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NPC1 silent variant induces skipping of exon 11 (p.V562V) and unfolded protein response was found in a specific Niemann-Pick type C patient

2020-11Artigo científico Acesso aberto
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dc.contributor.authorEncarnação, Marisa
dc.contributor.authorCoutinho, Maria Francisca
dc.contributor.authorCho, Soo Min
dc.contributor.authorCardoso, Maria Teresa
dc.contributor.authorRibeiro, Isaura
dc.contributor.authorChaves, Paulo
dc.contributor.authorSantos, Juliana Inês
dc.contributor.authorQuelhas, Dulce
dc.contributor.authorLacerda, Lúcia
dc.contributor.authorLeão Teles, Elisa
dc.contributor.authorFuterman, Anthony H.
dc.contributor.authorVilarinho, Laura
dc.contributor.authorAlves, Sandra
dc.date.accessioned2021-03-08T16:11:10Z
dc.date.available2021-03-08T16:11:10Z
dc.date.issued2020-11
dc.description.abstractBackground: Niemann-Pick type C (NPC, MIM #257220) is a neuro-visceral disease, caused predominantly by pathogenic variants in the NPC1 gene. Here we studied patients with clinical diagnosis of NPC but inconclusive results regarding the molecular analysis. Methods: We used a Next-Generation Sequencing (NGS)-panel followed by cDNA analysis. Latter, we used massively parallel single-cell RNA-seq (MARS-Seq) to address gene profiling changes and finally the effect of different variants on the protein and cellular levels. Results: We identified novel variants and cDNA analysis allowed us to establish the functional effect of a silent variant, previously reported as a polymorphism. We demonstrated that this variant induces the skipping of exon 11 leading to a premature stop codon and identified it in NPC patients from two unrelated families. MARS-Seq analysis showed that a number of upregulated genes were related to the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress in one specific patient. Also, for all analyzed variants, the NPC1 protein was partially retained in the ER. Conclusion: We showed that the NPC1 silent polymorphism (p.V562V) is a disease-causing variant in NPC and that the UPR is upregulated in an NPC patient.pt_PT
dc.description.sponsorshipThis work was partially supported by NORTE2020 (NORTE-01-0246- FEDER-000014 DESVENDAR “DEScobrir, VENcer as Doenças Raras”, FCT (Fundação para a Ciência e a Tecnologia - MCTES, Portugal) projects PTDC/BBB-BMD/6301/2014 and UIDB/00211/2020. MFC and JIS were grantees from the FCT (SFRH/BPD/101965/2014; SFRH/BD/124372/2016, respectively).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationMol Genet Genomic Med. 2020 Nov;8(11):e1451. doi: 10.1002/mgg3.1451. Epub 2020 Sep 15.pt_PT
dc.identifier.doi10.1002/mgg3.1451pt_PT
dc.identifier.issn2324-9269
dc.identifier.urihttp://hdl.handle.net/10400.18/7365
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWileypt_PT
dc.relationPTDC/BBB‐BMD/6301/2014pt_PT
dc.relationCenter for the Study of Animal Science
dc.relationLess is more – substrate reduction therapy for mucopolysaccharidoses through RNAi
dc.relationRNA-based therapies for Mucopolysaccharidoses
dc.relation.publisherversionhttps://onlinelibrary.wiley.com/doi/10.1002/mgg3.1451pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectLysosomal Storage Disorderspt_PT
dc.subjectNiemann Pick Type C Diseasept_PT
dc.subjectNPC1pt_PT
dc.subjectRNA-seqpt_PT
dc.subjectExon Skippingpt_PT
dc.subjectSilent Variantpt_PT
dc.subjectUnfolded Protein Responsept_PT
dc.subjectGenómica Funcionalpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleNPC1 silent variant induces skipping of exon 11 (p.V562V) and unfolded protein response was found in a specific Niemann-Pick type C patientpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCenter for the Study of Animal Science
oaire.awardTitleLess is more – substrate reduction therapy for mucopolysaccharidoses through RNAi
oaire.awardTitleRNA-based therapies for Mucopolysaccharidoses
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00211%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F101965%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F124372%2F2016/PT
oaire.citation.issue11pt_PT
oaire.citation.startPagee1451pt_PT
oaire.citation.titleMolecular Genetics and Genomic Medicinept_PT
oaire.citation.volume8pt_PT
oaire.fundingStream6817 - DCRRNI ID
project.funder.identifierhttp://doi.org/10.13039/501100001871
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
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctAcesso de acordo com página web do editor da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication69b75eb9-6f25-4ad8-98db-6cc7e9bcdcc7
relation.isProjectOfPublicationd1c04e35-3f6b-4a72-bc55-d760905299ad
relation.isProjectOfPublication562a3a9f-a750-448a-a10a-3237c343b669
relation.isProjectOfPublication.latestForDiscovery69b75eb9-6f25-4ad8-98db-6cc7e9bcdcc7

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