Shojaeinia, ElhamMastracci, Teresa L.Soliman, RemonDevinsky, OrrinEsguerra, Camila V.Crawford, Alexander D.2024-10-292024-10-292024-09-27Shojaeinia E, Mastracci TL, Soliman R, Devinsky O, Esguerra CV, Crawford AD. Deoxyhypusine synthase deficiency syndrome zebrafish model: aberrant morphology, epileptiform activity, and reduced arborization of inhibitory interneurons. Mol Brain. 2024;17(1):68. Published 2024 Sep 27. doi:10.1186/s13041-024-01139-whttps://hdl.handle.net/1805/44311DHPS deficiency syndrome is an ultra-rare neurodevelopmental disorder (NDD) which results from biallelic mutations in the gene encoding the enzyme deoxyhypusine synthase (DHPS). DHPS is essential to synthesize hypusine, a rare amino acid formed by post-translational modification of a conserved lysine in eukaryotic initiation factor 5 A (eIF5A). DHPS deficiency syndrome causes epilepsy, cognitive and motor impairments, and mild facial dysmorphology. In mice, a brain-specific genetic deletion of Dhps at birth impairs eIF5AHYP-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 dhps expression with an antisense morpholino oligomer (MO) targeting the exon 2/intron 2 (E2I2) splice site of the dhps pre-mRNA. dhps knockdown embryos exhibited dose-dependent developmental delay and dysmorphology, including microcephaly, axis truncation, and body curvature. In dhps 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 dhps model features of DHPS deficiency syndrome.en-USAttribution 4.0 InternationalDeoxyhypusine synthaseEpilepsyHypusineNeurodevelopmental disorderZebrafishArticle