Enhanced Production of Functional Proteins from Defective Genes

摘要

Nonsense mutations, which result in the truncation or absence of a key protein product, are associated with a host of genetic diseases. Recently, gentamicin and other aminoglycoside antibiotics have been shown to suppress premature stop codon arrest by inducing the ribosome to read past the nonsense mutation via insertion of a random amino acid by a noncognate tRNA. Although the precise mechanism of nonsense mutation suppression remains to be established, gentamicin exerts its antibiotic action by targeting the 30S ribosomal subunit, where it interferes with the initiation complex of protein formation. Presumably, a related binding event in mammalian cells enables gentamicin to actively promote premature stop codon suppression. Aminoglycosides have now been used to suppress nonsense mutations in human cell lines and animal models of Hurler's syndrome, Duchenne muscular dystrophy, late infantile neuronal ceroid lipofuscinosis, and cystic fibrosis. Unfortunately, gentamicin therapy has limitations. First and foremost, suppression rates tend to be low and attempts to enhance these rates could have devastating genome-wide consequences by repressing bona fide stop codon signals. Second, iototoxicity and nephrotoxicity are known and serious side effects of gentamicin therapy. Finally, aminoglycoside antibiotics suppress stop codons with dramatically different efficiencies (UGA > UAG > UAA) and the ability to read past these codons is further dependent upon the local sequence context.