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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Neuhold, Lisa
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University of Utah
Schools of Medicine
Salt Lake City
United States
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Sharif, Ali S; Yu, Dongmei; Loertscher, Stuart et al. (2018) C8ORF37 Is Required for Photoreceptor Outer Segment Disc Morphogenesis by Maintaining Outer Segment Membrane Protein Homeostasis. J Neurosci 38:3160-3176
Zou, Junhuang; Chen, Qian; Almishaal, Ali et al. (2017) The roles of USH1 proteins and PDZ domain-containing USH proteins in USH2 complex integrity in cochlear hair cells. Hum Mol Genet 26:624-636
Almishaal, Ali A; Mathur, Pranav D; Hillas, Elaine et al. (2017) Natural killer cells attenuate cytomegalovirus-induced hearing loss in mice. PLoS Pathog 13:e1006599
Ciardo, Maria Grazia; Andrés-Bordería, Amparo; Cuesta, Natalia et al. (2016) Whirlin increases TRPV1 channel expression and cellular stability. Biochim Biophys Acta 1863:115-27
Zou, Junhuang; Mathur, Pranav D; Zheng, Tihua et al. (2015) Individual USH2 proteins make distinct contributions to the ankle link complex during development of the mouse cochlear stereociliary bundle. Hum Mol Genet 24:6944-57
Mathur, Pranav; Yang, Jun (2015) Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities. Biochim Biophys Acta 1852:406-20
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
Mathur, Pranav Dinesh; Zou, Junhuang; Zheng, Tihua et al. (2015) Distinct expression and function of whirlin isoforms in the inner ear and retina: an insight into pathogenesis of USH2D and DFNB31. Hum Mol Genet 24:6213-28
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
Chen, Qian; Zou, Junhuang; Shen, Zuolian et al. (2014) Whirlin and PDZ domain-containing 7 (PDZD7) proteins are both required to form the quaternary protein complex associated with Usher syndrome type 2. J Biol Chem 289:36070-88

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