{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T14:11:03Z","timestamp":1767276663435,"version":"3.41.2"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T00:00:00Z","timestamp":1741219200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["1R01 EY032976"],"award-info":[{"award-number":["1R01 EY032976"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Heterozygous deletions predicting haploinsufficiency for the Cysteine Rich Motor Neuron 1 (<jats:italic>CRIM1<\/jats:italic>) gene have been identified in two families with macrophthalmia, colobomatous, with microcornea (MACOM), an autosomal dominant trait. <jats:italic>Crim1<\/jats:italic> encodes a type I transmembrane protein that is expressed at the cell membrane of lens epithelial and fiber cells at the stage of lens pit formation. Decreased Crim1 expression in the mouse reduced the number of lens epithelial cells and caused defective adhesion between lens epithelial cells and between the epithelial and fiber cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We present three patients with heterozygous deletions and truncating variants predicted to result in haploinsufficiency for <jats:italic>CRIM1<\/jats:italic> as further evidence for the role of this gene in eye defects, including retinal coloboma, optic pallor, and glaucoma. We used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)\/Cas9 to make a stable <jats:italic>Danio rerio<\/jats:italic> model of crim1 deficiency, generating zebrafish that were homozygous for a 2 basepair deletion, c.339_340delCT p.Leu112Leu<jats:italic>fs<\/jats:italic>*, in <jats:italic>crim1<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Homozygous, <jats:italic>crim1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> larvae demonstrated smaller eyes and small and misshapen lenses compared to controls, but we did not observe colobomas. Bulk RNA-Seq using dissected eyes from <jats:italic>crim1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> larvae and controls at 72\u00a0h post fertilization showed significant downregulation of crim1 and chloride intracellular channel 4 (<jats:italic>clic4<\/jats:italic>) and upregulation of fibroblast growth factor 1b (<jats:italic>fgf1b<\/jats:italic>) and complement component 1, q subcomponent (<jats:italic>c1q<\/jats:italic>), amongst other dysregulated genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our work strengthens the association between haploinsufficiency for <jats:italic>CRIM1<\/jats:italic> and eye defects and characterizes a stable model of <jats:italic>crim1<\/jats:italic> loss of function for future research.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcell.2025.1522094","type":"journal-article","created":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T06:53:04Z","timestamp":1741243984000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A zebrafish model of crim1 loss of function has small and misshapen lenses with dysregulated clic4 and fgf1b expression"],"prefix":"10.3389","volume":"13","author":[{"given":"Tien","family":"Le","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Htun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manoj Kumar","family":"Pandey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yihui","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albert Frank","family":"Magnusen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ehsan","family":"Ullah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Lauzon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shannon","family":"Beres","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chung","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Guan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert B.","family":"Hufnagel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian P.","family":"Brooks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergio E.","family":"Baranzini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Slavotinek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1750","DOI":"10.1002\/1873-3468.13766","article-title":"The chloride intracellular channel protein CLIC4 inhibits filopodium formation induced by constitutively active mutants of formin mDia2","volume":"594","author":"Argenzio","year":"2020","journal-title":"FEBS Lett."},{"key":"B2","doi-asserted-by":"publisher","first-page":"19161","DOI":"10.1074\/jbc.RA118.002779","article-title":"Profilin binding couples chloride intracellular channel protein CLIC4 to RhoA-mDia2 signaling and filopodium formation","volume":"293","author":"Argenzio","year":"2018","journal-title":"J. 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