Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. 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 EIF5A 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 1mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown eif5a partly recapitulates the human phenotype that can be rescued with 1 μM spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of EIF5A-related disorder and raise possibilities for its treatment. ; Health Innovation Challenge Fund HICF-1009-003 Wellcome Trust European Commission Wellcome Trust WT098051 National Institute for Health Research, through the Comprehensive Clinical Research Network, UK CONICYT, Chile's National Commission for Scientific and Technological Research 72160007 Kabuki Research Fund at Manchester University NHS Foundation Trust Action Medical Research GN2494 National Institute for Health Research (NIHR) IS-BRC-1215-20007 UK Research & Innovation (UKRI) Biotechnology and Biological Sciences Research Council (BBSRC) BB/N014049/1 Stroke Association (TSA LECT) 2017/02 NC/N002598/1 French National Research Agency (ANR) European Commission ANR-10-IAHU-01 MSDAvenir (DevoDecode project) UK Research & Innovation (UKRI) Biotechnology and Biological Sciences Research Council (BBSRC) BB/S014667/1 Origen de datos de financiación:UKRI Aparece en contenido como:BBSRC Importe total de ...