Stop-codon read-through for patients affected by a lysosomal storage disorder

Brooks, Doug A.; Muller, Viv; Hopwood, John J.

doi:10.1016/j.molmed.2006.06.001

Cited by 84 publications

(66 citation statements)

References 42 publications

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“…In our study, we focused on nonsense or frameshift mutations leading to PTC resulting in an almost complete absence of particular key proteins involved in lysosomal function and cell homeostasis maintenance. Preclinical studies with gentamicin or PTC124 had succeeded by enhancing stop codon readthrough and were able to be used as therapeutic agents for genetic diseases [9][10][11][12][13][14][15][16][17][18][36][37][38][39][40][41][42]. PTC124 has been successfully extended into clinical trials [18,43], although preliminary results are not clear for Duchenne muscular dystrophy [44].…”

Section: Discussionmentioning

confidence: 99%

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Effect of Readthrough Treatment in Fibroblasts of Patients Affected by Lysosomal Diseases Caused by Premature Termination Codons

et al. 2015

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Aminoglycoside antibiotics, such as gentamicin, may induce premature termination codon (PTC) readthrough and elude the nonsense-mediated mRNA decay mechanism. Because PTCs are frequently involved in lysosomal diseases, readthrough compounds may be useful as potential therapeutic agents. The aim of our study was to identify patients responsive to gentamicin treatment in order to be used as positive controls to further screen for other PTC readthrough compounds. With this aim, fibroblasts from 11 patients affected by 6 different lysosomal diseases carrying PTCs were treated with gentamicin. Treatment response was evaluated by measuring enzymatic activity, abnormal metabolite accumulation, mRNA expression, protein localization, and cell viability. The potential effect of readthrough was also analyzed by in silico predictions. Results showed that fibroblasts from 5/11 patients exhibited an up to 3-fold increase of enzymatic activity after gentamicin treatment. Accordingly, cell lines tested showed enhanced well-localized protein and/or increased mRNA expression levels and/or reduced metabolite accumulation. Interestingly, these cell lines also showed increased enzymatic activity after PTC124 treatment, which is a PTC readthroughpromoting compound. In conclusion, our results provide a proof-of-concept that PTCs can be effectively suppressed by readthrough drugs, with different efficiencies depending on the genetic context. The screening of new compounds with readthrough activity is a strategy that can be used to develop efficient therapies for diseases caused by PTC mutations.

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Section: Discussionmentioning

confidence: 99%

“…Glutamine is preferably inserted at nonsense UAG or UAA codons, whereas UGA miscode to tryptophan [36][37][38]. Taking into account these rules, the predicted amino acid changes were analyzed, using an in silico approach, for each patient (Polyphen-2 and SIFT analyses).…”

Section: In Silico Analysis Of the Predicted Substitutions Induced Bymentioning

confidence: 99%

Effect of Readthrough Treatment in Fibroblasts of Patients Affected by Lysosomal Diseases Caused by Premature Termination Codons

et al. 2015

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“…Recent studies indicate that it may be possible to correct the negative effect of mutations causing in-frame nonsense codons (stop codon read-through) using aminoglycoside antibiotics which, by virtue of their low molecular weight, are able to enter, by diffusion, cells, tissues and organs that are otherwise not easily accessible [38,39]. High levels of nonsense containing mRNAs, able to escape NMD, will result in an enhanced level of drug-induced read-through, making transcripts, from the allele with the c.385A NT mutation good candidates for this kind of therapy.…”

Section: Discussionmentioning

confidence: 99%

GALNS gene expression profiling in Morquio A patients' fibroblasts

Carraresi

Parini

Filoni

et al. 2008

Clinica Chimica Acta

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“…Molecular genetic studies show that most MPS I patients have a premature stop codon mutation in one or both alleles (Scott et al 1992b(Scott et al , 1993Hein et al 2004;Brooks et al 2006). At least 17 different a-L-iduronidase premature stop codon mutations have been detected, and over 90% of Caucasian MPS I patients have at least one of these mutations (Hein et al 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Aminoglycoside binding effectively lowers the docking energy required for the near-cognate transfer RNAs (tRNA), enabling amino acid substitution (Fourmy et al 1998a, b;Pape et al 2000). Glutamine and tryptophan have been reported to be the two most common amino acid insertions for mammalian stop codon read-through (Harrell et al 2002) and these coincidently relate to the high frequency of Q70X and W402X mutations in MPS I (Brooks et al 2006). Extended administration of aminoglycosides to patients can cause nephrotoxicity and ototoxicity, a complication that is not ideal for a therapeutic agent (Darlington and Smith 2003;Rougier et al 2004;Bitner-Glindzicz and Rahman 2007;Touw et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Aminoglycoside-Induced Premature Stop Codon Read-Through of Mucopolysaccharidosis Type I Patient Q70X and W402X Mutations in Cultured Cells

et al. 2013

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The premature stop codon mutations, Q70X and W402X, are the most common a-L-iduronidase gene (IDUA) mutations in mucopolysaccharidosis type I (MPS I) patients. Read-through drugs have been used to suppress premature stop codons, and this can potentially be used to treat patients who have this type of mutation. We examined the effects of aminoglycoside treatment on the IDUA mutations Q70X and W402X in cultured cells and show that 4,5-disubstituted aminoglycosides induced more readthrough for the W402X mutation, while 4,6-disubstituted aminoglycosides promoted more read-through for the Q70X mutation: lividomycin (4,5-disubstituted) induced a 7.8-fold increase in a-L-iduronidase enzyme activity for the W402X mutation; NB54 (4,5-disubstituted) induced a 3.7 fold increase in the amount of a-L-iduronidase enzyme activity for the W402X mutation, but had less effect on the Q70X mutation, whereas gentamicin (4,6-disubstituted) had the reverse effect on read-through for both mutations. The predicted mRNA secondary structural changes for both mutations were markedly different, which may explain these different effects on read-through for these two premature stop codons.

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Stop-codon read-through for patients affected by a lysosomal storage disorder

Cited by 84 publications

References 42 publications

Effect of Readthrough Treatment in Fibroblasts of Patients Affected by Lysosomal Diseases Caused by Premature Termination Codons

Effect of Readthrough Treatment in Fibroblasts of Patients Affected by Lysosomal Diseases Caused by Premature Termination Codons

GALNS gene expression profiling in Morquio A patients' fibroblasts

Aminoglycoside-Induced Premature Stop Codon Read-Through of Mucopolysaccharidosis Type I Patient Q70X and W402X Mutations in Cultured Cells

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