A breakthrough in readthrough? Could geneticin lead the way to effective treatment for cystinosis nonsense mutations?

Midgley, Julian

doi:10.1007/s00467-018-4173-2

Cited by 4 publications

(5 citation statements)

References 30 publications

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“…Since faulty mRNA with premature stop codons are unstable and liable for nonsense-mediated mRNA decay (NMD), this eventually results in overall little or no mRNA available for TRIDs to perform their read-through capabilities. Therefore, NMD inhibition has been suggested as an adjunctive therapy to TRIDs to improve treatment efficiency and serve as a plausible approach to overcome nonsense mutations in a considerable subpopulation of cystinosis patients [76]. While TRIDS originally aimed at translational read-through, some have been shown to be dual acting and also inhibit NMD decay, warranting their single-therapy use [77][78][79].…”

Section: Trends Trends In In Molecular Molecular Medicine Medicinementioning

confidence: 99%

Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis

Jamalpoor

Othman

Levtchenko

et al. 2021

Trends in Molecular Medicine

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Section: Trends Trends In In Molecular Molecular Medicine Medicinementioning

confidence: 99%

Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis

Jamalpoor

Othman

Levtchenko

et al. 2021

Trends in Molecular Medicine

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“…It has been reported that different readthrough-promoting RNA compounds have similar capacities to inhibit the nonsense-mediated mRNA decay (NMD) pathway and that the level of translational readthrough required to skip NMD depends on how distant is the PTC from the end of the mRNA (Baker and Hogg, 2017; Midgley, 2019). We used the IB3.1 cells to investigate if Ataluren (indicated as PTC124 in figures) is able to stabilize the mRNA containing nonsense mutations in addition to the suggested readthrough activity.…”

Section: Resultsmentioning

confidence: 99%

Caffeine boosts Ataluren's readthrough activity

Lentini

Melfi

Pibiri

et al. 2019

Heliyon

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The readthrough of nonsense mutations by small molecules like Ataluren is considered a novel therapeutic approach to overcome the gene defect in several genetic diseases as cystic fibrosis (CF). This pharmacological approach suppresses translation termination at premature termination codons (PTCs readthrough) thus restoring the expression of a functional protein. However, readthrough might be limited by the nonsense-mediated mRNA decay (NMD), a cell process that reduces the amount/level of PTCs containing mRNAs. Here we investigate the combined action of Ataluren and caffeine to enhance the readthrough of PTCs. IB3.1 CF cells with a nonsense mutation were treated with caffeine to attenuate the Nonsense-Mediated mRNA Decay (NMD) activity and thus enhance the stability of the nonsense (ns)-CFTR-mRNA to be targeted by Ataluren. Our results show that NMD attenuation by caffeine enhances mRNA stability and more importantly when combined with Ataluren increase the recovery of the full-length CFTR protein.

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“…Inducible translational readthrough of PTC is a suitable approach to reconstitute the expression of full-length proteins encoded by PTC-targeted genes. Aminoglycoside antibiotics, including G418 (Geneticin) and gentamicin, have been reported as readthrough inducers of different PTC-targeted genes in a variety of cell types (Hermann, 2007;Midgley, 2019). We tested the efficacy of G418 to induce readthrough in PTEN using COS-7 and U87MG cell lines transiently transfected with cDNA plasmids encoding the R130X (TGA) and R233X (TGA) PTEN mutations frequently found in association with human disease.…”

Section: Induction Of Translational Readthrough Of Ptenmentioning

confidence: 99%

A global analysis of the reconstitution of PTEN function by translational readthrough ofPTENpathogenic premature termination codons

et al. 2021

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The PTEN tumor suppressor gene is mutated with high incidence in tumors and in the germline of patients with cancer predisposition or with macrocephaly associated with autism. PTEN nonsense mutations generating premature termination codons (PTC) and producing nonfunctional truncated PTEN proteins are frequent in association with human disease. However, there are no studies addressing the restoration of full-length PTEN proteins from the PTC-mutated PTEN gene by translational readthrough. Here, we have performed a global translational and functional readthrough analysis of the complete collection of PTEN PTC somatic or hereditary mutations found in tumors or in the germline of patients (disease-associated PTEN PTCome), and we set standards for the analysis of the potential of readthrough functional reconstitution in diseaserelevant genes. Our analysis indicates that prevalent pathogenic PTEN PTC mutations are susceptible to PTEN functional restoration in response to readthrough-inducing compounds. Comprehensive readthrough analyses of disease-associated PTComes will be valuable tools for the implementation of readthrough-based precision interventions in specific groups of patients.

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A breakthrough in readthrough? Could geneticin lead the way to effective treatment for cystinosis nonsense mutations?

Cited by 4 publications

References 30 publications

Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis

Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis

Caffeine boosts Ataluren's readthrough activity

A global analysis of the reconstitution of PTEN function by translational readthrough ofPTENpathogenic premature termination codons

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