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

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.
Mythily Ganapathi 1,  Leah R Padgett 2,  Kentaro Yamada 3,  Orrin Devinsky 4,  Rebecca Willaert 5,  Richard Person 5,  Ping-Yee Billie Au 6,  Julia Tagoe 6,  Marie McDonald 7,  Danielle Karlowicz 7,  Barry Wolf 8,  Joanna Lee 8,  Yufeng Shen 9,  Volkan Okur 10,  Liyong Deng 10,  Charles A LeDuc 10,  Jiayao Wang 9,  Ashleigh Hanner 11,  Raghavendra G Mirmira 3,  Myung Hee Park 11,  Teresa L Mastracci 12,  Wendy K Chung 13
Affiliations

Affiliations

  • 1 Personalized Genomic Medicine, Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
  • 2 Regenerative Medicine & Metabolic Biology, Indiana Biosciences Research Institute, Indianapolis, IN 46202, USA.
  • 3 Department of Pediatrics and the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 4 Neurology Department, NYU Langone Medical Center, New York, NY 10016, USA.
  • 5 GeneDx, Gaithersburg, MD 20877, USA.
  • 6 Department of Medical Genetics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 7 Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
  • 8 Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA; Department of Pediatrics, Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 9 Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
  • 10 Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
  • 11 National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA.
  • 12 Regenerative Medicine & Metabolic Biology, Indiana Biosciences Research Institute, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 13 Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA; Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: [email protected].
PMID: 30661771 DOI: 10.1016/j.ajhg.2018.12.017
Abstract

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.

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