# Mechanisms of Vision Loss in X-Linked Juvenile Retinoschisis

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $481,045

## Abstract

Abstract
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.

## Key facts

- **NIH application ID:** 9872175
- **Project number:** 5R01EY029796-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** James JASON McAnany
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $481,045
- **Award type:** 5
- **Project period:** 2019-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872175

## Citation

> US National Institutes of Health, RePORTER application 9872175, Mechanisms of Vision Loss in X-Linked Juvenile Retinoschisis (5R01EY029796-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9872175. Licensed CC0.

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