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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
7P01HD022486-28
Application #
8906894
Study Section
Special Emphasis Panel (ZHD1-DSR-Y)
Project Start
Project End
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
28
Fiscal Year
2015
Total Cost
$48,490
Indirect Cost
$15,050
Name
University of Oregon
Department
Type
DUNS #
City
Eugene
State
OR
Country
United States
Zip Code
97403
Ferreira, Carlos R; Xia, Zhi-Jie; Clément, Aurélie et al. (2018) A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation. Am J Hum Genet 103:553-567
Logan, Savannah L; Dudley, Christopher; Baker, Ryan P et al. (2018) Automated high-throughput light-sheet fluorescence microscopy of larval zebrafish. PLoS One 13:e0198705
Clément, Aurélie; Blanco-Sánchez, Bernardo; Peirce, Judy L et al. (2018) Cog4 is required for protrusion and extension of the epithelium in the developing semicircular canals. Mech Dev :
Parthasarathy, Raghuveer (2018) Monitoring microbial communities using light sheet fluorescence microscopy. Curr Opin Microbiol 43:31-37
Troll, Joshua V; Hamilton, M Kristina; Abel, Melissa L et al. (2018) Microbiota promote secretory cell determination in the intestinal epithelium by modulating host Notch signaling. Development 145:
Dona, Margo; Slijkerman, Ralph; Lerner, Kimberly et al. (2018) Usherin defects lead to early-onset retinal dysfunction in zebrafish. Exp Eye Res 173:148-159
Blanco-Sánchez, Bernardo; Clément, Aurélie; Fierro Jr, Javier et al. (2018) Grxcr1 Promotes Hair Bundle Development by Destabilizing the Physical Interaction between Harmonin and Sans Usher Syndrome Proteins. Cell Rep 25:1281-1291.e4
Rolig, Annah S; Sweeney, Emily Goers; Kaye, Lila E et al. (2018) A bacterial immunomodulatory protein with lipocalin-like domains facilitates host-bacteria mutualism in larval zebrafish. Elife 7:
Logan, Savannah L; Thomas, Jacob; Yan, Jinyuan et al. (2018) The Vibrio cholerae type VI secretion system can modulate host intestinal mechanics to displace gut bacterial symbionts. Proc Natl Acad Sci U S A 115:E3779-E3787
Ganz, J; Baker, R P; Hamilton, M K et al. (2018) Image velocimetry and spectral analysis enable quantitative characterization of larval zebrafish gut motility. Neurogastroenterol Motil 30:e13351

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