USHER SYNDROME, RETINITIS PIGMENTOSA AND GENETIC MUTATIONS IN RHESUS MACAQUES

University Of Wisconsin-Madison, Madison WI

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: To develop a primate model of Usher Syndrome by genetic screening. Usher syndrome, a recessive disorder characterized by retinitis pigmentosa (RP) and sensorineural hearing loss, 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, we predict that screening 500 macaques has a 95% probability of detecting a pathologic mutation. We screened for macaque carriers of USH2A mutations because these mutations are a common genetic cause of RP in humans. Based on frequency, differences in physicochemical properties, rarity of the substitution in related proteins, and modeling of possible alterations of the 3 dimensional structure, the best candidate for a pathologic mutation is R878C which adds another cysteine next to the conserved cysteine that forms loop c in the 7th LE domain. A macaque model would 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. A manuscript describing these findings is currently under review. This research used WNPRC Research Services.