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

2020Journal article Open access
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dc.contributor.authorEncarnaĆ§Ć£o, 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 InĆŖs
dc.contributor.authorQuelhas, D
dc.contributor.authorLacerda, Lucia
dc.contributor.authorLeĆ£o Teles, Elisa
dc.contributor.authorFuterman, Anthony H.
dc.contributor.authorVilarinho, Laura
dc.contributor.authorAlves, Sandra
dc.date.accessioned2022-03-31T10:07:07Z
dc.date.available2022-03-31T10:07:07Z
dc.date.issued2020
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.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationEncarnaĆ§Ć£o M, Coutinho MF, Cho SM, et al. NPC1 silent variant induces skipping of exon 11 (p.V562V) and unfolded protein response was found in a specific Niemann-Pick type C patient. Mol Genet Genomic Med. 2020;8(11):e1451. doi:10.1002/mgg3.1451pt_PT
dc.identifier.doi10.1002/mgg3.1451pt_PT
dc.identifier.issn2324-9269
dc.identifier.urihttp://hdl.handle.net/10400.16/2678
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherJohn Wiley & Sonspt_PT
dc.relationCenter for the Study of Animal Science
dc.relationLess is more ā€“ 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.subjectNPC1pt_PT
dc.subjectNiemann-Pick type Cpt_PT
dc.subjectRNA-seqpt_PT
dc.subjectexon skippingpt_PT
dc.subjectsilent variantpt_PT
dc.subjectunfolded protein responsept_PT
dc.titleNPC1 silent variant induces skipping of exon 11 (p.V562V) and unfolded protein response was found in a specific Niemannā€Pick type C patientpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCenter for the Study of Animal Science
oaire.awardTitleLess is more ā€“ substrate reduction therapy for mucopolysaccharidoses through RNAi
oaire.awardTitleRNA-based therapies for Mucopolysaccharidoses
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBBB-BMD%2F6301%2F2014/PT
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.conferencePlaceUnited States of Americapt_PT
oaire.citation.issue11pt_PT
oaire.citation.startPagee1451pt_PT
oaire.citation.titleMolecular Genetics & Genomic Medicinept_PT
oaire.citation.volume8pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
person.familyNameQuelhas
person.familyNameWanzeller Guedes de Lacerda
person.givenNameDulce
person.givenNameLucia Maria
person.identifier.ciencia-id921C-8052-6FC5
person.identifier.ciencia-id6C13-8B6B-8E8E
person.identifier.orcid0000-0001-9989-9236
person.identifier.orcid0000-0002-7970-9535
person.identifier.scopus-author-id6507796178
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.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundaĆ§Ć£o para a CiĆŖncia e a Tecnologia
project.funder.nameFundaĆ§Ć£o para a CiĆŖncia e a Tecnologia
project.funder.nameFundaĆ§Ć£o para a CiĆŖncia e a Tecnologia
project.funder.nameFundaĆ§Ć£o para a CiĆŖncia e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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