# Genetic Modifiers of Retinal Disease

> **NIH NIH R01** · JACKSON LABORATORY · 2024 · $616,564

## Abstract

PROJECT SUMMARY/ABSTRACT
Heritable retinal disorders, for which effective treatments are generally unavailable, contributes to the 1.02
million adults who are blind in the US. Among children, the heritable disease - Leber Congenital Amaurosis,
accounts for 20% of blindness, and 10-15%of those are caused by mutations in the CRB1 gene. In addition to
LCA, CRB1 mutations can also cause congenital or early-onset retinitis pigmentosa (RP), a more slowly
progressive disease. CRB1 RP variants are sometimes associated with unique disease features, such as
retinal telangiectasia with or without exudative retinal detachment (Coat's disease), a loss of RPE pigmentation
except near arterioles (preservation of para-arteriolar RPE or PPRPE), pigment paravenous chorioretinal
atrophy, cone-rod dystrophy, nanophthalmos with optic disc drusen, retinoschisis, cystoid macular edema, and
macular dystrophic disease. The cause of the wide range of disease phenotypes associated
with CRB1 mutations is not fully understood. Genotype-phenotype correlations that could explain the disease
spectrum have not been detected among patients bearing CRB1 mutations, suggesting that environmental
factors or genetic background modifiers contribute to the variability in the disease phenotypes observed.
Another potential contributor to the phenotypic variability in disease presentation are Crb1 isoforms which have
recently been shown to have spatially and temporally distinct expression patterns. Clearly, understanding the
reasons for the variability and the mechanisms underlying the observed pathologies is extremely important for
developing effective therapies.
In this proposal, we will test the hypothesis that pathological changes due to Crb1 mutations depend upon the
isoform affected and the genetic background on which it occurs, and their potential interactions. We will identify
the molecular basis of genetic modifiers that enhance or suppress Crb1rd8 associated disease phenotypes or
are epistatic upon Crb1rd8. Through the use of mouse models with isoform specific knockout alleles and
controlled genetic backgrounds, we will determine their contribution to disease variability and the mechanisms
through which they function.
These studies address a critical unmet need for acquiring the basic biological knowledge necessary to develop
effective therapies that can target the pre-symptomatic stage to prevent, delay onset or decrease severity of
the disease. Animal models serve an important and unique role to further our understanding of the genetic
underpinnings of disease and as a resource to examine tissue pathology, and to perform pre-clinical
therapeutic tests that cannot be readily conducted in humans.

## Key facts

- **NIH application ID:** 10808074
- **Project number:** 5R01EY027305-07
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** Patsy M Nishina
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $616,564
- **Award type:** 5
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808074

## Citation

> US National Institutes of Health, RePORTER application 10808074, Genetic Modifiers of Retinal Disease (5R01EY027305-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10808074. Licensed CC0.

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