# Disease mechanisms of cone opsin mutants and treatment strategies

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $381,250

## Abstract

ABSTRACT
L- and M- cones constitute about 95% of the total cone population, primarily concentrated in the macula, they
are responsible for our daylight, central high resolution, and color vision. Mutations in the L-opsin and M-opsin
genes are associated with a variety of visual defects including red-green color vision deficiency, blue cone
monochromacy (BCM), X-linked cone dystrophy/dysfunction, and high myopia with abnormal cone function.
Currently studies on disease mechanisms of cone opsin mutations have been mostly carried out in vitro,
therefore the impact of these mutations on cone structure and their physiological consequences are not well
understood. Recent studies suggest that rhodopsin dimerization plays a central role in signal transduction and
that defects in dimerization are one molecular mechanism associated with some forms of rhodopsin-related
autosomal dominant retinitis pigmentosa. Relative to rhodopsin, studies of cone opsin organization in outer
segment membranes have been lagging primarily because cones are less abundant than rods thus hampering
a detailed structural analysis. Our goals are to elucidate the molecular mechanisms underlying cone opsin
mutations in vivo to develop effective treatment approaches, and to understand the organization of cone
opsins in outer segment membranes and pathophysiology associated with cone opsin dimerization disruption.
Our prior studies have demonstrated that AAV-mediated expression of human L-opsin and M-opsin promotes
regrowth of cone outer segments and rescues M-cone function in the treated M-opsin knockout (Opn1mw-/- )
mouse, a model for BCM. One critical observation from our work is that cone opsins are required for outer
segment formation, but not for cone viability. These results lead us to propose the use of the Opn1mw-/- mice
as an in vivo model to investigate disease mechanisms associated with cone opsin mutants via our well-
developed AAV-mediated cone targeting approach (Aim 1). Our preliminary results using this approach
indicate that the cone opsin C203R mutation, responsible for more than half of the BCM population, displays
a dominant-negative phenotype. We have generated a knock-in mouse line carrying this mutation and will test
gene therapy options (Aim 2). The success of these strategies can be employed to treat other cone opsin
mutations displaying dominant-negative phenotypes. We will also employ a combination of AAV technology,
biochemical approaches, and transgenic mice to define domains involved in cone opsin dimerization and
characterize the pathophysiology associated with dimerization disruption (Aim 3).
Completing these goals will provide us a solid foundation for developing effective strategies to treat different
categories of retinal disease caused by cone opsin mutations. This study will also improve our knowledge of
the roles cone opsins play in outer segment disc membrane formation and maintenance.

## Key facts

- **NIH application ID:** 10005358
- **Project number:** 5R01EY030056-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Wen-Tao Deng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2019-09-01 → 2021-03-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005358

## Citation

> US National Institutes of Health, RePORTER application 10005358, Disease mechanisms of cone opsin mutants and treatment strategies (5R01EY030056-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10005358. Licensed CC0.

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