X-linked retinoschisis (XLRS), the most common cause of juvenile onset retinal degeneration in males, is characterized by cystic-appearing retinal lesions and early visual deficit. XLRS is caused by mutations in the RS1 gene that encodes the protein retinoschisin (RS1), which is expressed panretinally. Changes in retinal structure and function observed in young XLRS patients and Rs1 KO mice raise new questions regarding the role of RS1 in early XLRS pathophysiology that may impact the severity of the disease in adulthood. Questions motivated by our preliminary findings that concern the nature and extent of visual deficits in XLRS, as well as the sites and mechanisms of disease action, will be addressed in the following 3 Specific Aims.
In Aims 1 and 2 we will use three Rs1 mutant mouse models, with differing levels of disease severity, to identify early retinal maladaptive changes and abnormalities associated with XLRS. In addition to a KO for Rs1, we are working with two novel ?humanized? mouse models that carry human disease causing Rs1 point mutations (C59S, R141C) chosen because of their distinct impacts on RS1 structure and function.
In Aim 1, we will define early changes in XLRS retinal structure and function using electroretinography (ERG), spectral domain optical coherence tomography (SD-OCT) and immunohistochemistry.
Aim 2 will determine the impact of aberrant retinal function on visual discrimination and how it differs among the animal models. We then assess visually driven behavior in living mice, to determine functional metrics such as contrast sensitivity and visual acuity that are translatable to the human subjects studied in Aim 3. Together, Aims 1 and 2 will test the hypothesis that the visual deficits are directly related to early structural changes and will identify the cell type(s) that are critical to define this relationship.
In Aim 3, we will use psychophysical assays to define the mechanisms that contribute to visual impairment in XLRS patients. These analyses will test the hypothesis that mutant RS1 results in behavioral abnormalities akin to those observed in the Rs1 mouse models, including reduced contrast sensitivity, elevated internal noise levels, and summation abnormalities. We anticipate the pattern of visual abnormalities to be consistent with disrupted visual maturation, as seen in other early onset retinal conditions. The completion of these Aims will greatly expand our understanding of the time course and impact of Rs1 mutations on the retina, will define the cellular basis for visual function loss in XLRS patients and will identify new therapeutic targets and outcome measures that may be more suitable for evaluating experimental therapies than SD-OCT and ERG analysis. Our findings will advance the general understanding of XLRS and how we approach and design trials of experimental therapy.

Public Health Relevance

X-linked retinoschisis (XLRS) is a common retinal disease causing early vision loss in patients. This project addresses the need to better understand the early changes that occur in the retina. This will be accomplished by examination of retinas of XLRS mice and by measuring vision in XLRS patients.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Diseases and Pathophysiology of the Visual System Study Section (DPVS)
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Shen, Grace L
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Cleveland Clinic Lerner
Schools of Medicine
United States
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