Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations.
Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR). A single recessive mutation, the deletion of phenylalanine 508 (deltaF508), causes severe CF and resides on 70% of mutant chromosomes. Severe CF is also caused by premature stop mutations, which are found on 5% of CF chromosomes. Here we report that two common, disease-associated stop mutations can be suppressed by treating cells with low doses of the aminoglycoside antibiotic G-418. Aminoglycoside treatment resulted in the expression of full-length CFTR and restored its cyclic AMP-activated chloride channel activity. Another aminoglycoside, gentamicin, also promoted the expression of full-length CFTR. These results suggest that treatment with aminoglycosides may provide a means of restoring CFTR function in patients with this class of mutation.
Howard
M
M
Department of Physiology, University of Alabama at Birmingham, 35294, USA.
Frizzell
R A
RA
Bedwell
D M
DM
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005839:Gentamicins / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D013489:Suppression, Genetic / Q000187:drug effects*
D000900:Anti-Bacterial Agents; C505032:CFTR protein, human; D005839:Gentamicins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C010680:antibiotic G 418