{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:47:29Z","timestamp":1791272849340,"version":"4.1.0"},"reference-count":45,"publisher":"National Academy of Sciences","issue":"14","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,4,3]]},"abstract":"<jats:p>\n                    We used antisense morpholino oligonucleotides (AMOs) to redirect and restore normal splicing of three prototypic splicing mutations in the\n                    <jats:italic>ataxia-telangiectasia mutated<\/jats:italic>\n                    (\n                    <jats:italic>ATM<\/jats:italic>\n                    ) gene. Two of the mutations activated cryptic 5\u2032 or 3\u2032 splice sites within exonic regions; the third mutation activated a downstream 5\u2032 splice site leading to pseudoexon inclusion of a portion of intron 28. AMOs were targeted to aberrant splice sites created by the mutations; this effectively restored normal ATM splicing at the mRNA level and led to the translation of full-length, functional ATM protein for at least 84 h in the three cell lines examined, as demonstrated by immunoblotting, ionizing irradiation-induced autophosphorylation of ATM, and transactivation of ATM substrates. Ionizing irradiation-induced cytotoxicity was markedly abrogated after AMO exposure. The\n                    <jats:italic>ex vivo<\/jats:italic>\n                    data strongly suggest that the disease-causing molecular pathogenesis of such prototypic mutations is not the amino acid change of the protein but the mutated DNA code itself, which alters splicing. Such prototypic splicing mutations may be correctable\n                    <jats:italic>in vivo<\/jats:italic>\n                    by systemic administration of AMOs and may provide an approach to customized, mutation-based treatment for ataxia-telangiectasia and other genetic disorders.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0608616104","type":"journal-article","created":{"date-parts":[[2007,3,27]],"date-time":"2007-03-27T23:41:55Z","timestamp":1175038915000},"page":"6007-6012","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":97,"title":["Correction of prototypic ATM splicing mutations and aberrant ATM function with antisense morpholino oligonucleotides"],"prefix":"10.1073","volume":"104","author":[{"given":"Liutao","family":"Du","sequence":"first","affiliation":[{"name":"*Department of Pathology and Laboratory Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julianne 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