Journal article
Envisioning the development of a CRISPR-Cas mediated base editing strategy for a patient with a novel pathogenic CRB1 single nucleotide variant
- Abstract:
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Background
Inherited retinal degeneration (IRD) associated with mutations in the Crumbs homolog 1 (CRB1) gene is associated with a severe, early-onset retinal degeneration for which no therapy currently exists. Base editing, with its capability to precisely catalyse permanent nucleobase conversion in a programmable manner, represents a novel therapeutic approach to targeting this autosomal recessive IRD, for which a gene supplementation is challenging due to the need to target three different retinal CRB1 isoforms.
Purpose
To report and classify a novel CRB1 variant and envision a possible therapeutic approach in form of base editing.
Methods
Case report.
Results
A 16-year-old male patient with a clinical diagnosis of early-onset retinitis pigmentosa (RP) and characteristic clinical findings of retinal thickening and coarse lamination was seen at the Oxford Eye Hospital. He was found to be compound heterozygous for two CRB1 variants: a novel pathogenic nonsense variant in exon 9, c.2885T>A (p.Leu962Ter), and a likely pathogenic missense change in exon 6, c.2056C>T (p.Arg686Cys). While a base editing strategy for c.2885T>A would encompass a CRISPR-pass mediated “read-through” of the premature stop codon, the resulting missense changes were predicted to be “possibly damaging” in in-silico analysis. On the other hand, the transversion missense change, c.2056C>T, is amenable to transition editing with an adenine base editor (ABE) fused to a SaCas9-KKH with a negligible chance of bystander edits due to an absence of additional Adenines (As) in the editing window.
Conclusions
This case report records a novel pathogenic nonsense variant in CRB1 and gives an example of thinking about a base editing strategy for a patient compound heterozygous for CRB1 variants.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 5.0MB, Terms of use)
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- Publisher copy:
- 10.1080/13816810.2022.2073599
Authors
- Publisher:
- Taylor and Francis
- Journal:
- Ophthalmic Genetics More from this journal
- Volume:
- 43
- Issue:
- 5
- Pages:
- 661-670
- Publication date:
- 2022-05-10
- Acceptance date:
- 2023-04-30
- DOI:
- EISSN:
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1744-5094
- ISSN:
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1381-6810
- Pmid:
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35538629
- Language:
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English
- Keywords:
- Pubs id:
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1259571
- Local pid:
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pubs:1259571
- Deposit date:
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2023-05-26
- ARK identifier:
Terms of use
- Copyright holder:
- Bellingrath et al.
- Copyright date:
- 2022
- Rights statement:
- © 2022 The Author(s). Published with license by Taylor & Francis Group, LLC. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
- Notes:
- This work is related to the thesis Advancing RNA base editing treatments for inherited retinal disease.
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