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

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

2041-1723
Faudes, Victor
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Jennings, Martin E.
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Crilly, Siobhan
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Legraie, Sarah
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Withers, Sarah E.
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Cuventino, Sara
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Davies, Sally J.
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Douglas, Andrew
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Fry, Andrew E.
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Harrison, Victoria
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Amiel, Jeanne
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Lehalle, Daphne
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Newman, William G.
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Newkirk, Patricia
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Ranells, Judith
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Splitt, Miranda
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Cross, Laura A.
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Saunders, Carol J.
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Sullivan, Bonnie R.
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Grandillo, Jorge L.
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Gordon, Christopher T.
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Kasher, Paul R.
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Pavitt, Graham D.
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Banka, Siddharth
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Faudes, Victor
b7d08efc-8846-43c4-9ac5-1c8957289c52
Jennings, Martin E.
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Crilly, Siobhan
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Legraie, Sarah
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Withers, Sarah E.
2f7961f7-614b-44ae-b1dd-3b3689952bd4
Cuventino, Sara
beec5672-f4ff-4722-8f3e-98d26ca33e10
Davies, Sally J.
119090f2-fa05-4005-aea2-41c68e06adbd
Douglas, Andrew
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Fry, Andrew E.
26e49fb0-865c-4621-aa01-ee02a6ff9adf
Harrison, Victoria
39844b8f-ebf6-40f9-a2b5-5fd8d588c672
Amiel, Jeanne
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Lehalle, Daphne
6df78f0a-d93d-4aa2-a95b-e7a542658ca4
Newman, William G.
771e4904-12d6-4b02-8f3f-a0285d95f1a7
Newkirk, Patricia
33cd9dde-17bd-4171-b8b4-c5883d779c97
Ranells, Judith
c9a33f72-0e7d-4914-88a0-69a6363814c7
Splitt, Miranda
6075f764-5f19-4a5e-8567-aa65781226f6
Cross, Laura A.
de9ec761-03e7-4a7e-b072-60ca18f120c5
Saunders, Carol J.
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Sullivan, Bonnie R.
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Grandillo, Jorge L.
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Gordon, Christopher T.
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Kasher, Paul R.
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Pavitt, Graham D.
cef4d91d-f07d-44ad-8aaa-74670d2b1ec0
Banka, Siddharth
26126fbc-e373-4dfa-959f-faa79129828b

Faudes, Victor, Jennings, Martin E., Crilly, Siobhan, Legraie, Sarah, Withers, Sarah E., Cuventino, Sara, Davies, Sally J., Douglas, Andrew, Fry, Andrew E., Harrison, Victoria, Amiel, Jeanne, Lehalle, Daphne, Newman, William G., Newkirk, Patricia, Ranells, Judith, Splitt, Miranda, Cross, Laura A., Saunders, Carol J., Sullivan, Bonnie R., Grandillo, Jorge L., Gordon, Christopher T., Kasher, Paul R., Pavitt, Graham D. and Banka, Siddharth (2021) Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine. Nature Communications, 12 (1), [833]. (doi:10.1038/s41467-021-21053-2).

Record type: Article

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.

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Faundes_2020_EIF5A_accepted - Accepted Manuscript
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Accepted/In Press date: 7 October 2020
Published date: 5 February 2021

Identifiers

Local EPrints ID: 446403
URI: http://eprints.soton.ac.uk/id/eprint/446403
ISSN: 2041-1723
PURE UUID: 966e4167-5900-46cd-abc3-238469b395d3
ORCID for Andrew Douglas: ORCID iD orcid.org/0000-0001-5154-6714

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Date deposited: 08 Feb 2021 17:30
Last modified: 17 Mar 2024 06:05

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Contributors

Author: Victor Faudes
Author: Martin E. Jennings
Author: Siobhan Crilly
Author: Sarah Legraie
Author: Sarah E. Withers
Author: Sara Cuventino
Author: Sally J. Davies
Author: Andrew Douglas ORCID iD
Author: Andrew E. Fry
Author: Victoria Harrison
Author: Jeanne Amiel
Author: Daphne Lehalle
Author: William G. Newman
Author: Patricia Newkirk
Author: Judith Ranells
Author: Miranda Splitt
Author: Laura A. Cross
Author: Carol J. Saunders
Author: Bonnie R. Sullivan
Author: Jorge L. Grandillo
Author: Christopher T. Gordon
Author: Paul R. Kasher
Author: Graham D. Pavitt
Author: Siddharth Banka

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