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.
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.
|Edmunds, Richard C; Su, Baofeng; Balhoff, James P et al. (2016) Phenoscape: Identifying Candidate Genes for Evolutionary Phenotypes. Mol Biol Evol 33:13-24|
|Burns, Adam R; Stephens, W Zac; Stagaman, Keaton et al. (2016) Contribution of neutral processes to the assembly of gut microbial communities in the zebrafish over host development. ISME J 10:655-64|
|Mason, Timothy; Snell, Kathy; Mittge, Erika et al. (2016) Strategies to Mitigate a Mycobacterium marinum Outbreak in a Zebrafish Research Facility. Zebrafish :|
|Wiles, Travis J; Jemielita, Matthew; Baker, Ryan P et al. (2016) Host Gut Motility Promotes Competitive Exclusion within a Model Intestinal Microbiota. PLoS Biol 14:e1002517|
|Hill, Jennifer Hampton; Franzosa, Eric A; Huttenhower, Curtis et al. (2016) A conserved bacterial protein induces pancreatic beta cell expansion during zebrafish development. Elife 5:|
|Zac Stephens, W; Burns, Adam R; Stagaman, Keaton et al. (2016) The composition of the zebrafish intestinal microbial community varies across development. ISME J 10:644-54|
|Talbot, Jared Coffin; Nichols, James T; Yan, Yi-Lin et al. (2016) Pharyngeal morphogenesis requires fras1-itga8-dependent epithelial-mesenchymal interaction. Dev Biol 416:136-48|
|Taylor, Charlotte R; Montagne, William A; Eisen, Judith S et al. (2016) Molecular fingerprinting delineates progenitor populations in the developing zebrafish enteric nervous system. Dev Dyn 245:1081-1096|
|Desvignes, Thomas; Detrich 3rd, H William; Postlethwait, John H (2016) Genomic conservation of erythropoietic microRNAs (erythromiRs) in white-blooded Antarctic icefish. Mar Genomics 30:27-34|
|Postlethwait, John H; Yan, Yi-Lin; Desvignes, Thomas et al. (2016) Embryogenesis and early skeletogenesis in the antarctic bullhead notothen, Notothenia coriiceps. Dev Dyn 245:1066-1080|
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