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Published on: March 22, 2015
Connecting cilium, stress response, and proteostasis abnormalities inform variant and therapy assessment in RPGRIP1
To Ha Loi1, Anson Cheng1, Hani Jieun Kim2
1Eye Genetics Research Unit, Children's Medical Research Institute, Sydney Children's Hospitals Network, Save Sight Institute, University of Sydney, Sydney, NSW, Australia.
Abstract:
RPGRIP1 encodes a connecting cilium (CC) protein essential for normal photoreceptor cell development and maintenance. Damaging variants in RPGRIP1 cause severe inherited retinal disease (IRD) and currently incurable vision loss, with mouse studies showing promising preclinical gene augmentation therapy results. Almost one-half of variants in RPGRIP1 in the ClinVar database are variants of uncertain significance (VUS), hindering genetic diagnosis for affected individuals and, hence, access to clinical trials of novel therapies and other management options. Here, we use human induced pluripotent stem cell (iPSC)-derived retinal organoids to model RPGRIP1-associated IRD, detecting biomarkers of disease including CC interactome dysfunction, stress response, and proteostasis abnormalities. In parallel, utilizing these novel disease biomarkers, we demonstrate the pathogenicity of a missense VUS, RPGRIP1 c.2108T>C p.(Ile703Thr). In addition, RPGRIP1 gene augmentation therapy rescued disease phenotypes, further supporting the utility of these biomarkers of RPGRIP1-IRD for reclassifying VUS and testing response to therapy.
Insights
RPGRIP1 variants cause inherited retinal disease (IRD). Researchers developed human retinal organoids to identify disease biomarkers, confirm a variant
Area of Science:
- Ophthalmology
- Genetics
- Cell Biology
Background:
- RPGRIP1 is crucial for photoreceptor development and maintenance.
- RPGRIP1 variants lead to inherited retinal disease (IRD), causing incurable vision loss.
- Variants of uncertain significance (VUS) in RPGRIP1 impede genetic diagnosis and treatment access.
Purpose of the Study:
- To model RPGRIP1-associated IRD using human induced pluripotent stem cell (iPSC)-derived retinal organoids.
- To identify novel biomarkers for RPGRIP1-IRD.
- To demonstrate the pathogenicity of a VUS and test gene augmentation therapy.
Main Methods:
- Generation of human iPSC-derived retinal organoids.
- Detection of biomarkers including connecting cilium (CC) interactome dysfunction, stress response, and proteostasis abnormalities.
- Assessment of RPGRIP1 gene augmentation therapy efficacy.
Main Results:
- Human iPSC-derived retinal organoids successfully modeled RPGRIP1-associated IRD.
- Biomarkers indicative of CC interactome dysfunction, stress, and proteostasis issues were identified.
- The pathogenicity of a missense VUS (RPGRIP1 c.2108T>C p.(Ile703Thr)) was confirmed.
- Gene augmentation therapy demonstrated efficacy in rescuing disease phenotypes.
Conclusions:
- Human iPSC-derived retinal organoids are a viable model for studying RPGRIP1-IRD.
- Identified biomarkers can aid in VUS reclassification and therapy response assessment.
- Gene augmentation therapy shows potential for treating RPGRIP1-associated vision loss.
