RETRACTED: Gentamicin B1 is a minor gentamicin component with major nonsense mutation suppression activity
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Post-publication record
- Nature
- Retraction
- Reason
- Error by Third Party;Error in Materials;Error in Results and/or Conclusions;
- Date
- 11/26/2018 0:00
- Flagged by OpenAlex?
- Yes
Source: Retraction Watch, joined by DOI. OpenAlex records retraction as is_retracted, a boolean over a state space with at least four values, so it cannot express an expression of concern, a correction or a reinstatement — it reports them as false, which reads as “fine”.
Abstract
Nonsense mutations underlie about 10% of rare genetic disease cases. They introduce a premature termination codon (PTC) and prevent the formation of full-length protein. Pharmaceutical gentamicin, a mixture of several related aminoglycosides, is a frequently used antibiotic in humans that can induce PTC readthrough and suppress nonsense mutations at high concentrations. However, testing of gentamicin in clinical trials has shown that safe doses of this drug produce weak and variable readthrough activity that is insufficient for use as therapy. In this study we show that the major components of pharmaceutical gentamicin lack PTC readthrough activity but the minor component gentamicin B1 (B1) is a potent readthrough inducer. Molecular dynamics simulations reveal the importance of ring I of B1 in establishing a ribosome configuration that permits pairing of a near-cognate complex at a PTC. B1 induced readthrough at all three nonsense codons in cultured cancer cells with TP53 (tumor protein p53) mutations, in cells from patients with nonsense mutations in the TPP1 (tripeptidyl peptidase 1), DMD (dystrophin), SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), and COL7A1 (collagen type VII alpha 1 chain) genes, and in an in vivo tumor xenograft model. The B1 content of pharmaceutical gentamicin is highly variable and major gentamicins suppress the PTC readthrough activity of B1. Purified B1 provides a consistent and effective source of PTC readthrough activity to study the potential of nonsense suppression for treatment of rare genetic disorders.
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The record
- Venue
- Proceedings of the National Academy of Sciences
- Topic
- RNA and protein synthesis mechanisms
- Field
- Biochemistry, Genetics and Molecular Biology
- Canadian institutions
- BC Cancer AgencyUniversity of British Columbia
- Funders
- Canadian Cancer Society Research InstituteCanadian Institutes of Health ResearchGenome British ColumbiaMitacsGovernment of Canada
- Keywords
- Nonsense mutationGentamicinNonsenseMutationAntibioticsBiologyAminoglycosideGeneticsGeneMissense mutation
- Has abstract in OpenAlex
- yes