Usher syndrome is the most common condition with vision and hearing loss. There is no cure for this disease. Our long-term goal is to understand the molecular mechanisms of retinal degeneration in Usher syndrome, which will lay a solid foundation for developing effective therapies for this disease. The main focus of this proposal is the formation and new components of the protein complex composed of USH2A, VLGR1 and WHRN in photoreceptors. The genes encoding these three proteins are the causative genes for Usher syndrome type 2, the most common form of Usher syndrome. Our recent research has demonstrated that the Usher 2 protein complex is located at the periciliary membrane complex (PMC) in mammalian photoreceptors. Defects in this protein complex cause ultra structural abnormalities surrounding the PMC and eventually lead to photoreceptor cell death. However, the formation, composition and biological function of this complex are largely not clear. The central HYPOTHESIS of this study is that WHRN, as a scaffold protein, associates with USH2A, VLGR1 and other components of the Usher 2 protein complex, and that these components contribute to the function of the whole complex in photoreceptors. To test this hypothesis, two specific aims will be addressed.
In specific aim 1, interactions among USH2A, VLGR1 and WHRN will be thoroughly studied using a series of biochemical assays in both in vitro and in vivo systems. The possibility of the existence of a ternary complex will be explored.
In specific aim 2, two newly identified candidate components of the Usher 2 protein complex will be studied in photoreceptors. The functional significance of these new components in this complex will be further analyzed using their mutant mice. This study will generate new insight into the function of the Usher 2 protein complex in photoreceptors, which may be applied in hair cells as well. Therefore, this study will help fill the gap in our knowledge about the mechanisms underlying retinal degeneration and, perhaps, hearing impairment in Usher syndrome, which might be valuable for the future development of therapeutic strategies for Usher syndrome. Furthermore, this study will provide a better understanding of the role of the PMC in photoreceptor cell biology.
Defects in the Usher 2 multi-protein complex cause Usher syndrome type 2, a condition with both retinitis pigmentosa and congenital hearing impairment. This proposal is to investigate the formation of this complex and its potential new components. Completion of this work is expected to provide more complete insight into the biological function of this complex and the disease mechanism underlying Usher syndrome.
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|Mathur, Pranav Dinesh; Vijayakumar, Sarath; Vashist, Deepti et al. (2015) A study of whirlin isoforms in the mouse vestibular system suggests potential vestibular dysfunction in DFNB31-deficient patients. Hum Mol Genet 24:7017-30|
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|Zou, Junhuang; Zheng, Tihua; Ren, Chongyu et al. (2014) Deletion of PDZD7 disrupts the Usher syndrome type 2 protein complex in cochlear hair cells and causes hearing loss in mice. Hum Mol Genet 23:2374-90|
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