{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T23:26:22Z","timestamp":1792106782862,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1009798","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T00:00:00Z","timestamp":1655769600000}}],"reference-count":116,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T00:00:00Z","timestamp":1654646400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01EY011996"],"award-info":[{"award-number":["R01EY011996"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01EY027305"],"award-info":[{"award-number":["R01EY027305"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01EY027860"],"award-info":[{"award-number":["R01EY027860"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01EY028561"],"award-info":[{"award-number":["R01EY028561"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30CA034196"],"award-info":[{"award-number":["P30CA034196"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012309","name":"Royal Golden Jubilee (RGJ) Ph.D. Programme","doi-asserted-by":"publisher","award":["PHD\/0102\/2559"],"award-info":[{"award-number":["PHD\/0102\/2559"]}],"id":[{"id":"10.13039\/501100012309","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Mutations in the apicobasal polarity gene\n                    <jats:italic>CRB1<\/jats:italic>\n                    lead to diverse retinal diseases, such as Leber congenital amaurosis, cone-rod dystrophy, retinitis pigmentosa (with and without Coats-like vasculopathy), foveal retinoschisis, macular dystrophy, and pigmented paravenous chorioretinal atrophy. Limited correlation between disease phenotypes and\n                    <jats:italic>CRB1<\/jats:italic>\n                    alleles, and evidence that patients sharing the same alleles often present with different disease features, suggest that genetic modifiers contribute to clinical variation. Similarly, the retinal phenotype of mice bearing the\n                    <jats:italic>Crb1<\/jats:italic>\n                    retinal degeneration 8 (\n                    <jats:italic>rd8<\/jats:italic>\n                    ) allele varies with genetic background. Here, we initiated a sensitized chemical mutagenesis screen in B6.Cg-\n                    <jats:italic>Crb1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>rd8<\/jats:italic>\n                    <\/jats:sup>\n                    \/Pjn, a strain with a mild clinical presentation, to identify genetic modifiers that cause a more severe disease phenotype. Two models from this screen,\n                    <jats:italic>Tvrm266<\/jats:italic>\n                    and\n                    <jats:italic>Tvrm323<\/jats:italic>\n                    , exhibited increased retinal dysplasia. Genetic mapping with high-throughput exome and candidate-gene sequencing identified causative mutations in\n                    <jats:italic>Arhgef12<\/jats:italic>\n                    and\n                    <jats:italic>Prkci<\/jats:italic>\n                    , respectively. Epistasis analysis of both strains indicated that the increased dysplastic phenotype required homozygosity of the\n                    <jats:italic>Crb1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>rd8<\/jats:italic>\n                    <\/jats:sup>\n                    allele. Retinal dysplastic lesions in\n                    <jats:italic>Tvrm266<\/jats:italic>\n                    mice were smaller and caused less photoreceptor degeneration than those in\n                    <jats:italic>Tvrm323<\/jats:italic>\n                    mice, which developed an early, large diffuse lesion phenotype. At one month of age, M\u00fcller glia and microglia mislocalization at dysplastic lesions in both modifier strains was similar to that in B6.Cg-\n                    <jats:italic>Crb1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>rd8<\/jats:italic>\n                    <\/jats:sup>\n                    \/Pjn mice but photoreceptor cell mislocalization was more extensive. External limiting membrane disruption was comparable in\n                    <jats:italic>Tvrm266<\/jats:italic>\n                    and B6.Cg-\n                    <jats:italic>Crb1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>rd8<\/jats:italic>\n                    <\/jats:sup>\n                    \/Pjn mice but milder in\n                    <jats:italic>Tvrm323<\/jats:italic>\n                    mice. Immunohistological analysis of mice at postnatal day 0 indicated a normal distribution of mitotic cells in\n                    <jats:italic>Tvrm266<\/jats:italic>\n                    and\n                    <jats:italic>Tvrm323<\/jats:italic>\n                    mice, suggesting normal early development. Aberrant electroretinography responses were observed in both models but functional decline was significant only in\n                    <jats:italic>Tvrm323<\/jats:italic>\n                    mice. These results identify\n                    <jats:italic>Arhgef12<\/jats:italic>\n                    and\n                    <jats:italic>Prkci<\/jats:italic>\n                    as modifier genes that differentially shape\n                    <jats:italic>Crb1<\/jats:italic>\n                    -associated retinal disease, which may be relevant to understanding clinical variability and underlying disease mechanisms in humans.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1009798","type":"journal-article","created":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T13:43:43Z","timestamp":1654695823000},"page":"e1009798","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Identification of Arhgef12 and Prkci as genetic modifiers of retinal dysplasia in the Crb1rd8 mouse model"],"prefix":"10.1371","volume":"18","author":[{"given":"Sonia M.","family":"Weatherly","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3332-0954","authenticated-orcid":true,"given":"Gayle B.","family":"Collin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy R.","family":"Charette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3998-9579","authenticated-orcid":true,"given":"Lisa","family":"Stone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7359-8547","authenticated-orcid":true,"given":"Nattaya","family":"Damkham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6230-4630","authenticated-orcid":true,"given":"Lillian F.","family":"Hyde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6126-2993","authenticated-orcid":true,"given":"James G.","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanda","family":"Hicks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2834-8186","authenticated-orcid":true,"given":"Gregory W.","family":"Carter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8213-0869","authenticated-orcid":true,"given":"J\u00fcrgen K.","family":"Naggert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9017-6066","authenticated-orcid":true,"given":"Mark 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