# Function of Ciliary Disease Protein Retinitis Pigmentosa GTPase Regulator (RPGR)

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $418,750

## Abstract

Project Summary
Mutations in ciliary proteins lead to a spectrum of debilitating disorders, collectively termed ciliopathies.
Retinitis pigmentosa (RP) due to ciliary dysfunction in photoreceptors (PRs) is a commonly observed
genetically heterogeneous retinal degenerative disease, for which there is no treatment. PRs (rods and cones)
are highly polarized neurons with an outer segment, responsible for light detection, and an inner segment,
which houses the protein production and trafficking machinery. The inner and outer segments are linked by a
bridge-like structure called the connecting cilium (CC), which facilitates the transport of proteins and lipids to
the outer segment. Our long term goal is to understand the modes of protein and lipid transport in PR cilia to
better understand the pathogenesis of retinal ciliopathies, identify therapeutic targets and design suitable
therapies. This application focuses on understanding the role of a major retinal ciliopathy protein, RPGR (RP
GTPase regulator) in regulating protein trafficking via the CC of PRs. The RPGR gene expresses two major
alternatively spliced isoforms: RPGRconst (constitutive; exons 1-19) and RPGRORF15 (exons 1-15+part of intron
15; ORF15). Our studies have revealed that RPGR isoforms are regulated both at the post-transcriptional and
post-translational levels and are involved in overlapping yet distinct functions in regulating PR health. Building
upon our progress during the funded period, we propose to understand RPGR function by examining precise
roles of RPGR isoforms. We hypothesize that post-transcriptional and post-translational cross-talk between
RPGRORF15 and RPGRconst isoforms modulates the resultant disease phenotype. The current application
proposes to delineate the role of ORF15 in regulating alternative splicing of RPGR isoforms (Aim 1) and
interrogate the interplay between RPGR isoforms in regulating PR phosphoinositide metabolism (Aim
2). All reagents, assays, model systems and equipments that are already on hand will be utilized. Under the
first aim, we will perform transcriptional analysis of RPGRORF15 and RPGRconst in dermal fibroblasts from
patients carrying RPGR mutations and identify specific splicing regulators that alter RPGR splicing. We will
also determine the photoreceptor-specific regulation of RPGR splicing by subretinally injecting RPGR
minigenes into mouse pups. Studies proposed in Aim 2 focus on delineating the role of isoform-specific post-
translational modifications of RPGR in regulating phosphoinositide composition of PR outer segment. We will
also determine the role of a phosphoinositide modulator in maintaining PR integrity and in altering the severity
of RPGR-associated retinal degeneration. Our approach is significant because it focuses on understanding the
mechanisms of one of the most severe and prevalent features of ciliopathies. Such knowledge will inform us
about the mechanisms employed by the cilium for long-term functional and structural...

## Key facts

- **NIH application ID:** 10011813
- **Project number:** 5R01EY022372-09
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Gregory J Pazour
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2012-05-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10011813

## Citation

> US National Institutes of Health, RePORTER application 10011813, Function of Ciliary Disease Protein Retinitis Pigmentosa GTPase Regulator (RPGR) (5R01EY022372-09). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10011813. Licensed CC0.

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