# Cilia Assembly and Transport in Photoreceptor Cells

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $434,222

## Abstract

Project Summary
Mutations in CEP290 result a number of genetic diseases termed ciliopathies, which manifest with a
variety of clinical symptoms, including retinal degeneration. While it is well-established that
photoreceptor survival requires Cep290 function, the causes of photoreceptor death remain largely
unknown. In vertebrate photoreceptors, Cep290 localizes to the connecting cilium, which is
analogous to the transition zone of primary cilia. Work from cell culture and invertebrates suggest
that Cep290 organizes the assembly of protein complexes that form a “ciliary gate” within the
transition zone. However, whether loss of Cep290 impacts such a ciliary gate have not been
demonstrated in photoreceptors. Furthermore, the highly variable nature of CEP290-associated
disease phenotypes cannot be explained by traditional genotype-phenotype correlations. Two
models have been proposed to explain this variability. One possibility is that second-site genetic
modifiers enhance disease severity in some patients. The second possibility is that exons harboring
nonsense mutations and that also begin and end in the same reading frame can be preferentially
skipped. In such a case the resulting mRNA transcript eludes nonsense-mediated decay and can
produce a near-full-length protein. Disease severity therefore correlates with the total amount of full-
length and near-full-length protein produced. This proposal seeks to address fundamental questions
related to photoreceptor cell biology and the role of Cep290 in photoreceptor degeneration. In Aim 1,
we will utilize two distinct zebrafish cep290 mutants to determine if defects in ciliary gating play a role
in degeneration. In Aim 2, we will determine if other genes associated with Joubert Syndrome,
namely arl13b, ahi1 or cc2d2a act as genetic modifiers to cep290-associated retinal degeneration in
zebrafish. Finally, in Aim 3, we will take fibroblasts from patients with CEP290 mutations and
generate human induced pluripotent stem cells (hiPSCs) and subsequently differentiated into 3D
retinal cups. These hiPSC-derived retinal cups (hiPSC-DRCs) will be used determine if basal exon
skipping occurs in from humans carrying CEP290 mutations and whether total protein levels correlate
with disease severity. In addition, how disease-causing mutations lead to alterations in cilia
architecture and protein trafficking will be investigated. These experiments will establish the
molecular and genetic mechanisms that determine the severity of disease progression.
Understanding the basis for phenotypic variability will provide much-needed clarification on the
mechanisms of pathogenesis and lead to better treatment of ciliary disease.

## Key facts

- **NIH application ID:** 9961598
- **Project number:** 5R01EY017037-15
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Brian D Perkins
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $434,222
- **Award type:** 5
- **Project period:** 2006-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961598

## Citation

> US National Institutes of Health, RePORTER application 9961598, Cilia Assembly and Transport in Photoreceptor Cells (5R01EY017037-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9961598. Licensed CC0.

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