Aminoglycosides, but not PTC124 (Ataluren), rescue nonsense mutations in the leptin receptor and in luciferase reporter genes

Abstract In rare cases, monogenetic obesity is caused by nonsense mutations in genes regulating energy balance. A key factor herein is the leptin receptor. Here, we focus on leptin receptor nonsense variants causing obesity, namely the human W31X, murine Y333X and rat Y763X mutations, and explored t...

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Autores principales:	Florian Bolze, Sabine Mocek, Anika Zimmermann, Martin Klingenspor
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f0773e3ac67b4598903c56673d8c39ce
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spelling	oai:doaj.org-article:f0773e3ac67b4598903c56673d8c39ce2021-12-02T11:52:44ZAminoglycosides, but not PTC124 (Ataluren), rescue nonsense mutations in the leptin receptor and in luciferase reporter genes10.1038/s41598-017-01093-92045-2322https://doaj.org/article/f0773e3ac67b4598903c56673d8c39ce2017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01093-9https://doaj.org/toc/2045-2322Abstract In rare cases, monogenetic obesity is caused by nonsense mutations in genes regulating energy balance. A key factor herein is the leptin receptor. Here, we focus on leptin receptor nonsense variants causing obesity, namely the human W31X, murine Y333X and rat Y763X mutations, and explored their susceptibilities to aminoglycoside and PTC124 mediated translational read-through in vitro. In a luciferase based assay, all mutations - when analysed within the mouse receptor - were prone to aminoglycoside mediated nonsense suppression with the highest susceptibility for W31X, followed by Y763X and Y333X. For the latter, the corresponding rodent models appear valuable for in vivo experiments. When W31X was studied in the human receptor, its superior read-through susceptibility – initially observed in the mouse receptor – was eliminated, likely due to the different nucleotide context surrounding the mutation in the two orthologues. The impact of the surrounding context on the read-through opens the possibility to discover novel sequence elements influencing nonsense suppression. As an alternative to toxic aminoglycosides, PTC124 was indicated as a superior nonsense suppressor but inconsistent data concerning its read-through activity are reported. PTC124 failed to rescue W31X as well as different nonsense mutated luciferase reporters, thus, challenging its ability to induce translational read-through.Florian BolzeSabine MocekAnika ZimmermannMartin KlingensporNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Florian Bolze Sabine Mocek Anika Zimmermann Martin Klingenspor Aminoglycosides, but not PTC124 (Ataluren), rescue nonsense mutations in the leptin receptor and in luciferase reporter genes
description	Abstract In rare cases, monogenetic obesity is caused by nonsense mutations in genes regulating energy balance. A key factor herein is the leptin receptor. Here, we focus on leptin receptor nonsense variants causing obesity, namely the human W31X, murine Y333X and rat Y763X mutations, and explored their susceptibilities to aminoglycoside and PTC124 mediated translational read-through in vitro. In a luciferase based assay, all mutations - when analysed within the mouse receptor - were prone to aminoglycoside mediated nonsense suppression with the highest susceptibility for W31X, followed by Y763X and Y333X. For the latter, the corresponding rodent models appear valuable for in vivo experiments. When W31X was studied in the human receptor, its superior read-through susceptibility – initially observed in the mouse receptor – was eliminated, likely due to the different nucleotide context surrounding the mutation in the two orthologues. The impact of the surrounding context on the read-through opens the possibility to discover novel sequence elements influencing nonsense suppression. As an alternative to toxic aminoglycosides, PTC124 was indicated as a superior nonsense suppressor but inconsistent data concerning its read-through activity are reported. PTC124 failed to rescue W31X as well as different nonsense mutated luciferase reporters, thus, challenging its ability to induce translational read-through.
format	article
author	Florian Bolze Sabine Mocek Anika Zimmermann Martin Klingenspor
author_facet	Florian Bolze Sabine Mocek Anika Zimmermann Martin Klingenspor
author_sort	Florian Bolze
title	Aminoglycosides, but not PTC124 (Ataluren), rescue nonsense mutations in the leptin receptor and in luciferase reporter genes
title_short	Aminoglycosides, but not PTC124 (Ataluren), rescue nonsense mutations in the leptin receptor and in luciferase reporter genes
title_full	Aminoglycosides, but not PTC124 (Ataluren), rescue nonsense mutations in the leptin receptor and in luciferase reporter genes
title_fullStr	Aminoglycosides, but not PTC124 (Ataluren), rescue nonsense mutations in the leptin receptor and in luciferase reporter genes
title_full_unstemmed	Aminoglycosides, but not PTC124 (Ataluren), rescue nonsense mutations in the leptin receptor and in luciferase reporter genes
title_sort	aminoglycosides, but not ptc124 (ataluren), rescue nonsense mutations in the leptin receptor and in luciferase reporter genes
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/f0773e3ac67b4598903c56673d8c39ce
work_keys_str_mv	AT florianbolze aminoglycosidesbutnotptc124atalurenrescuenonsensemutationsintheleptinreceptorandinluciferasereportergenes AT sabinemocek aminoglycosidesbutnotptc124atalurenrescuenonsensemutationsintheleptinreceptorandinluciferasereportergenes AT anikazimmermann aminoglycosidesbutnotptc124atalurenrescuenonsensemutationsintheleptinreceptorandinluciferasereportergenes AT martinklingenspor aminoglycosidesbutnotptc124atalurenrescuenonsensemutationsintheleptinreceptorandinluciferasereportergenes
_version_	1718394960401661952

Aminoglycosides, but not PTC124 (Ataluren), rescue nonsense mutations in the leptin receptor and in luciferase reporter genes

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