# Disease mechanism of Usher syndrome 2

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $469,144

## Abstract

Project Summary
Retinitis pigmentosa (RP) is the predominant inherited retinal degenerative disease with a prevalence of 1 in
4,000 worldwide. RP combined with hearing loss is characterized as Usher syndrome (USH), which is the
leading cause of inherited deaf-blindness. Currently, no cure is available for either RP or USH. USH2 is the
most common USH clinical type. USH2A (usherin), ADGRV1 (adhesion G protein-coupled receptor V1), and
WHRN (whirlin) have been identified as three USH2 causative genes. Among them, USH2A is the major
causative gene for USH and autosomal recessive RP (arRP), and ADGRV1 is the second most frequent USH2
causative gene. In photoreceptors, usherin and ADGRV1 proteins interact with whirlin and form a multiprotein
complex at the periciliary membrane between the inner and outer segment, but the functions of individual
USH2 proteins as well as the entire USH2 complex have not been fully elucidated. This knowledge gap hinders
the development of disease mechanism-based treatments. Since many patients carry USH2A mutations, the
development and evaluation of therapeutics that target USH2A is an active area of investigation. However, the
progress of these studies has been slowed down, because of the unknown early retinal molecular defects and
late onset retinal degeneration in USH2 animal and/or in vitro retinal models. In our preliminary studies, we
performed TMT-labeling quantitative proteomic and phosphoproteomic studies in USH2 mutant mouse retinas
at postnatal day 30 long before retinal degeneration. We discovered alterations in photoreceptor outer segment
membrane proteins, lipidated protein chaperones, BBSome and its cargos, extracellular matrix constituents,
and protein kinase A signaling pathway. Affinity purification coupled with mass spectrometry experiments
identified USH2 protein-interacting candidates that are enriched with proteins biologically associated with the
early affected molecular and cellular processes in USH2 mutant retinas. We also found protein mislocalization
and light response reduction in young USH2 mutant cones. Building on our extensive preliminary work, we
propose to address the following specific aims in this application: 1) identify and investigate usherin- and
ADGRV1-interacting proteins in the retina; 2) determine primary molecular defects in the retina of three
different Ush2a and Adgrv1 mutant mice; and 3) uncover the molecular cause of early onset cone dysfunction
in USH2 mutant retinas. If successful, our study will reveal the role of the USH2 complex in photoreceptors and
provide insight into the pathogenic mechanisms underlying retinal degeneration caused by USH2 gene
mutations. This study will also inform the development of mechanism-based new therapeutics for USH and
arRP and discover valuable biomarkers that can be applied to therapeutic evaluation.

## Key facts

- **NIH application ID:** 10910130
- **Project number:** 5R01EY034524-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Jun Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $469,144
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10910130

## Citation

> US National Institutes of Health, RePORTER application 10910130, Disease mechanism of Usher syndrome 2 (5R01EY034524-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10910130. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*