Whirlin Replacement Restores the Formation of the USH2 Protein Complex in Whirlin Knockout Photoreceptors

Abstract

Whirlin transgene recruits USH2A and VLGR1 to the PMC and is sufficient for the formation of the USH2 protein complex in photoreceptors. The combined hRK and AAV gene delivery system could be an effective gene therapy approach to treat retinal degeneration in USH2D patients.

Whirlin and PDZ Domain-containing 7 (PDZD7) Proteins Are Both Required to Form the Quaternary Protein Complex Associated with Usher Syndrome Type 2

“…This PBM of USH2A and GPR98 interacts with WHRN PDZ domains (13,22,25). Additionally, WHRN is able to recruit USH2A and GPR98 to their normal locations in photoreceptors (26). Therefore, WHRN may be a candidate link between USH2A and GPR98 in the USH2 protein complex.…”

“…Biochemical studies demonstrate that the PDZ domains of WHRN and PDZD7 are able to bind the PBMs of USH2A and GPR98 (1, 13, 16,22,25). In photoreceptors, USH2A, GPR98, and WHRN proteins show mutual dependence for normal localizations at the periciliary membrane complex, and WHRN is able to recruit USH2A and GPR98 to the periciliary membrane complex (22,26). In developing cochlear hair cells, some of the USH2A, GPR98, WHRN, and PDZD7 proteins have been demonstrated to be mutually required for normal localizations at the ankle link complex (11,16).…”

Emerging Gene Therapies for Retinal Degenerations

“…Vectors expressing such genes or knock-down cassettes have been developed and tested in animal models (LaVail et al, 2000;Schlichtenbrede et al, 2003;Pang et al, 2008;Chadderton et al, 2009;Raz-Prag et al, 2009;Palfi et al, 2010;Zou et al, 2011). While this approach may be successful for individual disease genes, and is a good one to establish the use of gene therapy vectors for ocular diseases, it likely will not be possible to extend such a targeted approach to all disease genes.…”

Gene supplementation therapy for recessive forms of inherited retinal dystrophies

“…89 AAV2/5-mediated gene transfer of Whirlin into the photoreceptors of these mice results in restoration of the USH2 complex of Whirlin, Usherin and Vlgr1 to the periciliary membrane complex, suggesting that the USH2D retinal pathology could be treated with AAV gene therapy. 90 However, the effect on the rate of photoreceptor cell loss in the Whirlin À/À mice has not been reported and it therefore remains to be determined whether the rescue of Whirlin function can slow the progression of the disease. 90 BBS comprises a group of B15 genetic loci causing various pathologies, including severe retinal degeneration, obesity, renal abnormalities and learning disabilities.…”

“…90 However, the effect on the rate of photoreceptor cell loss in the Whirlin À/À mice has not been reported and it therefore remains to be determined whether the rescue of Whirlin function can slow the progression of the disease. 90 BBS comprises a group of B15 genetic loci causing various pathologies, including severe retinal degeneration, obesity, renal abnormalities and learning disabilities. The proteins encoded by the BBS genes form a complex that is thought to be involved in ciliary transport processes.…”