PMID- 26648046 OWN - NLM STAT- MEDLINE DCOM- 20170109 LR - 20181113 IS - 1582-4934 (Electronic) IS - 1582-1838 (Print) IS - 1582-1838 (Linking) VI - 20 IP - 2 DP - 2016 Feb TI - Tissue-specific variation in nonsense mutant transcript level and drug-induced read-through efficiency in the Cln1(R151X) mouse model of INCL. PG - 381-5 LID - 10.1111/jcmm.12744 [doi] AB - About 10% of inherited diseases are caused by nonsense mutations [Trends Mol Med 18 (2012) 688], and nonsense suppression drug therapy promoting translation through premature stop codons is an emerging therapeutic approach. Infantile neuronal ceroid lipofuscinosis (INCL), a childhood neurodegenerative disease, results from mutations in the CLN1 gene encoding the lysosomal enzyme, palmitoyl-protein thioesterase 1 (PPT1) [Biochim Biophys Acta 1832 (2013) 1806, Hum Mutat (2012) 63, Biochim Biophys Acta 1832 (2013) 1881]. The nonsense mutation p.R151X is the most common disease-causing CLN1 mutation Hum Mutat (2012) 63. In the novel Cln1(R151X) mouse model of INCL, we found large, tissue-specific variations in Cln1(R151X) mRNA level and PPT1 residual enzyme activity. These tissue-specific differences strongly influenced the read-through efficiency of ataluren (PTC124), a well-known nonsense suppression drug. A two-day treatment with ataluren (10 mg/kg) increased PPT1 enzyme activity in the liver and muscle, but not in any other tissue examined. Our study identifies a new challenge/hurdle for read-through drug therapy: variable efficiency of read-through therapy in the different tissues/organs because of tissue-specific variations in nonsense mutant transcript levels. CI - (c) 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. FAU - Thada, Vaughn AU - Thada V AD - Department of Biology, Augustana College, Sioux Falls, SD, USA. AD - Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD, USA. FAU - Miller, Jake N AU - Miller JN AD - Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD, USA. AD - Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD, USA. FAU - Kovacs, Attila D AU - Kovacs AD AD - Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD, USA. FAU - Pearce, David A AU - Pearce DA AD - Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD, USA. AD - Department of Pediatrics, Sanford School of Medicine of the University of South Dakota, Sioux Falls, SD, USA. LA - eng GR - R01 NS044310/NS/NINDS NIH HHS/United States GR - NS044310/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151209 PL - England TA - J Cell Mol Med JT - Journal of cellular and molecular medicine JID - 101083777 RN - 0 (Codon, Nonsense) RN - 0 (RNA, Messenger) RN - EC 3.1.2.- (Thiolester Hydrolases) RN - EC 3.1.2.22 (palmitoyl-protein thioesterase) RN - Ceroid Lipofuscinosis, Neuronal, 1 SB - IM MH - Animals MH - Codon, Nonsense/*genetics MH - Disease Models, Animal MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Neuronal Ceroid-Lipofuscinoses/*genetics MH - RNA, Messenger/genetics MH - Thiolester Hydrolases/*genetics PMC - PMC4727554 OTO - NOTNLM OT - Cln1 R151X OT - ataluren OT - infantile neuronal ceroid lipofuscinosis OT - nonsense mutation OT - read-through drug EDAT- 2015/12/10 06:00 MHDA- 2017/01/10 06:00 PMCR- 2016/02/01 CRDT- 2015/12/10 06:00 PHST- 2015/08/10 00:00 [received] PHST- 2015/10/22 00:00 [accepted] PHST- 2015/12/10 06:00 [entrez] PHST- 2015/12/10 06:00 [pubmed] PHST- 2017/01/10 06:00 [medline] PHST- 2016/02/01 00:00 [pmc-release] AID - JCMM12744 [pii] AID - 10.1111/jcmm.12744 [doi] PST - ppublish SO - J Cell Mol Med. 2016 Feb;20(2):381-5. doi: 10.1111/jcmm.12744. Epub 2015 Dec 9.