# Genetic Modifiers of Enhanced S-cone Syndrome –Role of the External Limiting Membrane

> **NIH NIH R01** · JACKSON LABORATORY · 2020 · $437,500

## Abstract

PROJECT SUMMARY/ABSTRACT
 Enhanced S-cone syndrome (ESCS) is an inherited retinal degeneration characterized by an increased
number of S-cones, retinal dysplasia, and progressive photoreceptor degeneration leading to early night
blindness and loss of visual acuity. The disease is caused by mutations in the rod-fate determining
transcription factor NR2E3 in humans and the rd7 mouse model. The disease presentation is highly variable in
human and dependent on genetic background in the mouse, demonstrating the existence of genetic modifiers.
 The mouse model demonstrates that the retinal dysplasia is intimately associated with the occurrence
of breaks in the external limiting membrane (ELM), a network of adherens/tight junctions between Müller cell
apical processes and photoreceptor inner segments. Fragmentation of the ELM is also observed in other
retinal diseases associated with dysplasia, such as Leber's Congenital Amaurosis (LCA) due to mutations in
crumbs1 (CRB1) and RP27, and in diabetic retinopathy.
 We have identified a genetic modifier that prevents the fragmentation of the ELM in both the rd7 mouse
and the Nrl ko mouse (RP27) models. This discovery strongly suggests a causative role for the ELM
fragmentation in the development of photoreceptor dysplasia and provides a tool with which to establish the
mechanisms by which ELM breaks occur, how they lead to retinal dysplasia, and how this affects disease
progression.
 In order to identify these mechanisms we will: 1) Determine the natural history of ELM junction
formation and photoreceptor differentiation in wt and the rd7 model using marker analysis of cell junction
proteins. 2) Identify the cell types involved in the ELM fragmentation by single cell RNAseq analysis. 3)
Determine how the modifier protein alters recruitment of junctional proteins to the cell membrane. 4) Identify
the molecular basis of additional genetic modifier strains that we have generated to gain further insight into the
NR2E3 disease pathways.

## Key facts

- **NIH application ID:** 9849283
- **Project number:** 5R01EY028561-03
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** JUERGEN K. NAGGERT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,500
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849283

## Citation

> US National Institutes of Health, RePORTER application 9849283, Genetic Modifiers of Enhanced S-cone Syndrome –Role of the External Limiting Membrane (5R01EY028561-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9849283. Licensed CC0.

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