期刊
JOURNAL OF MOLECULAR MEDICINE-JMM
卷 94, 期 4, 页码 469-482出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00109-015-1364-1
关键词
Nonsense mutations; Premature termination codons (PTCs); Genetic diseases; Ribosomal read-through; Aminoglycoside and macrolide antibiotics
资金
- Rising Tide Foundation for Clinical Cancer Research
- Gateway for Cancer Research Foundation
- United States-Israel Binational Science Foundation
- Israel Science Foundation
A large number of human diseases are caused by nonsense mutations. These mutations result in premature protein termination and the expression of truncated, usually nonfunctional products. A promising therapeutic strategy for patients suffering from premature termination codon (PTC)-mediated disorders is to suppress the nonsense mutation and restore the expression of the affected protein. Such a suppression approach using specific antibiotics and other read-through promoting agents has been shown to suppress PTCs and restore the production of several important proteins. Here, we report the establishment of a novel, rapid, and very efficient method for screening stop-codon read-through agents. We also show that, in both mammalian cells and in a transgenic mouse model, distinct members of the macrolide antibiotic family can induce read-through of disease-causing stop codons leading to re-expression of several key proteins and to reduced disease phenotypes. Taken together, our results may help in the identification and characterization of well-needed customized pharmaceutical PTC suppression agents.
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