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C-terminal variants in the Myelin regulatory factor (\n                    <jats:italic>MYRF<\/jats:italic>\n                    ) gene, a retinal pigment epithelium\u2013derived (RPE-derived) transcription factor, lead to isolated nanophthalmos characterized by a small, though structurally sound eye. However, other MYRF loss-of-function variants cause syndromic disease. To address this discrepancy, in vitro and animal studies were performed on a pathogenic C-terminal variant dG-MYRF (p.Gly1126fs30*, c.3376-1G&gt;A). Human RPE cells or primary RPE transduced with dG-MYRF showed reduced target gene expression, with decreased steady-state levels of the C-terminal cleavage product, but normal cleavage and localization. A homozygous humanized MYRF C-terminal mouse model (\n                    <jats:italic>\n                      Myrf\n                      <jats:sup>humdG\/humdG<\/jats:sup>\n                    <\/jats:italic>\n                    ) was embryonic lethal by E18.5, while WT (\n                    <jats:italic>\n                      Myrf\n                      <jats:sup>humWT\/humWT<\/jats:sup>\n                    <\/jats:italic>\n                    ) mice were viable. Single-cell RNA-seq from E17.5\n                    <jats:italic>\n                      Myrf\n                      <jats:sup>humdG\/humdG<\/jats:sup>\n                    <\/jats:italic>\n                    and KO\n                    <jats:italic>\n                      RxCre;Myrf\n                      <jats:sup>fl\/fl<\/jats:sup>\n                    <\/jats:italic>\n                    (E15.5 and P0) mice revealed shared differentially expressed genes, with decreased effect size in the\n                    <jats:italic>\n                      Myrf\n                      <jats:sup>humdG\/humdG<\/jats:sup>\n                    <\/jats:italic>\n                    eyes. These findings support dG-MYRF as a hypomorphic allele. Additionally, 2\n                    <jats:italic>MYRF<\/jats:italic>\n                    splicing variants creating nonfunctional isoforms were found in families with isolated nanophthalmos. Overall, hypomorphic\n                    <jats:italic>MYRF<\/jats:italic>\n                    alleles underlie isolated nanophthalmos, supporting a tissue-specific threshold effect and highlighting unique roles for the MYRF C-terminus in the RPE.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.194681","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T17:00:45Z","timestamp":1772125245000},"source":"Crossref","is-referenced-by-count":0,"title":["Splicing variants in MYRF cause partial loss of function in the retinal pigment epithelium leading to nanophthalmos"],"prefix":"10.1172","volume":"11","author":[{"given":"Gabrielle M.","family":"Rozumek","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences,"},{"name":"Department of Pathology, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle L.","family":"Brinkmeier","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5986-5189","authenticated-orcid":true,"given":"Bin","family":"Guan","sequence":"additional","affiliation":[{"name":"National Eye Institute, NIH, Bethesda, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Su Qing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Tower","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina T.","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel S.","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dejuan","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Soden","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qitao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John Y.S.","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason M.L.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences,"},{"name":"Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7401-9511","authenticated-orcid":true,"given":"Lijin","family":"Dong","sequence":"additional","affiliation":[{"name":"National Eye Institute, NIH, Bethesda, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D. 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