title: Tissue-specific variation in nonsense mutant transcript level and drug-induced read-through efficiency in the Cln1(R151X) mouse model of INCL.
abstract: 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.
authors.affiliation: Department of Biology, Augustana College, Sioux Falls, SD, USA.|Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD, USA.
authors.forename: Vaughn
authors.initials: V
authors.lastname: Thada
authors.affiliation: Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD, USA.|Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD, USA.
authors.forename: Jake N
authors.initials: JN
authors.lastname: Miller
authors.affiliation: Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD, USA.
authors.forename: Attila D
authors.initials: AD
authors.lastname: Kovács
authors.affiliation: Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD, USA.|Department of Pediatrics, Sanford School of Medicine of the University of South Dakota, Sioux Falls, SD, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Pearce
mesh_terms: D000818:Animals; D018389:Codon, Nonsense / Q000235:genetics*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D013869:Thiolester Hydrolases / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D012333:RNA, Messenger; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase
keywords: Cln1
  
  R151X; ataluren; infantile neuronal ceroid lipofuscinosis; nonsense mutation; read-through drug