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Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous\n                    <jats:italic>EIF5A<\/jats:italic>\n                    variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total\/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1\u2009mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown\n                    <jats:italic>eif5a<\/jats:italic>\n                    partly recapitulates the human phenotype that can be rescued with 1\u2009\u00b5M spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of\n                    <jats:italic>EIF5A<\/jats:italic>\n                    -related disorder and raise possibilities for its treatment.\n                  <\/jats:p>","DOI":"10.1038\/s41467-021-21053-2","type":"journal-article","created":{"date-parts":[[2021,2,5]],"date-time":"2021-02-05T06:24:30Z","timestamp":1612506270000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6746-0103","authenticated-orcid":false,"given":"V\u00edctor","family":"Faundes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6173-0988","authenticated-orcid":false,"given":"Martin D.","family":"Jennings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1046-9884","authenticated-orcid":false,"given":"Siobhan","family":"Crilly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Legraie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E.","family":"Withers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Cuvertino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally J.","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew G. 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