{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T05:58:38Z","timestamp":1771653518044,"version":"3.50.1"},"posted":{"date-parts":[[2024,1,27]]},"group-title":"Genetics","reference-count":95,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,1,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>UBA5<\/jats:italic>\n                  encodes for the E1 enzyme of the UFMylation cascade, which plays an essential role in ER homeostasis. The clinical phenotypes of UBA5-associated encephalopathy include developmental delays, epilepsy and intellectual disability. To date, there is no humanized neuronal model to study the cellular and molecular consequences of\n                  <jats:italic>UBA5<\/jats:italic>\n                  pathogenic variants. We developed and characterized patient-derived cortical organoid cultures and identified defects in GABAergic interneuron development. We demonstrated aberrant neuronal firing and microcephaly phenotypes in patient-derived organoids. Mechanistically, we show that ER homeostasis is perturbed along with exacerbated unfolded protein response pathway in cells and organoids expressing\n                  <jats:italic>UBA5<\/jats:italic>\n                  pathogenic variants. We also assessed two gene expression modalities that augmented\n                  <jats:italic>UBA5<\/jats:italic>\n                  expression to rescue aberrant molecular and cellular phenotypes. Our study provides a novel humanized model that allows further investigations of\n                  <jats:italic>UBA5<\/jats:italic>\n                  variants in the brain and highlights novel systemic approaches to alleviate cellular aberrations for this rare, developmental disorder.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One-sentence summary<\/jats:title>\n                  <jats:p>Patient derived model of UBA5-assoicated DEE recapitulated disease phenotype, revealed defects in neurodevelopment, and highlighted potential therapies.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.01.25.577254","type":"posted-content","created":{"date-parts":[[2024,1,27]],"date-time":"2024-01-27T23:25:11Z","timestamp":1706397911000},"source":"Crossref","is-referenced-by-count":2,"title":["Patient derived model of\n                  <i>UBA5-<\/i>\n                  associated encephalopathy identifies defects in neurodevelopment and highlights potential therapies"],"prefix":"10.64898","author":[{"given":"Helen","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong-Dong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aidan W.","family":"Blan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edith P.","family":"Almanza-Fuerte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily S.","family":"Bonkowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richa","family":"Bajpai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shondra M.","family":"Pruett-Miller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather C.","family":"Mefford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024013012150696000_2024.01.25.577254v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23534"},{"key":"2024013012150696000_2024.01.25.577254v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2018.06.009"},{"key":"2024013012150696000_2024.01.25.577254v1.3","doi-asserted-by":"publisher","DOI":"10.1684\/epd.2018.0981"},{"key":"2024013012150696000_2024.01.25.577254v1.4","doi-asserted-by":"crossref","unstructured":". 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