TY - JOUR
T1 - Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine
AU - Faundes, Víctor
AU - Jennings, Martin D.
AU - Crilly, Siobhan
AU - Legraie, Sarah
AU - Withers, Sarah E.
AU - Cuvertino, Sara
AU - Davies, Sally J.
AU - Douglas, Andrew G.L.
AU - Fry, Andrew E.
AU - Harrison, Victoria
AU - Amiel, Jeanne
AU - Lehalle, Daphné
AU - Newman, William G.
AU - Newkirk, Patricia
AU - Ranells, Judith
AU - Splitt, Miranda
AU - Cross, Laura A.
AU - Saunders, Carol J.
AU - Sullivan, Bonnie R.
AU - Granadillo, Jorge L.
AU - Gordon, Christopher T.
AU - Kasher, Paul R.
AU - Pavitt, Graham D.
AU - Banka, Siddharth
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85100582617&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-21053-2
DO - 10.1038/s41467-021-21053-2
M3 - Article
C2 - 33547280
AN - SCOPUS:85100582617
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 833
ER -