{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T14:27:01Z","timestamp":1760711221135,"version":"3.41.2"},"reference-count":80,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T00:00:00Z","timestamp":1692835200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Rare <jats:italic>DRAM2<\/jats:italic> coding variants cause retinal dystrophy with early macular involvement via unknown mechanisms. We found that <jats:italic>DRAM2<\/jats:italic> is ubiquitously expressed in the human eye and expression changes were observed in eyes with more common maculopathy such as Age-related Macular Degeneration (AMD). To gain insights into pathogenicity of DRAM2-related retinopathy, we used a combination of <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> models. We found that <jats:italic>DRAM2<\/jats:italic> loss in human pluripotent stem cell (hPSC)-derived retinal organoids caused the presence of additional mesenchymal cells. Interestingly, <jats:italic>Dram2<\/jats:italic> loss in mice also caused increased proliferation of cells from the choroid <jats:italic>in vitro<\/jats:italic> and exacerbated choroidal neovascular lesions <jats:italic>in vivo<\/jats:italic>. Furthermore, we observed that <jats:italic>DRAM2<\/jats:italic> loss in human retinal pigment epithelial (RPE) cells resulted in increased susceptibility to stress-induced cell death <jats:italic>in vitro<\/jats:italic> and that <jats:italic>Dram2<\/jats:italic> loss in mice caused age-related photoreceptor degeneration. This highlights the complexity of DRAM2 function, as its loss in choroidal cells provided a proliferative advantage, whereas its loss in post-mitotic cells, such as photoreceptor and RPE cells, increased degeneration susceptibility. Different models such as human pluripotent stem cell-derived systems and mice can be leveraged to study and model human retinal dystrophies; however, cell type and species-specific expression must be taken into account when selecting relevant systems.<\/jats:p>","DOI":"10.3389\/fcell.2023.1252547","type":"journal-article","created":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T13:25:21Z","timestamp":1692883521000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Integration of human stem cell-derived in vitro systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy"],"prefix":"10.3389","volume":"11","author":[{"given":"Melissa K.","family":"Jones","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luz D.","family":"Orozco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom","family":"Truong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Caplazi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin","family":"Elstrott","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zora","family":"Modrusan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shawnta Y.","family":"Chaney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marion","family":"Jeanne","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"107752","DOI":"10.1016\/j.exer.2019.107752","article-title":"Characterization of the cone-rod dystrophy retinal phenotype caused by novel homozygous DRAM2 mutations","volume":"187","author":"Abad-Morales","year":"2019","journal-title":"Exp. 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