Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder

Am J Hum Genet. 2019 Feb 7;104(2):287-298. doi: 10.1016/j.ajhg.2018.12.017. Epub 2019 Jan 17.


Hypusine is formed post-translationally from lysine and is found in a single cellular protein, eukaryotic translation initiation factor-5A (eIF5A), and its homolog eIF5A2. Biosynthesis of hypusine is a two-step reaction involving the enzymes deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). eIF5A is highly conserved throughout eukaryotic evolution and plays a role in mRNA translation, cellular proliferation, cellular differentiation, and inflammation. DHPS is also highly conserved and is essential for life, as Dhps-null mice are embryonic lethal. Using exome sequencing, we identified rare biallelic, recurrent, predicted likely pathogenic variants in DHPS segregating with disease in five affected individuals from four unrelated families. These individuals have similar neurodevelopmental features that include global developmental delay and seizures. Two of four affected females have short stature. All five affected individuals share a recurrent missense variant (c.518A>G [p.Asn173Ser]) in trans with a likely gene disrupting variant (c.1014+1G>A, c.912_917delTTACAT [p.Tyr305_Ile306del], or c.1A>G [p.Met1?]). cDNA studies demonstrated that the c.1014+1G>A variant causes aberrant splicing. Recombinant DHPS enzyme harboring either the p.Asn173Ser or p.Tyr305_Ile306del variant showed reduced (20%) or absent in vitro activity, respectively. We co-transfected constructs overexpressing HA-tagged DHPS (wild-type or mutant) and GFP-tagged eIF5A into HEK293T cells to determine the effect of these variants on hypusine biosynthesis and observed that the p.Tyr305_Ile306del and p.Asn173Ser variants resulted in reduced hypusination of eIF5A compared to wild-type DHPS enzyme. Our data suggest that rare biallelic variants in DHPS result in reduced enzyme activity that limits the hypusination of eIF5A and are associated with a neurodevelopmental disorder.

Keywords: DHPS; DOHH; deoxyhypusine synthase; eIF5A; exome sequencing; hypusination; hypusine; inborn errors of metabolism; neurodevelopmental disorder; polyamine pathway.

Publication types

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

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Child
  • Child, Preschool
  • Developmental Disabilities / enzymology
  • Developmental Disabilities / genetics
  • Female
  • Genes, Recessive / genetics*
  • Haplotypes
  • Humans
  • Lysine / analogs & derivatives*
  • Lysine / biosynthesis
  • Male
  • Metabolism, Inborn Errors / enzymology
  • Metabolism, Inborn Errors / genetics
  • Mutation*
  • Neurodevelopmental Disorders / enzymology*
  • Neurodevelopmental Disorders / genetics*
  • Oxidoreductases Acting on CH-NH Group Donors / chemistry
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism
  • Pedigree
  • Peptide Initiation Factors / chemistry
  • Peptide Initiation Factors / metabolism
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism
  • Seizures / enzymology
  • Seizures / genetics
  • Young Adult


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