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ARPE-19-A Stable Cell Line Expressing a Variant of Unknown Significance in the NPC1 Gene

2026-02-27Artigo científico Acesso aberto
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datacite.subject.fosCiências Médicas
datacite.subject.sdg03:Saúde de Qualidade
dc.contributor.authorMonteiro, Beatriz
dc.contributor.authorPeixoto, Maria Inês
dc.contributor.authorOrtigoza-Escobar, Juan Darío
dc.contributor.authorAlves, Mariana
dc.contributor.authorSandiares, Ana Catarina
dc.contributor.authorGonçalves, Mariana
dc.contributor.authorVaz Moreira, Luciana
dc.contributor.authorCoutinho, Maria Francisca
dc.contributor.authorMatos, Liliana
dc.contributor.authorAlves, Sandra
dc.contributor.authorEncarnação, Marisa
dc.date.accessioned2026-10-01T13:39:10Z
dc.date.available2026-10-01T13:39:10Z
dc.date.issued2026-02-27
dc.description(This article belongs to the Section Molecular Genetics and Genomics)
dc.description.abstractBackground: Niemann-Pick type C is a lysosomal storage disorder that results from pathogenic variants in the NPC1 gene or in some cases from NPC2 pathogenic alterations. The disease presents a remarkable clinical variability that in some cases resembles common diseases, often resulting in a diagnostic odyssey or at least delaying proper diagnosis. In addition, the NPC1 gene is highly polymorphic, and consequently, when missense variants are identified after gene sequencing, accurate classification of their pathogenicity is essential to ensure appropriate access to available therapies and to provide reliable genetic counseling. Objectives: To get insights into the pathogenicity of a novel variant in NPC1, p.Cys800Ser, we created stable cell lines expressing this variant, in parallel with cell lines expressing the NPC1 wild-type and NPC1 pathogenic variants. Methods: We leveraged an isogenic cell line in which the NPC1 gene was knocked down and subsequently infected it with retroviruses carrying NPC1-WT and NPC1 variants C-terminally fused with an mNeonGreen tag. Three different NPC1 variants were included in this study: two known pathogenic variants, p.Ala1035Val and p.Pro1007Ala, and the novel p.Cys800Ser, whose significance was unknown. Results: We observed in the stable cell line expressing NPC1 p.Cys800Ser that the mutated NPC1 protein is transported to the lysosome similarly to the p.Pro1007Ala variant and affects lysosomal distribution. Conclusions: Using this approach, we could analyze the pathogenicity of each variant separately and these cell lines could be used for personalized medicine-based approaches and multi-omic studies.eng
dc.description.sponsorshipCECA (UIDB/00211/2020) and AL4AnimalS (LA/P/0059/2020) funded by the Portuguese Foundation for Science and Technology (FCT).
dc.identifier.citationGenes (Basel). 2026 Feb 27;17(3):288. doi: 10.3390/genes17030288
dc.identifier.doi10.3390/genes17030288
dc.identifier.eissn2073-4425
dc.identifier.pmid41898822
dc.identifier.urihttp://hdl.handle.net/10400.18/11365
dc.language.isoeng
dc.peerreviewedyes
dc.publisherMDPI
dc.relationCenter for the Study of Animal Science
dc.relationAssociate Laboratory for Animal and Veterinary Sciences
dc.relationLA/P/0059/2020
dc.relation.hasversionhttps://www.mdpi.com/2073-4425/17/3/288
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectNiemann–Pick Disease Type C
dc.subjectCellular Model
dc.subjectFunctional Characterization
dc.subjectLysosomal Storage Diseases
dc.subjectVariants of Unknown Significance
dc.subjectDoenças Genéticas
dc.subjectGenética Humana
dc.subjectDoenças Lisossomais de Sobrecarga
dc.subjectVariantes de Significado Incerto
dc.subjectModelos Celulares
dc.titleARPE-19-A Stable Cell Line Expressing a Variant of Unknown Significance in the NPC1 Geneeng
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberUIDB/00211/2020
oaire.awardNumberLA/P/0059/2020
oaire.awardTitleCenter for the Study of Animal Science
oaire.awardTitleAssociate Laboratory for Animal and Veterinary Sciences
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00211%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/LA%2FP%2F0059%2F2020/PT
oaire.citation.issue3
oaire.citation.startPage288
oaire.citation.titleGenes
oaire.citation.volume17
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
relation.isProjectOfPublication69b75eb9-6f25-4ad8-98db-6cc7e9bcdcc7
relation.isProjectOfPublication93de5af7-dedc-4696-ae11-592584b020a8
relation.isProjectOfPublication.latestForDiscovery69b75eb9-6f25-4ad8-98db-6cc7e9bcdcc7

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