*7.5. Readthrough Therapy with Gentamicin*

Nonsense mutations result in an in-frame premature termination codon and the absence of functional protein. This results in severe phenotypes of the disease and an increased risk for the development of hepatocellular carcinoma [139]. The aminoglycoside antibiotic gentamicin binds to ribosomes and induces a translational readthrough at the premature termination codon, thereby leading to fractional restoration of synthesis of the full-length protein [140,141]. In a recent study, Amzal et al. [118] evaluated the impact of gentamicin on six BSEP nonsense mutations (Y354X, R415X, R470X, R1057X, R1090X and E1302X) in vitro. Readthrough results were significantly increased for all mutations. The strongest responses were seen for the R1090X mutation, with partial restoration and correct localization at the plasma membrane of HepG2 and Can 10 cells. The rescued protein was shown to mediate transcellular transport of [3H]TC in MDCK cells. Expression of the R1090X mutant was shown to be further enhanced by simultaneous treatment with 4-PB [118].
