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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
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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.
2f7961f7-614b-44ae-b1dd-3b3689952bd4
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
6075f764-5f19-4a5e-8567-aa65781226f6
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, 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

Catalogue record

Date deposited: 08 Feb 2021 17:30
Last modified: 05 Aug 2021 04:01

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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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