Usher syndrome is the most prevalent cause of hereditary deaf blindness, characterized by congenital sensorineural hearing loss and progressive photoreceptor degeneration beginning in childhood or adolescence. Diagnosis and management of this disease are complex, owing to a significant degree of clinical, genetic, and molecular heterogeneity. Patients present clinically with significant variation in the onset, progression, and severity of hearing and vision symptoms, and the presence or absence of balance problems due to vestibular dysfunction. Some of this variation is due to different mutations;12 different loci are implicated as causative of Usher syndrome. But even siblings with the same mutation can present with different symptoms, severity, and disease progression. The basis of this variation is completely unknown. We also see phenotypic variation in zebrafish models of Usher syndrome, caused by mutations in orthologs of known human Usher genes. In vitro studies have suggested that the Usher proteins can bind together to form a multimolecular complex, but what the function of such a complex may be or even whether it forms in vivo are unknown. Our preliminary analysis of zebrafish demonstrate that at least some of the Usher proteins form a complex in vivo and that Usher gene mutations disrupt transport of the complex from the endoplasmic reticulum (ER) through the Golgi network. We hypothesize that such defects could lead to ER stress, causing stochastic cell dysfunction and apoptosis that manifests as developmental instability, which leads to phenotypic variation. We will examine these hypotheses in zebrafish Usher gene mutants using in situ protein proximity labeling and live imaging of the progression of cell death.

Public Health Relevance

R E L E V A N C E (See instructions): Usher syndrome is the most prevalent cause of hereditary deaf blindness affecting 1:6000 Americans. The proposed studies will identify the basis of phenotypic variation in Usher syndrome, paving the way toward better clinical diagnoses and treatments.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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University of Oregon
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