DOI: 10.1038/s41467-021-21053-2; PMCID: PMC7864902
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.
Adolescent; Amino Acid Sequence; Animals; Child; Developmental Disabilities; Embryo, Nonmammalian; Female; Gene Expression Regulation, Developmental; Humans; Lysine; Male; Microcephaly; Micrognathism; Peptide Initiation Factors; Peptides; Protein Biosynthesis; Protein Conformation; Protein Isoforms; RNA-Binding Proteins; Ribosomes; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Sequence Alignment; Sequence Homology, Amino Acid; Spermidine; Zebrafish; Zebrafish Proteins
Amino Acid Sequence; Developmental Disabilities; Embryo, Nonmammalian; Female; Gene Expression Regulation, Developmental; Humans; Lysine; Male; Microcephaly; Micrognathism; Peptide Initiation Factors; Peptides; Protein Biosynthesis; Protein Conformation; Protein Isoforms; RNA-Binding Proteins; Ribosomes; Saccharomyces cerevisiae Proteins; Sequence Alignment; Spermidine; Zebrafish Proteins
Faundes V, Jennings MD, Crilly S, et al. Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine. Nat Commun. 2021;12(1):833. Published 2021 Feb 5. doi:10.1038/s41467-021-21053-2