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Avigail Beryozkin, Ananya Samanta, Samer Khateb, Eyal Banin, Dror Sharon, Uwe Wolfrum, Kerstin Nagel-Wolfrum; Ataluren-mediated read-through of a nonsense mutation in FAM161A gene which causes retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5324.
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© ARVO (1962-2015); The Authors (2016-present)
FAM161A mutations are currently the most common cause of autosomal recessive retinitis pigmentosa (ARRP) in the Israeli population. This gene is responsible for approximately 12% of all RP cases in Israeli Jewish patients, with only two mutations identified in this population. One of these mutations is a nonsense mutation (p.Arg523*) which results in a premature stop codon (PTC). Transitional read-through inducing drugs (TRIDs) suppress PTCs and thereby induce the re-expression of full-length proteins. Ataluren is one of the promising compounds for transitional read-through of nonsense mutations currently being used in clinical phase II trials for nonsense mutations in Aniridia. In this research, we investigate Ataluren as a potential treatment option for patients with the FAM161A nonsense mutation.
We generated fibroblast cell lines from 8 Israeli patients affected with ARRP due to the p.Arg523* nonsense mutation in FAM161A and age- matched healthy controls. FAM161A protein expression and localization was monitored in control, untreated and Ataluren-treated patient-derived fibroblasts by immunocytochemistry. Furthermore, primary ciliogenesis and cilia length was analyzed in starved control fibroblasts, patient-derived and Ataluren treated patient-derived fibroblasts by immunofluorescence analysis.
We observed FAM161A expression in ciliated fibroblasts from healthy individuals located along cytoplasmic microtubules and in the Golgi apparatus. In patient-derived cells FAM161A expression was barely or not at all detectable after starvation. We detected defective ciliogenesis in patient-derived cells compared to healthy cells. However, Ataluren treatment of patient-derived cells restored FAM161A localization and furthermore restored ciliogenesis in the FAM161A p.Arg523* patient cells.
FAM161A is expressed in fibroblast cells along microtubules and the Golgi apparatus. In patient-derived cells, FAM161A localization and ciliogenesis can be restored after Ataluren treatment. These results emphasize the feasibility of Ataluren as a therapeutic strategy tackling RP caused by the FAM161A nonsense mutation.Supports: FFB PPA-0717-0719-RAD (UW); FAUN-Stiftung (KNW)
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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