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

• DOI: 10.1073/pnas.0405155101
• Publication Date: 2004-10-22T00:24:05Z
• Authors: Chih-Hung Lai; Helen H. Chun; Shareef A. Nahas; Midori Mitui; Kristin M. Gamo; Liutao Du; Richard A. Gatti
• Keywords: 0303 health sciences; Base Sequence; Paromomycin; Tumor Suppressor Proteins; Cell Cycle Proteins; Ataxia Telangiectasia Mutated Proteins; DNA; In Vitro Techniques; Protein Serine-Threonine Kinases; Radiation Tolerance; Cell Line; 3. Good health; DNA-Binding Proteins; Ataxia Telangiectasia; 03 medical and health sciences; Aminoglycosides; Codon, Nonsense; Tobramycin; Humans; Point Mutation; Gentamicins

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