Correction of ATM gene function by aminoglycoside-induced read-through of premature termination codons.


Approximately 14% of genetic mutations in patients with ataxia-telangiectsia (A-T) are single-nucleotide changes that result in primary premature termination codons (PTCs), either UAA, UAG, or UGA. The purpose of this study was to explore a potential therapeutic approach for this subset of patients by using aminoglycosides to induce PTC read-through, thereby restoring levels of full-length ATM (A-T mutated) protein. In experiments using a modified in vitro cDNA coupled transcription/translation protein truncation test, 13 A-T cell lines carrying PTC mutations in different contexts exhibited read-through expression of ATM fragments, with three of four aminoglycosides tested. In ex vivo experiments with lymphoblastoid cell lines, we used radiosensitivity, radioresistant DNA synthesis, and irradiation-induced autophosphorylation of ATM Ser-1981 to show that the aminoglycoside-induced full-length ATM protein was functional and corrected, to various extents, the phenotype of A-T cells. These results encourage further testing of other compounds in this class, as well as follow up animal studies. Because some A-T patients with 5-20% of normal levels of ATM protein show slower neurological progression, A-T may prove to be a good model for aminoglycoside-induced read-through therapy.

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@article{Lai2004CorrectionOA, title={Correction of ATM gene function by aminoglycoside-induced read-through of premature termination codons.}, author={Chih-Hung Lai and Helen H Chun and Shareef A. Nahas and Midori Mitui and Kristin M Gamo and Liutao Du and Richard A. Gatti}, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2004}, volume={101 44}, pages={15676-81} }