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Establishment of a Human iPSC Line from Mucolipidosis Type II That Expresses the Key Markers of the Disease

2025-04-19Artigo científico Acesso aberto
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dc.contributor.authorMoutinho, Maria Eduarda
dc.contributor.authorGonçalves, Mariana
dc.contributor.authorDuarte, Ana J.
dc.contributor.authorEncarnação, Marisa
dc.contributor.authorCoutinho, Maria Francisca
dc.contributor.authorMatos, Liliana
dc.contributor.authorSantos, Juliana I.
dc.contributor.authorRibeiro, Diogo
dc.contributor.authorAmaral, Olga
dc.contributor.authorGaspar, Paulo
dc.contributor.authorAlves, Sandra
dc.contributor.authorMoreira, Luciana V.
dc.date.accessioned2026-01-23T11:42:09Z
dc.date.available2026-01-23T11:42:09Z
dc.date.issued2025-04-19
dc.descriptionThis article belongs to the Section Biochemistry.
dc.description.abstractMucolipidosis 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.eng
dc.description.sponsorshipThis work received financial support from Portuguese national funds (FCT/MCTES, Fundação para a Ciência e Tecnologia, and Ministério da Ciência, Tecnologia e Ensino Superior) through the project ModellingMLII-2022.03836.PTDC (https://doi.org/10.54499/2022.03836.PTDC).
dc.identifier.citationInt J Mol Sci. 2025 Apr 19;26(8):3871. doi: 10.3390/ijms26083871
dc.identifier.doi10.3390/ ijms26083871
dc.identifier.eissn1422-0067
dc.identifier.issn1661-6596
dc.identifier.pmid40332602
dc.identifier.urihttp://hdl.handle.net/10400.18/10755
dc.language.isoeng
dc.peerreviewedyes
dc.publisherMDPI
dc.relationNew models for the most frequent Mucolipidosis II-causing mutation using iPSCs and zebrafish: a crucial step towards the development of new therapies
dc.relation.hasversionhttps://www.mdpi.com/1422-0067/26/8/3871
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCRISPR/Cas-9
dc.subjectLSD
dc.subjectML II
dc.subjectCellular Model
dc.subjectiPSCs
dc.subjectLysosomal Storage Disorder
dc.subjectStem Cells
dc.subjectDoenças Lisossomais de Sobrecarga
dc.subjectMucolipidose
dc.subjectDoenças Genéticas
dc.subjectGenética Humana
dc.titleEstablishment of a Human iPSC Line from Mucolipidosis Type II That Expresses the Key Markers of the Diseaseeng
dc.typejournal article
dcterms.referenceshttps://www.mdpi.com/article/10.3390/ijms26083871/s1
dspace.entity.typePublication
oaire.awardNumber2022.03836.PTDC
oaire.awardTitleNew models for the most frequent Mucolipidosis II-causing mutation using iPSCs and zebrafish: a crucial step towards the development of new therapies
oaire.awardURIhttp://hdl.handle.net/10400.18/10754
oaire.citation.issue8
oaire.citation.startPage3871
oaire.citation.titleInternational Journal of Molecular Sciences
oaire.citation.volume26
oaire.fundingStreamConcurso de Projetos de I&D em Todos os Domínios Científicos - 2022 - PEX
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
relation.isProjectOfPublicationa20ed1d9-a33a-4e24-bc8d-2de74d02a22d
relation.isProjectOfPublication.latestForDiscoverya20ed1d9-a33a-4e24-bc8d-2de74d02a22d

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