Tamar Ben-Yosef, PhD

Evaluating suppression of nonsense mutations by aminoglycoside antibiotics and their derivatives as an intervention for vision loss in type 1 Usher syndrome

Type 1 Usher syndrome (USH1) is a genetically heterogenous disease, and is characterized by congenital profound deafness and progressive loss of vision due to retinitis pigmentosa (RP). While truncating mutations of the different USH1 genes cause

USH1, some missense mutations of these genes cause nonsyndromic deafness. These observations suggest that partial activity of the encoded proteins may be sufficient for normal retinal function, but not for normal hearing. We are examining suppression of nonsense mutations by aminoglycoside antibiotics as a potential intervention for vision loss in USH1 patients due to nonsense mutations of two genes: PCDH15 and CDH23. The approach is being tested both in vitro and ex vivo, and in mouse models of USH1. In parallel, we are developing a series of new aminoglycoside derivatives with suppressive activity and reduced toxicity. This research will have important implications for development of targeted interventions for patients with USH1 and nonsyndromic RP that is caused by various nonsense mutations.

Figure 1:

Aminoglycosides interfere with the proofreading activity of the ribosome during translation of proteins. This interference results in the insertion of an amino acid instead of a stop codon, and translation of a full-length protein.

Representative publications

Rebibo-Sabbah, A., Nudelman, I., Ahmed, Z. M., Baasov, T., Ben-Yosef, T. 2009. In vitro and ex vivo suppression by aminoglycosides of PCDH15  nonsense mutations underlying type 1 Usher syndrome. Hum Genet 122, 373-381.

Auslender, N., Sharon, D., Abbasi, A. H., Garzozi, H. J., Banin, E., Ben-Yosef, T. 2007. A common founder mutation of CERKL underlies autosomal recessive retinal degeneration with early macular involvement among Yemenite Jews. Invest Ophthalmol Vis Sci 48, 5431-5438.

Nudelman, I., Rebibo-Sabbah, A., Shallom-Shezifi, D., Hainrichson, M., Stahl, I., Ben-Yosef, T., Baasov, T. 2006. Redesign of aminoglycosides for treatment of human genetic diseases caused by premature stop mutations. Bioorg Med Chem Lett 16, 6310-6315.