Deoxyhypusine synthase mutations alter the post-translational modification of eukaryotic initiation factor 5A resulting in impaired human and mouse neural homeostasis

HGG Adv. 2023 May 18;4(3):100206. doi: 10.1016/j.xhgg.2023.100206. eCollection 2023 Jul 13.


DHPS deficiency is a rare genetic disease caused by biallelic hypomorphic variants in the Deoxyhypusine synthase (DHPS) gene. The DHPS enzyme functions in mRNA translation by catalyzing the post-translational modification, and therefore activation, of eukaryotic initiation factor 5A (eIF5A). The observed clinical outcomes associated with human mutations in DHPS include developmental delay, intellectual disability, and seizures. Therefore, to increase our understanding of this rare disease, it is critical to determine the mechanisms by which mutations in DHPS alter neurodevelopment. In this study, we have generated patient-derived lymphoblast cell lines and demonstrated that human DHPS variants alter DHPS protein abundance and impair enzyme function. Moreover, we observe a shift in the abundance of the post-translationally modified forms of eIF5A; specifically, an increase in the nuclear localized acetylated form (eIF5AAcK47) and concomitant decrease in the cytoplasmic localized hypusinated form (eIF5AHYP). Generation and characterization of a mouse model with a genetic deletion of Dhps in the brain at birth shows that loss of hypusine biosynthesis impacts neuronal function due to impaired eIF5AHYP-dependent mRNA translation; this translation defect results in altered expression of proteins required for proper neuronal development and function. This study reveals new insight into the biological consequences and molecular impact of human DHPS deficiency and provides valuable information toward the goal of developing treatment strategies for this rare disease.

Keywords: DHPS; DHPS deficiency; eIF5A; hypusination; hypusine; mRNA translation; neurodevelopment; rare disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Homeostasis / genetics
  • Humans
  • Infant, Newborn
  • Mice
  • Mutation
  • Oxidoreductases Acting on CH-NH Group Donors* / genetics
  • Peptide Initiation Factors* / genetics
  • Protein Processing, Post-Translational / genetics
  • Rare Diseases*


  • deoxyhypusine synthase
  • Peptide Initiation Factors
  • Oxidoreductases Acting on CH-NH Group Donors
  • eukaryotic translation initiation factor 5A