Artículos de revistas
Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine
Fecha
2021Registro en:
Nature Communications (2021) 12:833
10.1038/s41467-021-21053-2
Autor
Faúndes Gómez, Víctor Manuel
Jennings, Martin D.
Crilly, Siobhan
Legraie, Sarah
Withers, Sarah E.
Cuvertino, Sara
Davies, Sally J.
Douglas L., Andrew G.
Fry, Andrew E.
Harrison, Victoria
Amiel, Jeanne
Lehalle, Daphné
Newman, William G.
Newkirk, Patricia
Ranells, Judith
Splitt, Miranda
Cross, Laura A.
Saunders, Carol J.
Sullivan, Bonnie R.
Granadillo, Jorge L.
Gordon, Christopher T.
Kasher, Paul R.
Pavitt, Graham D.
Banka, Siddharth
Institución
Resumen
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.