Human Usher syndrome, the most frequent cause of deaf blindness, is characterized by congenital deafness, due to loss of sensory hair cells, and progressive retinal degeneration, due to retinitis pigmentosa. Twelve different chromosomal loci have been linked to Usher syndrome and nine of the genes have been identified to date. Identification of the missing Usher genes is crucial for diagnosis and patient counseling. The nine known genes encode a surprisingly broad range of different types of proteins. Although the roles of these proteins are poorly understood, recent studies suggest that they function together in a multimolecular complex. This project focuses on analysis of the two scaffold proteins that play a central role in organizing the complex, and a new potential member of this organizing scaffold. The project has three main aims: 1) to determine whether the newly discovered gene encodes an Usher scaffold protein, 2) to analyze the functions of the scaffold proteins in organizing the Usher proteins into a complex, and 3) to determine how the Usher protein complex functions in cells of the inner ear and retina.

Public Health Relevance

Usher syndrome, the leading cause of deaf blindness, is a genetically heritable disorder that affects tens of thousands of Americans. Deafness in Usher syndrome is due to loss of inner ear sensory hair cells and can range from moderate to profound. Blindness is due to retinitis pigmentosa. Mutations in any one of at least a dozen different genes can cause Usher syndrome, only nine of the genes have been identified. Recent research suggests that the various proteins encoded by the Usher genes act together in a multimolecular complex, although the processes that lead to loss of inner ear and retinal cells when the complex is defective are unknown. This project will elucidate how and where the complex functions and the mechanisms by which it assembles. The project will also identify new members of the Usher gene family. This information is important for diagnosis, genetic counseling, and design of therapies for Usher patients.

National Institute of Health (NIH)
Research Project (R01)
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Development - 2 Study Section (DEV2)
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Freeman, Nancy
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University of Oregon
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United States
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Blanco-Sánchez, Bernardo; Clément, Aurélie; Fierro Jr, Javier et al. (2014) Complexes of Usher proteins preassemble at the endoplasmic reticulum and are required for trafficking and ER homeostasis. Dis Model Mech 7:547-59
Phillips, Jennifer B; Westerfield, Monte (2014) Zebrafish models in translational research: tipping the scales toward advancements in human health. Dis Model Mech 7:739-43
Beck, Bodo B; Phillips, Jennifer B; Bartram, Malte P et al. (2014) Mutation of POC1B in a severe syndromic retinal ciliopathy. Hum Mutat 35:1153-62
Phillips, Jennifer B; Västinsalo, Hanna; Wegner, Jeremy et al. (2013) The cone-dominant retina and the inner ear of zebrafish express the ortholog of CLRN1, the causative gene of human Usher syndrome type 3A. Gene Expr Patterns 13:473-81
Phillips, Jennifer B; Blanco-Sanchez, Bernardo; Lentz, Jennifer J et al. (2011) Harmonin (Ush1c) is required in zebrafish Muller glial cells for photoreceptor synaptic development and function. Dis Model Mech 4:786-800