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DHPS is essential to synthesize hypusine, a rare amino acid formed by post-translational modification of a conserved lysine in eukaryotic initiation factor 5\u00a0A (eIF5A). DHPS deficiency syndrome causes epilepsy, cognitive and motor impairments, and mild facial dysmorphology. In mice, a brain-specific genetic deletion of <jats:italic>Dhps<\/jats:italic> at birth impairs eIF5A<jats:sup>HYP<\/jats:sup>-dependent mRNA translation. This alters expression of proteins required for neuronal development and function, and phenotypically models features of human DHPS deficiency. We studied the role of DHPS in early brain development using a zebrafish loss-of-function model generated by knockdown of <jats:italic>dhps<\/jats:italic> expression with an antisense morpholino oligomer (MO) targeting the exon 2\/intron 2 (E2I2) splice site of the <jats:italic>dhps<\/jats:italic> pre-mRNA. <jats:italic>dhps<\/jats:italic> knockdown embryos exhibited dose-dependent developmental delay and dysmorphology, including microcephaly, axis truncation, and body curvature. In <jats:italic>dhps<\/jats:italic> knockdown larvae, electrophysiological analysis showed increased epileptiform activity, and confocal microscopy analysis revealed reduced arborisation of GABAergic neurons. Our findings confirm that hypusination of eIF5A by DHPS is needed for early brain development, and zebrafish with an antisense knockdown of <jats:italic>dhps<\/jats:italic> model features of DHPS deficiency syndrome.<\/jats:p>","DOI":"10.1186\/s13041-024-01139-w","type":"journal-article","created":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T10:02:34Z","timestamp":1727431354000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Deoxyhypusine synthase deficiency syndrome zebrafish model: aberrant morphology, epileptiform activity, and reduced arborization of inhibitory interneurons"],"prefix":"10.1186","volume":"17","author":[{"given":"Elham","family":"Shojaeinia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa L.","family":"Mastracci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remon","family":"Soliman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orrin","family":"Devinsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila V.","family":"Esguerra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander D.","family":"Crawford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,9,27]]},"reference":[{"key":"1139_CR1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.TM118.003341","author":"MH Park","year":"2018","unstructured":"Park MH, Wolff EC. 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