{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T10:51:06Z","timestamp":1788173466688,"version":"build-2803163510"},"reference-count":53,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,19]],"date-time":"2025-04-19T00:00:00Z","timestamp":1745020800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Portuguese national funds","award":["ModellingMLII-2022.03836.PTDC"],"award-info":[{"award-number":["ModellingMLII-2022.03836.PTDC"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mucolipidosis type II (ML II) is a rare and fatal disease of acid hydrolase trafficking. It is caused by pathogenic variants in the GNPTAB gene, leading to the absence of GlcNAc-1-phosphotransferase activity, an enzyme that catalyzes the first step in the formation of the mannose 6-phosphate (M6P) tag, essential for the trafficking of most lysosomal hydrolases. Without M6P, these do not reach the lysosome, which accumulates undegraded substrates. The lack of samples and adequate disease models limits the investigation into the pathophysiological mechanisms of the disease and potential therapies. Here, we report the generation and characterization of an ML II induced pluripotent stem cell (iPSC) line carrying the most frequent ML II pathogenic variant [NM_024312.5(GNPTAB):c.3503_3504del (p.Leu1168fs)]. Skin fibroblasts were successfully reprogrammed into iPSCs that express pluripotency markers, maintain a normal karyotype, and can differentiate into the three germ layers. Furthermore, ML II iPSCs showed a phenotype comparable to that of the somatic cells that originated them in terms of key ML II hallmarks: lower enzymatic activity of M6P-dependent hydrolases inside the cells but higher in conditioned media, and no differences in an M6P-independent hydrolase and accumulation of free cholesterol. Thus, ML II iPSCs constitute a novel model for ML II disease, with the inherent iPSC potential to become a valuable model for future studies on the pathogenic mechanisms and testing potential therapeutic approaches.<\/jats:p>","DOI":"10.3390\/ijms26083871","type":"journal-article","created":{"date-parts":[[2025,4,20]],"date-time":"2025-04-20T20:24:16Z","timestamp":1745180656000},"page":"3871","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Establishment of a Human iPSC Line from Mucolipidosis Type II That Expresses the Key Markers of the Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7582-8324","authenticated-orcid":false,"given":"Maria Eduarda","family":"Moutinho","sequence":"first","affiliation":[{"name":"Centre for the Study of Animal Science (CECA)-Institute of Sciences, Technologies and Agroenvironment (ICETA), University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"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":"Biology Department, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3111-4612","authenticated-orcid":false,"given":"Mariana","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Centre for the Study of Animal Science (CECA)-Institute of Sciences, Technologies and Agroenvironment (ICETA), University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"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":"Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculty of Veterinary Medicine, University of Lisboa, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"},{"name":"Centre for the Research and Technology of Agro-Environmental and Biological Sciences, CITAB, Inov4Agro, University of Tr\u00e1s-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6005-7322","authenticated-orcid":false,"given":"Ana Joana","family":"Duarte","sequence":"additional","affiliation":[{"name":"Centre for the Study of Animal Science (CECA)-Institute of Sciences, Technologies and Agroenvironment (ICETA), University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"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":"Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculty of Veterinary Medicine, University of Lisboa, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"},{"name":"School of Medicine and Biomedical Sciences (ICBAS), University of Porto, R. de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3726-2851","authenticated-orcid":false,"given":"Marisa","family":"Encarna\u00e7\u00e3o","sequence":"additional","affiliation":[{"name":"Centre for the Study of Animal Science (CECA)-Institute of Sciences, Technologies and Agroenvironment (ICETA), University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"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":"Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculty of Veterinary Medicine, University of Lisboa, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2222-3622","authenticated-orcid":false,"given":"Maria Francisca","family":"Coutinho","sequence":"additional","affiliation":[{"name":"Centre for the Study of Animal Science (CECA)-Institute of Sciences, Technologies and Agroenvironment (ICETA), University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"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":"Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculty of Veterinary Medicine, University of Lisboa, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Matos","sequence":"additional","affiliation":[{"name":"Centre for the Study of Animal Science (CECA)-Institute of Sciences, Technologies and Agroenvironment (ICETA), University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"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":"Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculty of Veterinary Medicine, University of Lisboa, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana In\u00eas","family":"Santos","sequence":"additional","affiliation":[{"name":"Centre for the Study of Animal Science (CECA)-Institute of Sciences, Technologies and Agroenvironment (ICETA), University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"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":"Biology Department, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal"},{"name":"Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculty of Veterinary Medicine, University of Lisboa, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4681-0354","authenticated-orcid":false,"given":"Diogo","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Centre for the Study of Animal Science (CECA)-Institute of Sciences, Technologies and Agroenvironment (ICETA), University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"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":"Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculty of Veterinary Medicine, University of Lisboa, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Amaral","sequence":"additional","affiliation":[{"name":"Centre for the Study of Animal Science (CECA)-Institute of Sciences, Technologies and Agroenvironment (ICETA), University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"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":"Associate Laboratory for Animal and Veterinary Sciences, 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Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, INSA I.P., Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal"},{"name":"Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculty of Veterinary Medicine, University of Lisboa, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana Vaz","family":"Moreira","sequence":"additional","affiliation":[{"name":"Centre for the Study of Animal Science (CECA)-Institute of Sciences, Technologies and Agroenvironment (ICETA), University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"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":"Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculty of Veterinary Medicine, University of Lisboa, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2047","DOI":"10.1038\/s41436-021-01244-4","article-title":"Mucolipidosis Type II and Type III: A Systematic Review of 843 Published Cases","volume":"23","author":"Dogterom","year":"2021","journal-title":"Genet. 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