Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine.
Adolescent
Amino Acid Sequence
Animals
Child
Developmental Disabilities
/ genetics
Embryo, Nonmammalian
Female
Gene Expression Regulation, Developmental
Humans
Lysine
/ analogs & derivatives
Male
Microcephaly
/ genetics
Micrognathism
/ genetics
Peptide Initiation Factors
/ deficiency
Peptides
/ genetics
Protein Biosynthesis
Protein Conformation
Protein Isoforms
/ deficiency
RNA-Binding Proteins
/ genetics
Ribosomes
/ genetics
Saccharomyces cerevisiae
/ drug effects
Saccharomyces cerevisiae Proteins
/ genetics
Sequence Alignment
Sequence Homology, Amino Acid
Spermidine
/ pharmacology
Zebrafish
Zebrafish Proteins
/ genetics
Eukaryotic Translation Initiation Factor 5A
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
05 02 2021
05 02 2021
Historique:
received:
24
03
2020
accepted:
07
10
2020
entrez:
6
2
2021
pubmed:
7
2
2021
medline:
18
2
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33547280
doi: 10.1038/s41467-021-21053-2
pii: 10.1038/s41467-021-21053-2
pmc: PMC7864902
doi:
Substances chimiques
Peptide Initiation Factors
0
Peptides
0
Protein Isoforms
0
RNA-Binding Proteins
0
Saccharomyces cerevisiae Proteins
0
Zebrafish Proteins
0
polyproline
25191-13-3
hypusine
3874VXF092
Lysine
K3Z4F929H6
Spermidine
U87FK77H25
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
833Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/N014049/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT098051
Pays : United Kingdom
Organisme : Department of Health
ID : IS-BRC-1215-20007
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
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