnologias e Agroambiente da Universidade do Porto (CECA-ICETA), University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"name":"Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), Faculdade de Medicina Veterin\u00e1ria, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}]},{"given":"Luciana","family":"Moreira","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge (INSA, I. P.), Rua Alexandre Herculano 321, 4000-055 Porto, Portugal"},{"name":"Center for the Study of Animal Science\u2014Instituto de Ci\u00eancias, Tecnologias e Agroambiente da Universidade do Porto (CECA-ICETA), University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"name":"Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), Faculdade de Medicina Veterin\u00e1ria, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2222-3622","authenticated-orcid":false,"given":"Maria Francisca","family":"Coutinho","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge (INSA, I. P.), Rua Alexandre Herculano 321, 4000-055 Porto, Portugal"},{"name":"Center for the Study of Animal Science\u2014Instituto de Ci\u00eancias, Tecnologias e Agroambiente da Universidade do Porto (CECA-ICETA), University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"name":"Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), Faculdade de Medicina Veterin\u00e1ria, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}]},{"given":"Dulce","family":"Quelhas","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioqu\u00edmica Gen\u00e9tica, Servi\u00e7o de Gen\u00e9tica Laboratorial, Cl\u00ednica de Gen\u00e9tica e de Patologia, Centro de Gen\u00e9tica M\u00e9dica Jacinto de Magalh\u00e3es, Unidade Local de Sa\u00fade de Santo Ant\u00f3nio, 4099-001 Porto, Portugal"},{"name":"Unidade Multidisciplinar de Investiga\u00e7\u00e3o Biom\u00e9dica (UMIB), Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS), University of Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"Laboratory for Integrative and Translational Research in Population Health (ITR), Institute of Public Health, University of Porto, Rua das Taipas 135, 4050-600 Porto, Portugal"}]},{"given":"Andrea","family":"Ballabio","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8881-9197","authenticated-orcid":false,"given":"Sandra","family":"Alves","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge (INSA, I. 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