{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T22:08:21Z","timestamp":1762898901047},"reference-count":32,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2013,3,27]],"date-time":"2013-03-27T00:00:00Z","timestamp":1364342400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2013,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Phenylketonuria (PKU, OMIM 261600) is an autosomal recessive inborn error of phenylalanine metabolism, predominantly caused by mutations in the phenylalanine hydroxylase (<jats:italic>PAH<\/jats:italic>) gene. Approximately 10 % of patients carry a nonsense mutation, which results in an inactive or unstable truncated protein. In some genetic disorders, including cystic fibrosis and Duchenne muscular dystrophy, restoration of full\u2010length protein has been achieved by aminoglycoside antibiotics, such as gentamicin and G\u2010418 (Geneticin). More recently, nonsense read\u2010through has been induced at greater rates using a non\u2010aminoglycoside drug, PTC124 (Ataluren), which has the advantage of being non\u2010toxic in contrast to the antibiotics. The efficacy of read\u2010through induced by three compounds, aminoglycosides G418 and gentamicin, and PTC124 were evaluated for four nonsense mutations of <jats:italic>PAH<\/jats:italic> in an in vitro expression system in two mammalian cell lines (COS\u20107 and HEK293). The production of full\u2010length PAH was investigated using western blotting and the functionality confirmed by enzyme activity. Gentamicin and G\u2010418 induced read\u2010through of nonsense <jats:italic>PAH<\/jats:italic> mutations in HEK293 cells. The read\u2010through product partially restored enzymatic activity, which was significantly less than that of wild\u2010type, but comparable to a missense mutation of <jats:italic>PAH<\/jats:italic> associated with less severe forms of PKU. Treatment with PTC124 up to 100 \u03bcM did not result in full\u2010length PAH polypeptide. Nonsense read\u2010through drugs are a potential form of treatment for PKU, although the high dosage of aminoglycosides used is not appropriate in a clinical setting. In vitro studies with new non\u2010toxic read\u2010through agents as well as in vivo studies would also be essential to determine the extent of read\u2010through required to restore normal phenylalanine levels.<\/jats:p>","DOI":"10.1007\/s10545-013-9602-6","type":"journal-article","created":{"date-parts":[[2013,3,26]],"date-time":"2013-03-26T16:55:22Z","timestamp":1364316922000},"page":"955-959","source":"Crossref","is-referenced-by-count":17,"title":["In vitro read\u2010through of phenylalanine hydroxylase (<i>PAH<\/i>) nonsense mutations using aminoglycosides: a potential therapy for phenylketonuria"],"prefix":"10.1002","volume":"36","author":[{"given":"Gladys","family":"Ho","sequence":"first","affiliation":[{"name":"Genetic Metabolic Disorders Research Unit Children's Hospital at Westmead Sydney Australia"},{"name":"Discipline of Paediatrics &amp; Child Health University of Sydney Sydney Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juergen","family":"Reichardt","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Molecular Sciences James Cook University Townsville Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Christodoulou","sequence":"additional","affiliation":[{"name":"Genetic Metabolic Disorders Research Unit Children's Hospital at Westmead Sydney Australia"},{"name":"Discipline of Paediatrics &amp; Child Health University of Sydney Sydney Australia"},{"name":"Western Sydney Genetics Program The Children's Hospital at Westmead Locked Bag 4001, Westmead Sydney NSW 2145 Australia"},{"name":"Discipline of Genetic Medicine University of Sydney Sydney Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,3,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvg203"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI7866"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/oby.2011.202"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2744(69)90244-7"},{"key":"e_1_2_8_6_1","first-page":"805","article-title":"Drug profile: sapropterin dihydrochloride (Kuvan\/Phenoptin), an orally active synthetic form of BH4 for the treatment of phenylketonuria","volume":"10","author":"Burnett JR","year":"2007","journal-title":"IDrugs"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2008.17"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.22979"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20081940"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2010.05.017"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1086\/301920"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1006\/mgme.2000.3104"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-010-9099-1"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270006297140"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0496-467"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(200008)48:2<164::AID-ANA5>3.0.CO;2-B"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.38.11.2517"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2009.09.002"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)64850-1"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10038-004-0197-5"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28523"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2011.08.023"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1355838200000716"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1996.4508"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.5.1003"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm801640k"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2010.03.060"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1060612"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/29.9.e45"},{"key":"e_1_2_8_30_1","first-page":"1015","volume-title":"The metabolic and molecular bases of inherited disease","author":"Scriver CR","year":"1995"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10200"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddh023"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05756"}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1007\/s10545-013-9602-6","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T07:37:00Z","timestamp":1694763420000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1007\/s10545-013-9602-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,3,27]]},"references-count":32,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2013,11]]}},"alternative-id":["10.1007\/s10545-013-9602-6"],"URL":"https:\/\/doi.org\/10.1007\/s10545-013-9602-6","archive":["Portico"],"relation":{},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,3,27]]}}}