The aminoglycoside geneticin permits translational readthrough of the CTNS W138X nonsense mutation in fibroblasts from patients with nephropathic cystinosis

Brasell, Emma; Chu, LeeLee; Kares, Reyhan El; Seo, Jung Hwa; Loesch, Robin; Iglesias, Diana M.; Goodyer, Paul

doi:10.1007/s00467-018-4094-0

Cited by 18 publications

(32 citation statements)

References 30 publications

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“…Our choice of readthrough compounds was meant to reflect different types of compounds, not to cover the entire and constantly expanding spectrum of compounds. Amlexanox, Ataluren, RTC13 and G418 have proven to be effective in read-through induction in several different PTCs both in vitro and in vivo (Gonzalez-Hilarion et al, 2012;Howard et al, 1996;Heier and DiDonato, 2009;Floquet et al, 2011;Salvatori et al, 2009;Brasell et al, 2019;Yu et al, 2014;Tan et al, 2011;Wilschanski et al, 2011;Du et al, 2008;Sánchez-Alcudia et al, 2012;Schwarz et al, 2015;Martorell et al, 2019). However, it is also important to mention that some criticism has been raised against Ataluren, its mode of action and its ability to induce PTC read-through (Chowdhury et al, 2018;McElroy et al, 2013;Auld et al, 2009;Dranchak et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Absence of p.R50X Pygm read-through in McArdle disease cellular models

Tarrasó

Real-Martinez

Parés

et al. 2020

Disease Models &Amp; Mechanisms

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McArdle disease is an autosomal recessive disorder caused by the absence of muscle glycogen phosphorylase, which leads to blocked muscle glycogen breakdown. We used three different cellular models to evaluate the efficiency of different read-through agents (including amlexanox, Ataluren, RTC13 and G418) in McArdle disease. The first model consisted of HeLa cells transfected with two different GFP-PYGM constructs presenting the Pygm p.R50X mutation (GFP-PYGM p.R50X and PYGM Ex1-GFP p.R50X). The second cellular model was based on the creation of HEK293T cell lines stably expressing the PYGM Ex1-GFP p.R50X construct. As these plasmids encode murine Pygm cDNA without any intron sequence, their transfection in cells would allow for analysis of the efficacy of readthrough agents with no concomitant nonsense-mediated decay interference. The third model consisted of skeletal muscle cultures derived from the McArdle mouse model (knock-in for the p.R50X mutation in the Pygm gene). We found no evidence of read-through at detectable levels in any of the models evaluated. We performed a literature search and compared the premature termination codon context sequences with reported positive and negative read-through induction, identifying a potential role for nucleotide positions −9, −8, −3, −2, +13 and +14 (the first nucleotide of the stop codon is assigned as +1). The Pygm p.R50X mutation presents TGA as a stop codon, G nucleotides at positions −1 and −9, and a C nucleotide at −3, which potentially generate a good context for read-through induction, counteracted by the presence of C at −2 and its absence at +4.

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Section: Discussionmentioning

confidence: 99%

Absence of p.R50X Pygm read-through in McArdle disease cellular models

Tarrasó

Real-Martinez

Parés

et al. 2020

Disease Models &Amp; Mechanisms

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“…To date, there is no market-approved LD-specific drug in this category. However, some aminoglycoside and nonaminoglycoside compounds have shown promising results in cell-based studies for cystinosis [76], neuronal ceroid lipofuscinosis, and others [77].…”

Section: Premature Termination Codon Read-throughmentioning

confidence: 99%

Precision Medicine for Lysosomal Disorders

et al. 2020

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Precision medicine (PM) is an emerging approach for disease treatment and prevention that accounts for the individual variability in the genes, environment, and lifestyle of each person. Lysosomal diseases (LDs) are a group of genetic metabolic disorders that include approximately 70 monogenic conditions caused by a defect in lysosomal function. LDs may result from primary lysosomal enzyme deficiencies or impairments in membrane-associated proteins, lysosomal enzyme activators, or modifiers that affect lysosomal function. LDs are heterogeneous disorders, and the phenotype of the affected individual depends on the type of substrate and where it accumulates, which may be impacted by the type of genetic change and residual enzymatic activity. LDs are individually rare, with a combined incidence of approximately 1:4000 individuals. Specific therapies are already available for several LDs, and many more are in development. Early identification may enable disease course prediction and a specific intervention, which is very important for clinical outcome. Driven by advances in omics technology, PM aims to provide the most appropriate management for each patient based on the disease susceptibility or treatment response predictions for specific subgroups. In this review, we focused on the emerging diagnostic technologies that may help to optimize the management of each LD patient and the therapeutic options available, as well as in clinical developments that enable customized approaches to be selected for each subject, according to the principles of PM.

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“…Individuals who have only one CTNS allele mutated, such as parents of a child with cystinosis, have 50% transport capacity in their lysosomes [19] and somewhat increased WBC cystine levels, but do not manifest disease. In the paper by Brasell et al, lysosomal transport was restored equally with one missense mutation as with two missense mutations [1]. Whether the efficiency of PTC suppression therapy in possible clinical trials of individuals with cystinosis will be similar is yet to be determined.…”

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confidence: 99%

“…The report by Brasell et al in this issue of Pediatric Nephrology [1] raises the possibility that individuals with cystinosis who have a nonsense mutation that is transcribed into a premature termination codon (PTC) can have functional cystinosin by taking a medication that allows translation of the complete CTNS gene. This is achieved by reducing translational fidelity which allows a change in one nucleotide of a PTC, turning it into a sense codon.…”

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confidence: 99%