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Abstract/Summary
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<jats:sec>
<jats:title>Abstract</jats:title>
<jats:p>Rett syndrome (RTT) is a neurodevelopmental disorder resulting from genetic mutations in the <jats:italic>methyl CpG binding protein 2</jats:italic> (<jats:italic>MeCP2</jats:italic>) gene. Specifically, around 35% of RTT patients harbor premature termination codons (PTCs) within the <jats:italic>MeCP2</jats:italic> gene due to nonsense mutations. A promising therapeutic avenue for these individuals involves the use of aminoglycosides, which stimulate translational readthrough (TR) by causing stop codons to be interpreted as sense codons. However, the effectiveness of this treatment depends on several factors, including the type of stop codon and the surrounding nucleotides, collectively referred to as the stop codon context (SCC). Here, we develop a high-content reporter system to precisely measure TR efficiency at different SCCs, assess the recovery of the full-length <jats:italic>MeCP2</jats:italic> protein, and evaluate its subcellular localization. We have conducted a comprehensive investigation into the intricate relationship between SCC characteristics and TR induction, examining a total of 14 pathogenic <jats:italic>MeCP2</jats:italic> nonsense mutations with the aim to advance the prospects of personalized therapy for individuals with RTT. Our results demonstrate that TR induction can successfully restore full-length <jats:italic>MeCP2</jats:italic> protein, albeit to varying degrees, contingent upon the SCC and the specific position of the PTC within the <jats:italic>MeCP2</jats:italic> mRNA. TR induction can lead to the re-establishment of nuclear localization of <jats:italic>MeCP2</jats:italic>, indicating the potential restoration of protein functionality. In summary, our findings underscore the significance of SCC-specific approaches in the development of tailored therapies for RTT. By unraveling the relationship between SCC and TR therapy, we pave the way for personalized, individualized treatment strategies that hold promise for improving the lives of individuals affected by this debilitating neurodevelopmental disorder. </jats:p>
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<jats:title>Key messages</jats:title>
<jats:p><jats:list list-type='bullet'>
<jats:list-item>
<jats:p>The efficiency of readthrough induction at <jats:italic>MeCP2</jats:italic> premature termination codons strongly depends on the stop codon context.</jats:p>
</jats:list-item>
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<jats:p>The position of the premature termination codon on the transcript influences the readthrough inducibility.</jats:p>
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<jats:p>A new high-content dual reporter assay facilitates the measurement and prediction of readthrough efficiency of specific nucleotide stop contexts.</jats:p>
</jats:list-item>
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<jats:p>Readthrough induction results in the recovery of full-length <jats:italic>MeCP2</jats:italic> and its re-localization to the nucleus.</jats:p>
</jats:list-item>
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<jats:p><jats:italic>MeCP2</jats:italic> requires only one of its annotated nuclear localization signals.</jats:p>
</jats:list-item>
</jats:list></jats:p>
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Hinweis
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DeepGreen-ID: 17085c7da16443088f0f42a34d3cfcd7 ; metadata provieded by: DeepGreen (https://www.oa-deepgreen.de/api/v1/), LIVIVO search scope life sciences (http://z3950.zbmed.de:6210/livivo), Crossref Unified Resource API (https://api.crossref.org/swagger-ui/index.html), to.science.api (https://frl.publisso.de/), ZDB JSON-API (beta) (https://zeitschriftendatenbank.de/api/), lobid - Dateninfrastruktur für Bibliotheken (https://lobid.org/resources/search) ;
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