Nonaminoglycoside compounds induce readthrough of nonsense mutations
Copyright policy )Nonaminoglycoside compounds induce readthrough of nonsense mutations
Large numbers of genetic disorders are caused by nonsense mutations for which compound-induced readthrough of premature termination codons (PTCs) might be exploited as a potential treatment strategy. We have successfully developed a sensitive and quantitative high-throughput screening (HTS) assay, protein transcription/translation (PTT)–enzyme-linked immunosorbent assay (ELISA), for identifying novel PTC-readthrough compounds using ataxia-telangiectasia (A-T) as a genetic disease model. This HTS PTT-ELISA assay is based on a coupled PTT that uses plasmid templates containing prototypic A-T mutated (ATM) mutations for HTS. The assay is luciferase independent. We screened ∼34,000 compounds and identified 12 low-molecular-mass nonaminoglycosides with potential PTC-readthrough activity. From these, two leading compounds consistently induced functional ATM protein in ATM-deficient cells containing disease-causing nonsense mutations, as demonstrated by direct measurement of ATM protein, restored ATM kinase activity, and colony survival assays for cellular radiosensitivity. The two compounds also demonstrated readthrough activity in mdx mouse myotube cells carrying a nonsense mutation and induced significant amounts of dystrophin protein.
- UNIVERSITY OF CALIFORNIA United States
- University of California United States
- University of California, Los Angeles United States
- University of California United States
- University of California United States
DNA-Binding Proteins (mesh), Inbred C57BL (mesh), Skeletal (mesh), Chromosomal Proteins, Non-Histone, Muscle Fibers, Skeletal, Cell Survival (mesh), Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Neurodegenerative, Inbred C57BL, 11 Medical and Health Sciences (for), Medical and Health Sciences, Cell Cycle Proteins (mesh), Nonsense (mesh), Mice, 2.1 Biological and endogenous factors, Animals (mesh), Phosphorylation, 32 Biomedical and Clinical Sciences (for-2020), Neurosciences (rcdc), Neurodegenerative (rcdc), Pediatric, Mice (mesh), Non-Histone (mesh), Skeletal, Chromosomal Proteins, DNA-Binding Proteins, Codon, Nonsense, Protein Serine-Threonine Kinases (mesh), Aminoglycosides (mesh), Structural Maintenance of Chromosome Protein 1, Biotechnology, Tumor Suppressor Proteins (mesh), Immunology (science-metrix), 570, Cell Survival, Immunology, Enzyme-Linked Immunosorbent Assay, Biotechnology (rcdc), Protein Serine-Threonine Kinases, Muscle Fibers, Article, 576, Cell Line, Rare Diseases (rcdc), Ataxia Telangiectasia, Rare Diseases, 42 Health sciences (for-2020), Ataxia Telangiectasia (rcdc), Enzyme-Linked Immunosorbent Assay (mesh), Genetics, Animals, Codon, Pediatric (rcdc), Biomedical and Clinical Sciences, Genetics (rcdc), Tumor Suppressor Proteins, Phosphorylation (mesh), Neurosciences, Health sciences, Non-Histone, 2.1 Biological and endogenous factors (hrcs-rac), Structural Maintenance of Chromosome Protein 1 (mesh), Mice, Inbred C57BL, Aminoglycosides, Nonsense, 32 Biomedical and clinical sciences (for-2020), Cell Line (mesh), Ataxia Telangiectasia Mutated Proteins (mesh)
DNA-Binding Proteins (mesh), Inbred C57BL (mesh), Skeletal (mesh), Chromosomal Proteins, Non-Histone, Muscle Fibers, Skeletal, Cell Survival (mesh), Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Neurodegenerative, Inbred C57BL, 11 Medical and Health Sciences (for), Medical and Health Sciences, Cell Cycle Proteins (mesh), Nonsense (mesh), Mice, 2.1 Biological and endogenous factors, Animals (mesh), Phosphorylation, 32 Biomedical and Clinical Sciences (for-2020), Neurosciences (rcdc), Neurodegenerative (rcdc), Pediatric, Mice (mesh), Non-Histone (mesh), Skeletal, Chromosomal Proteins, DNA-Binding Proteins, Codon, Nonsense, Protein Serine-Threonine Kinases (mesh), Aminoglycosides (mesh), Structural Maintenance of Chromosome Protein 1, Biotechnology, Tumor Suppressor Proteins (mesh), Immunology (science-metrix), 570, Cell Survival, Immunology, Enzyme-Linked Immunosorbent Assay, Biotechnology (rcdc), Protein Serine-Threonine Kinases, Muscle Fibers, Article, 576, Cell Line, Rare Diseases (rcdc), Ataxia Telangiectasia, Rare Diseases, 42 Health sciences (for-2020), Ataxia Telangiectasia (rcdc), Enzyme-Linked Immunosorbent Assay (mesh), Genetics, Animals, Codon, Pediatric (rcdc), Biomedical and Clinical Sciences, Genetics (rcdc), Tumor Suppressor Proteins, Phosphorylation (mesh), Neurosciences, Health sciences, Non-Histone, 2.1 Biological and endogenous factors (hrcs-rac), Structural Maintenance of Chromosome Protein 1 (mesh), Mice, Inbred C57BL, Aminoglycosides, Nonsense, 32 Biomedical and clinical sciences (for-2020), Cell Line (mesh), Ataxia Telangiectasia Mutated Proteins (mesh)
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