Integrity and Stability of PTC Bearing CFTR mRNA and Relevance to Future Modulator Therapies in Cystic Fibrosis

Major advances have recently been made in the development and application of CFTR (cystic fibrosis transmembrane conductance regulator) mutation class-specific modulator therapies, but to date, there are no approved modulators for Class I mutations, i.e., those introducing a premature termination co...

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Autores principales:	Luka A. Clarke, Vanessa C. C. Luz, Szymon Targowski, Sofia S. Ramalho, Carlos M. Farinha, Margarida D. Amaral
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cystic fibrosis CFTR PTC mutations nonsense-mediated decay readthrough Genetics QH426-470
Acceso en línea:	https://doaj.org/article/7aff388cfffa47b4af85772b5d7bb515
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spelling	oai:doaj.org-article:7aff388cfffa47b4af85772b5d7bb5152021-11-25T17:42:17ZIntegrity and Stability of PTC Bearing CFTR mRNA and Relevance to Future Modulator Therapies in Cystic Fibrosis10.3390/genes121118102073-4425https://doaj.org/article/7aff388cfffa47b4af85772b5d7bb5152021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4425/12/11/1810https://doaj.org/toc/2073-4425Major advances have recently been made in the development and application of CFTR (cystic fibrosis transmembrane conductance regulator) mutation class-specific modulator therapies, but to date, there are no approved modulators for Class I mutations, i.e., those introducing a premature termination codon (PTC) into the CFTR mRNA. Such mutations induce nonsense-mediated decay (NMD), a cellular quality control mechanism that reduces the quantity of PTC bearing mRNAs, presumably to avoid translation of potentially deleterious truncated CFTR proteins. The NMD-mediated reduction of PTC-CFTR mRNA molecules reduces the efficacy of one of the most promising approaches to treatment of such mutations, namely, PTC readthrough therapy, using molecules that induce the incorporation of near-cognate amino acids at the PTC codon, thereby enabling translation of a full-length protein. In this study, we measure the effect of three different PTC mutations on the abundance, integrity, and stability of respective CFTR mRNAs, using CFTR specific RT-qPCR-based assays. Altogether, our data suggest that optimized rescue of PTC mutations has to take into account (1) the different steady-state levels of the CFTR mRNA associated with each specific PTC mutation; (2) differences in abundance between the 3′ and 5′ regions of CFTR mRNA, even following PTC readthrough or NMD inhibition; and (3) variable effects on CFTR mRNA stability for each specific PTC mutation.Luka A. ClarkeVanessa C. C. LuzSzymon TargowskiSofia S. RamalhoCarlos M. FarinhaMargarida D. AmaralMDPI AGarticlecystic fibrosisCFTRPTC mutationsnonsense-mediated decayreadthroughGeneticsQH426-470ENGenes, Vol 12, Iss 1810, p 1810 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cystic fibrosis CFTR PTC mutations nonsense-mediated decay readthrough Genetics QH426-470
spellingShingle	cystic fibrosis CFTR PTC mutations nonsense-mediated decay readthrough Genetics QH426-470 Luka A. Clarke Vanessa C. C. Luz Szymon Targowski Sofia S. Ramalho Carlos M. Farinha Margarida D. Amaral Integrity and Stability of PTC Bearing CFTR mRNA and Relevance to Future Modulator Therapies in Cystic Fibrosis
description	Major advances have recently been made in the development and application of CFTR (cystic fibrosis transmembrane conductance regulator) mutation class-specific modulator therapies, but to date, there are no approved modulators for Class I mutations, i.e., those introducing a premature termination codon (PTC) into the CFTR mRNA. Such mutations induce nonsense-mediated decay (NMD), a cellular quality control mechanism that reduces the quantity of PTC bearing mRNAs, presumably to avoid translation of potentially deleterious truncated CFTR proteins. The NMD-mediated reduction of PTC-CFTR mRNA molecules reduces the efficacy of one of the most promising approaches to treatment of such mutations, namely, PTC readthrough therapy, using molecules that induce the incorporation of near-cognate amino acids at the PTC codon, thereby enabling translation of a full-length protein. In this study, we measure the effect of three different PTC mutations on the abundance, integrity, and stability of respective CFTR mRNAs, using CFTR specific RT-qPCR-based assays. Altogether, our data suggest that optimized rescue of PTC mutations has to take into account (1) the different steady-state levels of the CFTR mRNA associated with each specific PTC mutation; (2) differences in abundance between the 3′ and 5′ regions of CFTR mRNA, even following PTC readthrough or NMD inhibition; and (3) variable effects on CFTR mRNA stability for each specific PTC mutation.
format	article
author	Luka A. Clarke Vanessa C. C. Luz Szymon Targowski Sofia S. Ramalho Carlos M. Farinha Margarida D. Amaral
author_facet	Luka A. Clarke Vanessa C. C. Luz Szymon Targowski Sofia S. Ramalho Carlos M. Farinha Margarida D. Amaral
author_sort	Luka A. Clarke
title	Integrity and Stability of PTC Bearing CFTR mRNA and Relevance to Future Modulator Therapies in Cystic Fibrosis
title_short	Integrity and Stability of PTC Bearing CFTR mRNA and Relevance to Future Modulator Therapies in Cystic Fibrosis
title_full	Integrity and Stability of PTC Bearing CFTR mRNA and Relevance to Future Modulator Therapies in Cystic Fibrosis
title_fullStr	Integrity and Stability of PTC Bearing CFTR mRNA and Relevance to Future Modulator Therapies in Cystic Fibrosis
title_full_unstemmed	Integrity and Stability of PTC Bearing CFTR mRNA and Relevance to Future Modulator Therapies in Cystic Fibrosis
title_sort	integrity and stability of ptc bearing cftr mrna and relevance to future modulator therapies in cystic fibrosis
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/7aff388cfffa47b4af85772b5d7bb515
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Integrity and Stability of PTC Bearing CFTR mRNA and Relevance to Future Modulator Therapies in Cystic Fibrosis

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