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D.J. Orten, A.M. Hemje, C.A. Carney, M. Neuringer, L.A. Lyons, W.J. Kimberling; Towards a Macaque Model for Usher Syndrome and Autosomal Recessive Retinitis Pigmentosa . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4535.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Usher syndrome is an autosomal recessive disorder characterized by progressive retinitis pigmentosa (RP) and moderate to profound sensorineural hearing loss. It is the leading cause of combined hearing and vision loss in the industrialized world, affecting 25,000-30,000 people in the United States. Mutations in the USH2A gene account for over half of Usher syndrome cases and 25-50% of autosomal recessive RP cases, which affects about 67,000 people in the United States. Disparities in retina function indicate that rodents may not be ideal models for this type of RP. Based on the carrier rate for the average recessive gene of 1/100 in humans, we predict that screening 378 macaques has an 85% probability of detecting a pathologic mutation in any recessive disease gene. Because mutations in the USH2A gene are the most common genetic cause of RP, we have chosen this gene for our initial screen. Exons 12 and 13 were evaluated first, because they contain the most common human Usher syndrome and RP mutations. Methods: DNA samples from 378 unrelated macaques were obtained from two primate centers. Segments (323-486 bp) of USH2A exons 12 and 13 plus flanking intronic DNA were amplified and sequenced. Pathology of putative mutations was evaluated based on frequency and predicted alteration of protein structure. Results: Four common variants (>20% of alleles) were found, two of which altered amino acids. Twenty-seven rare variants (0.1 to 8% of alleles) were found, 13 of which altered amino acids. Conclusions: The best missense mutation candidates are L803F (0.7%), G805R (1%), G832R (1.3%), R868C (0.5%) and P905R (0.1%), which alter partially conserved residues in the 6th, 7th and 8th USH2A laminin EGF domains. Putative pathologic mutations will be further evaluated via analysis of USH2A RNA and protein in lip biopsies and by competitive assays in vitro. If loss of protein function is indicated, mating or in vitro fertilization will be arranged to produce homozygous offspring. A macaque model will provide insights into pathologic mechanisms for retinitis pigmentosa, and may be better suited than mice for testing new treatments that could reduce or prevent inherited blindness.
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