USH2014 Presentations - Dr. Dominic Cosgrove, Functional Genetics

Presentation delivered by Dr. Dominic Cosgrove at the International Symposium on Usher Syndrome.

Download the presentation slides here.

Cosgrove, D., Zallocchi, M., Cheung, L., Peng, YW. and Delimont, D.

Boys Town National Research Hospital, Omaha, NE, USA


Usher mouse models show elevated light thresholds, following dark adaptation, required to activate the movement of α-transducin and arrestin between photoreceptor outer and inner segments. While the threshold shifts vary somewhat, we have found this to be true for all Usher models tested to date, including shaker-1,whirler, waltzer, Aims waltzer, Usherin hypomorph, VLGR1 carboxy terminal deletion mutant, and clarin-1 knockout. Thus this appears to constitute a common functional defect in protein trafficking. Recently we demonstrated that RGS9-1 and Gβ5L, components of the GTPase-accelerating complex which determines photoresponse duration, also move between photoreceptor segments in response to light, albeit at much lower light thresholds. This threshold is also shifted to a higher light level in Usher mouse models tested to date. These observations predict that photoreceptors in Usher mouse models would be susceptible to light induced degeneration under conditions that are insufficient to damage wild type retinas. Several different light induced degeneration protocols have proven this to be the case. We used a lentiviral gene therapy vector to deliver wild type human Myosin VIIa to Shaker -1 photoreceptors. We were able to rescue both the light threshold for α-transducin translocation and the retinal degeneration phenotype, proving that these phenotypes are due to the defective myosin VIIa function. Thus we predict humans with Usher syndrome may be more susceptible to light –induced damage due to the inability of the retina to rapidly quench phototransduction when exposed to bright light. This is predictably a direct consequence of defective light-induced trafficking of phototransduction proteins.