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Updated: Jul 23, 2025
Functional Assessment of BRCA1 variants using CRISPR-Mediated Base Editors
Published on: February 28, 2021
Analysis of CRB1 Pathogenic Variants Correctable with CRISPR Base and Prime Editing
Bruna Lopes da Costa1,2,3, Laura A Jenny2,3, Irene H Maumenee2,3
1Department of Biomedical Engineering, Columbia University, New York, NY, USA.
Insights
Gene editing offers a promising alternative for CRB1-associated retinal degenerations. Base and prime editing can correct a significant percentage of pathogenic CRB1 variants, paving the way for new therapeutics.
Area of Science:
- Ophthalmology
- Genetics
- Molecular Biology
Background:
- The retina has three Crumbs homologue-1 (CRB1) isoforms with cell-specific expression.
- CRB1 mutations cause retinal degenerations, and gene augmentation strategies face challenges.
- Gene editing presents a potential alternative for treating CRB1-associated retinal diseases.
Purpose of the Study:
- To analyze the prevalence and spectrum of CRB1 pathogenic variants.
- To determine the amenability of these variants to base and prime editing.
Main Methods:
- Analysis of the Leiden Open Variation Database for CRB1 variants.
- Assessment of variant types suitable for base and prime editing techniques.
Main Results:
- 54.5% of CRB1 pathogenic variants are amenable to base editing.
- 99.8% of CRB1 pathogenic variants are amenable to prime editing.
- The c.2843G>A, p.(Cys948Tyr) variant is the most common editable CRB1 mutation.
Conclusions:
- Base and prime editing are highly efficient for correcting CRB1 pathogenic variants.
- Gene editing therapeutics offer a viable alternative to gene augmentation for CRB1 retinal degenerations.
Abstract:
The mouse and human retina contain three major Crumbs homologue-1 (CRB1) isoforms. CRB1-A and CRB1-B have cell-type-specific expression patterns making the choice of gene augmentation strategy unclear. Gene editing may be a viable alternative for the amelioration of CRB1-associated retinal degenerations. To assess the prevalence and spectrum of CRB1-associated pathogenic variants amenable to base and prime editing, we carried out an analysis of the Leiden Open Variation Database. Editable variants accounted for 54.5% for base editing and 99.8% for prime editing of all CRB1 pathogenic variants in the Leiden Open Variation Database. The 10 most common editable pathogenic variants for CRB1 accounted for 34.95% of all pathogenic variants, with the c.2843G>A, p.(Cys948Tyr) being the most common editable CRB1 variant. These findings outline the next step toward developing base and prime editing therapeutics as an alternative to gene augmentation for the amelioration of CRB1-associated retinal degenerations.
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