{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:50:10Z","timestamp":1782867010979,"version":"3.54.5"},"reference-count":54,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,11,27]],"date-time":"2021-11-27T00:00:00Z","timestamp":1637971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Mutations in the Crumbs homolog 1 (CRB1) gene cause both autosomal recessive retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). Since three separate CRB1 isoforms are expressed at meaningful levels in the human retina, base editing shows promise as a therapeutic approach. This retrospective analysis aims to summarise the reported pathogenic CRB1 variants and investigate their amenability to treatment with currently available DNA base editors. Pathogenic single nucleotide variants (SNVs) were extracted from the Leiden open-source variation database (LOVD) and ClinVar database and coded by mutational consequence. They were then analyzed for their amenability to currently available DNA base editors and available PAM sites from a selection of different Cas proteins. Of a total of 1115 unique CRB1 variants, 69% were classified as pathogenic SNVs. Of these, 62% were amenable to currently available DNA BEs. Adenine base editors (ABEs) alone have the potential of targeting 34% of pathogenic SNVs; 19% were amenable to a CBE while GBEs could target an additional 9%. Of the pathogenic SNVs targetable with a DNA BE, 87% had a PAM site for a Cas protein. Of the 33 most frequently reported pathogenic SNVs, 70% were targetable with a base editor. The most common pathogenic variant was c.2843G&gt;A, p.Cys948Arg, which is targetable with an ABE. Since 62% of pathogenic CRB1 SNVs are amenable to correction with a base editor and 87% of these mutations had a suitable PAM site, gene editing represents a promising therapeutic avenue for CRB1-associated retinal degenerations.<\/jats:p>","DOI":"10.3390\/genes12121908","type":"journal-article","created":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T05:23:02Z","timestamp":1638163382000},"page":"1908","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["In Silico Analysis of Pathogenic CRB1 Single Nucleotide Variants and Their Amenability to Base Editing as a Potential Lead for Therapeutic Intervention"],"prefix":"10.3390","volume":"12","author":[{"given":"Julia-Sophia","family":"Bellingrath","sequence":"first","affiliation":[{"name":"Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK"},{"name":"Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Headley Way, Oxford OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2941-4464","authenticated-orcid":false,"given":"Michelle E.","family":"McClements","sequence":"additional","affiliation":[{"name":"Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK"},{"name":"Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Headley Way, Oxford OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kaukonen","sequence":"additional","affiliation":[{"name":"Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK"},{"name":"Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Headley Way, Oxford OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel Dominik","family":"Fischer","sequence":"additional","affiliation":[{"name":"Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK"},{"name":"Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Headley Way, Oxford OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"MacLaren","sequence":"additional","affiliation":[{"name":"Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK"},{"name":"Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Headley Way, Oxford OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1126\/science.1225829","article-title":"A Programmable Dual-Rna-Guided DNA Endonuclease in Adaptive Bacterial Immunity","volume":"337","author":"Jinek","year":"2012","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/nature17946","article-title":"Programmable Editing of a Target Base in Genomic DNA without Double-Stranded DNA Cleavage","volume":"533","author":"Komor","year":"2016","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"8194","DOI":"10.1073\/pnas.1607580113","article-title":"Cytosine Deamination and the Precipitous Decline of Spontaneous Mutation During Earth\u2019s History","volume":"113","author":"Lewis","year":"2016","journal-title":"Proc. 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