Tissue-specific variation in nonsense mutant transcript level and drug-induced read-through efficiency in the
Vaughn Thada1,2, Jake N Miller2,3, Attila D Kovács2
1Department of Biology, Augustana College, Sioux Falls, SD, USA.
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.
Insights
Nonsense suppression therapy shows variable efficacy across tissues due to differing mutant gene levels. This highlights a significant challenge for treating genetic disorders like infantile neuronal ceroid lipofuscinosis with read-through drugs.
Area of Science:
- Genetics
- Pharmacology
- Neuroscience
Background:
- Nonsense mutations cause ~10% of inherited diseases.
- Infantile neuronal ceroid lipofuscinosis (INCL) is a neurodegenerative disorder caused by CLN1 gene mutations.
- The p.R151X nonsense mutation is the most common CLN1 mutation.
Purpose of the Study:
- To investigate the efficacy of nonsense suppression therapy in a novel mouse model of INCL.
- To explore tissue-specific variations in read-through drug efficiency.
Main Methods:
- Development of a Cln1(R151X) mouse model for INCL.
- Assessment of tissue-specific Cln1(R151X) mRNA levels and PPT1 enzyme activity.
- Treatment with ataluren (a nonsense suppression drug) and evaluation of PPT1 activity.
Main Results:
- Significant tissue-specific variations in Cln1(R151X) mRNA and PPT1 activity were observed.
- Ataluren treatment increased PPT1 activity in liver and muscle, but not other tissues.
- These results indicate variable read-through efficiency influenced by transcript levels.
Conclusions:
- Tissue-specific variations in nonsense mutant transcript levels present a challenge for read-through drug therapy.
- Understanding these variations is crucial for developing effective treatments for genetic disorders like INCL.
