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Investigating p.Ala1035Val in NPC1: New Cellular Models for Niemann–Pick Type C Disease

2024-11-13Research article Open access
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dc.contributor.authorDavid, Hugo
dc.contributor.authorMonfregola, Jlenia
dc.contributor.authorRibeiro, Isaura
dc.contributor.authorCardoso, Maria Teresa
dc.contributor.authorSandiares, Ana Catarina
dc.contributor.authorMoreira, Luciana
dc.contributor.authorCoutinho, Maria Francisca
dc.contributor.authorQuelhas, Dulce
dc.contributor.authorBallabio, Andrea
dc.contributor.authorAlves, Sandra
dc.contributor.authorEncarnação, Marisa
dc.date.accessioned2025-03-11T15:26:51Z
dc.date.available2025-03-11T15:26:51Z
dc.date.issued2024-11-13
dc.description.abstractNiemann-Pick 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-/- 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.eng
dc.description.sponsorshipThis research was funded by national funds through Fundação para a Ciência e a Tecnologia, I. P. (FCT), within the scope of the project EXPL/BTM-TEC/1477/2021. This work was also financially supported with funding from FCT/MCTES, through national funds (UIDB/00211/2020).
dc.identifier.citationInt J Mol Sci. 2024 Nov 13;25(22):12186. doi: 10.3390/ijms252212186
dc.identifier.doidoi.org/10.3390/ijms252212186
dc.identifier.issn1661-6596
dc.identifier.pmid39596250
dc.identifier.urihttp://hdl.handle.net/10400.18/10433
dc.language.isoeng
dc.peerreviewedyes
dc.publisherMDPI
dc.relationRNA-Seq based methods to identify novel disease biomarkers in neurodegenerative metabolic diseases
dc.relationCenter for the Study of Animal Science
dc.relation.hasversionhttps://www.mdpi.com/1422-0067/25/22/12186
dc.relation.ispartofseries12186
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectNiemann–Pick type C
dc.subjectLysosomal Storage Disorders
dc.subjectCell Models
dc.subjectComplex alleles
dc.subjectp.Ala1035Val
dc.subjectp.Ile1061Thr
dc.subjectp.Ile858Val
dc.subjectPhenotypic Variability
dc.subjectDoenças Genéticas
dc.subjectGenética Humana
dc.titleInvestigating p.Ala1035Val in NPC1: New Cellular Models for Niemann–Pick Type C Diseaseeng
dc.typeresearch article
dspace.entity.typePublication
oaire.awardTitleRNA-Seq based methods to identify novel disease biomarkers in neurodegenerative metabolic diseases
oaire.awardTitleCenter for the Study of Animal Science
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Concurso de Projetos de Investigação de Caráter Exploratório (PeX) em Todos os Domínios Científicos/EXPL%2FBTM-TEC%2F1477%2F2021/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00211%2F2020/PT
oaire.citation.issue25
oaire.citation.startPage12186
oaire.citation.titleInternational Journal of Molecular Sciences
oaire.fundingStreamConcurso de Projetos de Investigação de Caráter Exploratório (PeX) em Todos os Domínios Científicos
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.isProjectOfPublication88e7e17f-1ff1-4024-b104-311c6dead773
relation.isProjectOfPublication69b75eb9-6f25-4ad8-98db-6cc7e9bcdcc7
relation.isProjectOfPublication.latestForDiscovery88e7e17f-1ff1-4024-b104-311c6dead773

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