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

Nat Commun. 2021 Feb 5;12(1):833. doi: 10.1038/s41467-021-21053-2.

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Animals
  • Child
  • Developmental Disabilities / genetics*
  • Developmental Disabilities / metabolism
  • Developmental Disabilities / pathology
  • Embryo, Nonmammalian
  • Eukaryotic Translation Initiation Factor 5A
  • Female
  • Gene Expression Regulation, Developmental*
  • Humans
  • Lysine / analogs & derivatives
  • Lysine / genetics
  • Lysine / metabolism
  • Male
  • Microcephaly / genetics*
  • Microcephaly / metabolism
  • Microcephaly / pathology
  • Micrognathism / genetics*
  • Micrognathism / metabolism
  • Micrognathism / pathology
  • Peptide Initiation Factors / deficiency
  • Peptide Initiation Factors / genetics*
  • Peptides / genetics
  • Peptides / metabolism
  • Protein Biosynthesis
  • Protein Conformation
  • Protein Isoforms / deficiency
  • Protein Isoforms / genetics
  • RNA-Binding Proteins / genetics*
  • Ribosomes / genetics
  • Ribosomes / metabolism
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / growth & development
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Spermidine / pharmacology
  • Zebrafish
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism

Substances

  • Peptide Initiation Factors
  • Peptides
  • Protein Isoforms
  • RNA-Binding Proteins
  • Saccharomyces cerevisiae Proteins
  • Zebrafish Proteins
  • polyproline
  • hypusine
  • Lysine
  • Spermidine