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.
|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|
|McMenamin, Sarah K; Bain, Emily J; McCann, Anna E et al. (2014) Thyroid hormone-dependent adult pigment cell lineage and pattern in zebrafish. Science 345:1358-61|
|Santos, M Emília; Braasch, Ingo; Boileau, Nicolas et al. (2014) The evolution of cichlid fish egg-spots is linked with a cis-regulatory change. Nat Commun 5:5149|
|Beahm, Brendan J; Dehnert, Karen W; Derr, Nicolas L et al. (2014) A visualizable chain-terminating inhibitor of glycosaminoglycan biosynthesis in developing zebrafish. Angew Chem Int Ed Engl 53:3347-52|
|DeLaurier, April; Huycke, Tyler R; Nichols, James T et al. (2014) Role of mef2ca in developmental buffering of the zebrafish larval hyoid dermal skeleton. Dev Biol 385:189-99|
|Kimmel, Charles B (2014) Skull developmental modularity: a view from a single bone - or two. J Appl Ichthyol 30:600-607|
|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|
|Sheehan-Rooney, Kelly; Swartz, Mary E; Zhao, Feng et al. (2013) Ahsa1 and Hsp90 activity confers more severe craniofacial phenotypes in a zebrafish model of hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR). Dis Model Mech 6:1285-91|
|Paquette, Colleen E; Kent, Michael L; Buchner, Cari et al. (2013) A retrospective study of the prevalence and classification of intestinal neoplasia in zebrafish (Danio rerio). Zebrafish 10:228-36|
|Rodriguez-Mari, Adriana; Canestro, Cristian; BreMiller, Ruth A et al. (2013) Retinoic acid metabolic genes, meiosis, and gonadal sex differentiation in zebrafish. PLoS One 8:e73951|
Showing the most recent 10 out of 260 publications