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      Advances in therapeutic use of a drug-stimulated translational readthrough of premature termination codons

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          Abstract

          Premature termination codons (PTCs) in the coding regions of mRNA lead to the incorrect termination of translation and generation of non-functional, truncated proteins. Translational readthrough of PTCs induced by pharmaceutical compounds is a promising way of restoring functional protein expression and reducing disease symptoms, without affecting the genome or transcriptome of the patient. While in some cases proven effective, the clinical use of readthrough-inducing compounds is still associated with many risks and difficulties. This review focuses on problems directly associated with compounds used to stimulate PTC readthrough, such as their interactions with the cell and organism, their toxicity and bioavailability (cell permeability; tissue deposition etc.). Various strategies designed to overcome these problems are presented.

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          A meta-analysis of nonsense mutations causing human genetic disease.

          Matthew Cooper, Dobril Ivanov, Nadia A Chuzhanova … (2008)
          Nonsense mutations account for approximately 11% of all described gene lesions causing human inherited disease and approximately 20% of disease-associated single-basepair substitutions affecting gene coding regions. Pathological nonsense mutations resulting in TGA (38.5%), TAG (40.4%), and TAA (21.1%) occur in different proportions to naturally occurring stop codons. Of the 23 different nucleotide substitutions giving rise to nonsense mutations, the most frequent are CGA --> TGA (21%; resulting from methylation-mediated deamination) and CAG --> TAG (19%). The differing nonsense mutation frequencies are largely explicable in terms of variable nucleotide substitution rates such that it is unnecessary to invoke differential translational termination efficiency or differential codon usage. Some genes are characterized by numerous nonsense mutations but relatively few if any missense mutations (e.g., CHM) whereas other genes exhibit many missense mutations but few if any nonsense mutations (e.g., PSEN1). Genes in the latter category have a tendency to encode proteins characterized by multimer formation. Consistent with the operation of a clinical selection bias, genes exhibiting an excess of nonsense mutations are also likely to display an excess of frameshift mutations. Tumor suppressor (TS) genes exhibit a disproportionate number of nonsense mutations while most mutations in oncogenes are missense. A total of 12% of somatic nonsense mutations in TS genes were found to occur recurrently in the hypermutable CpG dinucleotide. In a comparison of somatic and germline mutational spectra for 17 TS genes, approximately 43% of somatic nonsense mutations had counterparts in the germline (rising to 98% for CpG mutations). Finally, the proportion of disease-causing nonsense mutations predicted to elicit nonsense-mediated mRNA decay (NMD) is significantly higher (P=1.56 x 10(-9)) than among nonobserved (potential) nonsense mutations, implying that nonsense mutations that elicit NMD are more likely to come to clinical attention.
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            Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease.

            Mehrdad Khajavi, Ken Inoue, James R. Lupski (2006)
            The nonsense-mediated decay (NMD) pathway is an mRNA surveillance system that typically degrades transcripts containing premature termination codons (PTCs) in order to prevent translation of unnecessary or aberrant transcripts. Failure to eliminate these mRNAs with PTCs may result in the synthesis of abnormal proteins that can be toxic to cells through dominant-negative or gain-of-function effects. Recent studies have expanded our understanding of the mechanism by which nonsense transcripts are recognized and targeted for decay. Here, we review the physiological role of this surveillance pathway, its implications for human diseases, and why knowledge of NMD is important to an understanding of genotype-phenotype correlations in various genetic disorders.
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              Therapeutics based on stop codon readthrough.

              Kim M Keeling, Xiaojiao Xue, Gwen Gunn … (2014)
              Nonsense suppression therapy encompasses approaches aimed at suppressing translation termination at in-frame premature termination codons (PTCs, also known as nonsense mutations) to restore deficient protein function. In this review, we examine the current status of PTC suppression as a therapy for genetic diseases caused by nonsense mutations. We discuss what is currently known about the mechanism of PTC suppression as well as therapeutic approaches under development to suppress PTCs. The approaches considered include readthrough drugs, suppressor tRNAs, PTC pseudouridylation, and inhibition of nonsense-mediated mRNA decay. We also discuss the barriers that currently limit the clinical application of nonsense suppression therapy and suggest how some of these difficulties may be overcome. Finally, we consider how PTC suppression may play a role in the clinical treatment of genetic diseases caused by nonsense mutations.
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                Author and article information

                Contributors
                Maciej Dabrowski: maciej.dabrowski@igcz.poznan.pl
                Zuzanna Bukowy-Bieryllo: zuzanna.bukowy-bieryllo@igcz.poznan.pl
                Ewa Zietkiewicz: ewa.zietkiewicz@igcz.poznan.pl
                Journal
                Journal ID (nlm-ta): Mol Med
                Journal ID (iso-abbrev): Mol. Med
                Title: Molecular Medicine
                Publisher: BioMed Central (London )
                ISSN (Print): 1076-1551
                ISSN (Electronic): 1528-3658
                Publication date (Electronic): 29 May 2018
                Publication date PMC-release: 29 May 2018
                Publication date Collection: 2018
                Volume: 24
                Electronic Location Identifier: 25
                Affiliations
                ISNI 0000 0004 0499 2422, GRID grid.420230.7, Institute of Human Genetics; Polish Academy of Sciences, ; Poznan, Poland
                Article
                Publisher ID: 24
                DOI: 10.1186/s10020-018-0024-7
                PMC ID: 6016875
                PubMed ID: 30134808
                SO-VID: da0059f5-f4ca-4d2e-a12d-ea573152468d
                Copyright © © The Author(s) 2018
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 6 April 2018
                Date accepted : 1 May 2018
                Funding
                Funded by: National Science Centre, Poland
                Award ID: 2016/23/N/NZ4/03228
                Award ID: 2016/20/T/NZ4/00525
                Award ID: 2013/09/D/NZ4/01692
                Award Recipient :
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2018

                Keywords: translational readthrough,stop codon suppression,nonsense suppression,premature termination codon,genetic diseases
                Data availability:
                Keywords: translational readthrough, stop codon suppression, nonsense suppression, premature termination codon, genetic diseases

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