Pharmaceutical therapies to recode nonsense mutations in inherited diseases

Lee, Hui-Ling Rose; Dougherty, Joseph P.

doi:10.1016/j.pharmthera.2012.07.007

Cited by 126 publications

(158 citation statements)

References 197 publications

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“…One-third of inherited human diseases are due to PTCs that are introduced by nonsense mutations, frameshift mutations or splicing errors (Frischmeyer and Dietz, 1999;Linde and Kerem, 2008), and nonsense mutations account for ∼20% of the around 43,000 disease-associated single-base pair substitutions (Mort et al, 2008) and for 5 to 70% of genetic disorders (Lee and Dougherty, 2012). NMD functions to eliminate transcripts that harbor nonsense codons that would otherwise result in the production of truncated proteins that have the potential to increase disease severity.…”

Section: Therapeutic Approaches For Ptc-associated Diseasesmentioning

confidence: 99%

Nonsense-mediated mRNA decay in humans at a glance

Kurosaki

Maquat

2016

Journal of Cell Science

288

290

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Nonsense-mediated mRNA decay (NMD) is an mRNA quality-control mechanism that typifies all eukaryotes examined to date. NMD surveys newly synthesized mRNAs and degrades those that harbor a premature termination codon (PTC), thereby preventing the production of truncated proteins that could result in disease in humans. This is evident from dominantly inherited diseases that are due to PTC-containing mRNAs that escape NMD. Although many cellular NMD targets derive from mistakes made during, for example, pre-mRNA splicing and, possibly, transcription initiation, NMD also targets ∼10% of normal physiological mRNAs so as to promote an appropriate cellular response to changing environmental milieus, including those that induce apoptosis, maturation or differentiation. Over the past ∼35 years, a central goal in the NMD field has been to understand how cells discriminate mRNAs that are targeted by NMD from those that are not. In this Cell Science at a Glance and the accompanying poster, we review progress made towards this goal, focusing on human studies and the role of the key NMD factor upframeshift protein 1 (UPF1).

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Section: Therapeutic Approaches For Ptc-associated Diseasesmentioning

confidence: 99%

Nonsense-mediated mRNA decay in humans at a glance

Kurosaki

Maquat

2016

Journal of Cell Science

288

290

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“…Several compounds have been described as inducing translational readthrough of premature stop codons and production of full-length protein by interfering with ribosomal proofreading. Gentamycin, an aminoglycoside antibiotic, for example, has been shown to promote readthrough in several different genetic diseases, 3,4 but just as with other promoting aminoglycosides, toxicity is a complicating issue. 5 Recently, however, a non-aminoglycoside drug called PTC124 was described as being effective in suppressing nonsense mutations in vitro and in vivo in different disease models, 6 whereas this drug was well-tolerated in a phase I clinical trial.…”

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confidence: 99%

Readthrough-Promoting Drugs Gentamicin and PTC124 Fail to Rescue Na _v 1.5 Function of Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes Carrying Nonsense Mutations in the Sodium Channel Gene SCN5A

Kosmidis

Veerman

Casini

et al. 2016

Circ: Arrhythmia and Electrophysiology

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Background-Several compounds have been reported to induce translational readthrough of premature stop codons resulting in the production of full-length protein by interfering with ribosomal proofreading. Here we examined the effect of 2 of these compounds, gentamicin and PTC124, in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes bearing nonsense mutations in the sodium channel gene SCN5A, which are associated with conduction disease and potential lethal arrhythmias. Methods and Results-We generated hiPSC from 2 patients carrying the mutations R1638X and W156X. hiPSC-derived cardiomyocytes from both patients recapitulated the expected electrophysiological phenotype, as evidenced by reduced Na + currents and action potential upstroke velocities compared with hiPSC-derived cardiomyocytes from 2 unrelated control individuals. While we were able to confirm the readthrough efficacy of the 2 drugs in Human Embryonic Kidney 293 cells, we did not observe rescue of the electrophysiological phenotype in hiPSC-derived cardiomyocytes from the patients. Conclusions-We conclude that these drugs are unlikely to present an effective treatment for patients carrying the loss-of-function SCN5A gene mutations examined in this study. (Circ Arrhythm Electrophysiol. 2016;9:e004227.

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“…As ∼30% of human disease mutations stem from the introduction of stop codons that cause premature translation termination (17), such investigations suggest that a deeper understanding of negamycin's mode of action may one day be harnessed for therapeutic purpose (reviewed in ref. 18). …”

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confidence: 99%

Negamycin induces translational stalling and miscoding by binding to the small subunit head domain of the Escherichia coli ribosome

Olivier

Altman

Noeske

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Negamycin is a natural product with broad-spectrum antibacterial activity and efficacy in animal models of infection. Although its precise mechanism of action has yet to be delineated, negamycin inhibits cellular protein synthesis and causes cell death. Here, we show that single point mutations within 16S rRNA that confer resistance to negamycin are in close proximity of the tetracycline binding site within helix 34 of the small subunit head domain. As expected from its direct interaction with this region of the ribosome, negamycin was shown to displace tetracycline. However, in contrast to tetracycline-class antibiotics, which serve to prevent cognate tRNA from entering the translating ribosome, single-molecule fluorescence resonance energy transfer investigations revealed that negamycin specifically stabilizes near-cognate ternary complexes within the A site during the normally transient initial selection process to promote miscoding. The crystal structure of the 70S ribosome in complex with negamycin, determined at 3.1 Å resolution, sheds light on this finding by showing that negamycin occupies a site that partially overlaps that of tetracycline-class antibiotics. Collectively, these data suggest that the small subunit head domain contributes to the decoding mechanism and that small-molecule binding to this domain may either prevent or promote tRNA entry by altering the initial selection mechanism after codon recognition and before GTPase activation.egamycin, a natural product originally isolated from cultures of Streptomyces purpeofuscus, exhibits broad-spectrum antibacterial activity against key pathogens for which clinical treatment options are dwindling (1, 2). The chemical structure of negamycin, [2-[(3R, 5R)-3,6-diamino-5-hydroxyhexanoyl]-1-methylhydrazino]acetic acid, and synthetic routes for its synthesis were elucidated in the early 1970s ( Fig. 1A) (3,4). Early toxicity studies in dogs revealed that daily administration of negamycin led to the formation of N-methylhydrazinoacetic acid, an inhibitor of glutamate pyruvate transaminase, an outcome that caused reversible hepatic coma. Consequently, further clinical studies were not pursued (5). Although the antimicrobial activity and efficacy of negamycin have since been confirmed, analogs exhibiting an improved therapeutic window have yet to be found (6, 7). Progress on this front has been hampered, at least in part, by the fact that the molecular mechanisms of negamycin-induced cell growth inhibition have yet to be discerned conclusively.Negamycin decreases the viability of Escherichia coli by preferentially targeting protein synthesis (8). Early mechanistic investigations proposed that negamycin may act by inhibiting translation initiation (8), decreasing translational fidelity during the elongation phase of protein synthesis (9, 10), and disrupting proper translation termination (9,(11)(12)(13). Uncertainties regarding negamycin's inhibition mechanism, its highly polar physicochemical properties, and the lack of streptomycin cross-resistance led som...

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Pharmaceutical therapies to recode nonsense mutations in inherited diseases

Cited by 126 publications

References 197 publications

Nonsense-mediated mRNA decay in humans at a glance

Nonsense-mediated mRNA decay in humans at a glance

Readthrough-Promoting Drugs Gentamicin and PTC124 Fail to Rescue Na _v 1.5 Function of Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes Carrying Nonsense Mutations in the Sodium Channel Gene SCN5A

Negamycin induces translational stalling and miscoding by binding to the small subunit head domain of the Escherichia coli ribosome

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Pharmaceutical therapies to recode nonsense mutations in inherited diseases

Cited by 126 publications

References 197 publications

Nonsense-mediated mRNA decay in humans at a glance

Nonsense-mediated mRNA decay in humans at a glance

Readthrough-Promoting Drugs Gentamicin and PTC124 Fail to Rescue Na v 1.5 Function of Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes Carrying Nonsense Mutations in the Sodium Channel Gene SCN5A

Negamycin induces translational stalling and miscoding by binding to the small subunit head domain of the Escherichia coli ribosome

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Readthrough-Promoting Drugs Gentamicin and PTC124 Fail to Rescue Na _v 1.5 Function of Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes Carrying Nonsense Mutations in the Sodium Channel Gene SCN5A