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

Víctor Faundes, Martin D. Jennings, Siobhan Crilly, Sarah Legraie, Sarah E. Withers, Sara Cuvertino, Sally J. Davies, Andrew G. L. Douglas, Andrew E. Fry, Victoria Harrison, Jeanne Amiel, Daphné Lehalle, William G. Newman, Patricia Newkirk, Judith Ranells, Miranda Splitt, Laura A. Cross, Carol J. Saunders, Bonnie R. Sullivan, Jorge L. Granadillo, Christopher T. Gordon, Paul R. Kasher (), Graham D. Pavitt () and Siddharth Banka ()
Additional contact information
Víctor Faundes: University of Manchester
Martin D. Jennings: University of Manchester
Siobhan Crilly: University of Manchester
Sarah Legraie: University of Manchester
Sarah E. Withers: University of Manchester
Sara Cuvertino: University of Manchester
Sally J. Davies: University Hospital of Wales
Andrew G. L. Douglas: Princess Anne Hospital
Andrew E. Fry: University Hospital of Wales
Victoria Harrison: Princess Anne Hospital
Jeanne Amiel: Hôpital Necker Enfants Malades
Daphné Lehalle: Hôpital Necker Enfants Malades
William G. Newman: University of Manchester
Patricia Newkirk: University of South Florida
Judith Ranells: University of South Florida
Miranda Splitt: Institute of Genetic Medicine
Laura A. Cross: Division of Clinical Genetics, Children’s Mercy
Carol J. Saunders: Center for Pediatric Genomic Medicine Children’s Mercy
Bonnie R. Sullivan: Division of Clinical Genetics, Children’s Mercy
Jorge L. Granadillo: Washington University School of Medicine
Christopher T. Gordon: Institut Imagine
Paul R. Kasher: University of Manchester
Graham D. Pavitt: University of Manchester
Siddharth Banka: University of Manchester

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract 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 1 mM 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.

Date: 2021
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DOI: 10.1038/s41467-021-21053-2

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