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The effect of premature termination codon mutations on CFTR mRNA abundance in human nasal epithelium and intestinal organoids: a basis for read-through therapies in cystic fibrosis

2019Journal article Open access
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dc.contributor.authorClarke, LA
dc.contributor.authorAwatade, NT
dc.contributor.authorFelício, VM
dc.contributor.authorSilva, IA
dc.contributor.authorCalucho, M
dc.contributor.authorPereira, L
dc.contributor.authorAzevedo, P
dc.contributor.authorCavaco, J
dc.contributor.authorBarreto, C
dc.contributor.authorBertuzzo, C
dc.contributor.authorGartner, S
dc.contributor.authorBeekman, J
dc.contributor.authorAmaral, MD
dc.date.accessioned2020-08-10T14:38:43Z
dc.date.available2020-08-10T14:38:43Z
dc.date.issued2019
dc.description.abstractA major challenge in cystic fibrosis (CF) research is applying mutation-specific therapy to individual patients with diverse and rare CF transmembrane conductance regulator (CFTR) genotypes. Read-through agents are currently the most promising approach for Class I mutations that introduce premature termination codons (PTCs) into CFTR mRNA. However, variations in degradation of PTC containing transcripts by nonsense mediated decay (NMD) might lower read-through efficacy. Allele specific quantitative real time (qRT)-PCR was used to measure variations in CFTR mRNA abundance for several PTC mutations in respiratory cells and intestinal organoids. The majority of PTC mutations were associated with reduced levels of relative mRNA transcript abundance (∼33% and 26% of total CFTR mRNA in respiratory cells and intestinal organoids, respectively, compared to >50% for non-PTC causing mutations). These levels were generally not affected by PTC mutation type or position, but there could be twofold variations between individuals bearing the same genotype. Most PTC mutations in CFTR are subject to similar levels of NMD, which reduce but do not abolish PTC bearing mRNAs. Measurement of individual NMD levels in intestinal organoids and HNE cells might, therefore, be useful in predicting efficacy of PTC read-through in the context of personalized CFTR modulator therapy.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationHum Mutat . 2019 Mar;40(3):326-334pt_PT
dc.identifier.doi10.1002/humu.23692pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.17/3494
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWileypt_PT
dc.subjectAnimalspt_PT
dc.subjectCodon, Nonsensept_PT
dc.subjectCystic Fibrosispt_PT
dc.subjectCystic Fibrosis Transmembrane Conductance Regulatorpt_PT
dc.subjectHumanspt_PT
dc.subjectIntestinespt_PT
dc.subjectMicept_PT
dc.subjectMutationpt_PT
dc.subjectNIH 3T3 Cellspt_PT
dc.subjectNasal Mucosapt_PT
dc.subjectNonsense Mediated mRNA Decaypt_PT
dc.subjectOrganoidspt_PT
dc.subjectRNA, Messengerpt_PT
dc.subjectHDE PEDpt_PT
dc.titleThe effect of premature termination codon mutations on CFTR mRNA abundance in human nasal epithelium and intestinal organoids: a basis for read-through therapies in cystic fibrosispt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage334pt_PT
oaire.citation.issue3pt_PT
oaire.citation.startPage326pt_PT
oaire.citation.titleHuman mutationpt_PT
oaire.citation.volume40pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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