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

Mythily Ganapathi, Leah R. Padgett, Kentaro Yamada, Orrin Devinsky, Rebecca Willaert, Richard Person, Ping Yee Billie Au, Julia Tagoe, Marie McDonald, Danielle Karlowicz, Barry Wolf, Joanna Lee, Yufeng Shen, Volkan Okur, Liyong Deng, Charles A. LeDuc, Jiayao Wang, Ashleigh Hanner, Raghu Mirmira, Myung Hee Park & 2 others Teresa L. Mastracci, Wendy K. Chung

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)287-298
Number of pages12
JournalAmerican Journal of Human Genetics
Volume104
Issue number2
DOIs
StatePublished - Feb 7 2019

Fingerprint

Enzymes
deoxyhypusine hydroxylase
Translational Peptide Chain Initiation
Exome
Protein Biosynthesis
hypusine
Neurodevelopmental Disorders
deoxyhypusine synthase
Lysine
Seizures
Complementary DNA
Cell Proliferation
eukaryotic translation initiation factor 5A
Inflammation
Genes

Keywords

  • deoxyhypusine synthase
  • DHPS
  • DOHH
  • eIF5A
  • exome sequencing
  • hypusination
  • hypusine
  • inborn errors of metabolism
  • neurodevelopmental disorder
  • polyamine pathway

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder. / Ganapathi, Mythily; Padgett, Leah R.; Yamada, Kentaro; Devinsky, Orrin; Willaert, Rebecca; Person, Richard; Au, Ping Yee Billie; Tagoe, Julia; McDonald, Marie; Karlowicz, Danielle; Wolf, Barry; Lee, Joanna; Shen, Yufeng; Okur, Volkan; Deng, Liyong; LeDuc, Charles A.; Wang, Jiayao; Hanner, Ashleigh; Mirmira, Raghu; Park, Myung Hee; Mastracci, Teresa L.; Chung, Wendy K.

In: American Journal of Human Genetics, Vol. 104, No. 2, 07.02.2019, p. 287-298.

Research output: Contribution to journalArticle

Ganapathi, M, Padgett, LR, Yamada, K, Devinsky, O, Willaert, R, Person, R, Au, PYB, Tagoe, J, McDonald, M, Karlowicz, D, Wolf, B, Lee, J, Shen, Y, Okur, V, Deng, L, LeDuc, CA, Wang, J, Hanner, A, Mirmira, R, Park, MH, Mastracci, TL & Chung, WK 2019, 'Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder', American Journal of Human Genetics, vol. 104, no. 2, pp. 287-298. https://doi.org/10.1016/j.ajhg.2018.12.017
Ganapathi, Mythily ; Padgett, Leah R. ; Yamada, Kentaro ; Devinsky, Orrin ; Willaert, Rebecca ; Person, Richard ; Au, Ping Yee Billie ; Tagoe, Julia ; McDonald, Marie ; Karlowicz, Danielle ; Wolf, Barry ; Lee, Joanna ; Shen, Yufeng ; Okur, Volkan ; Deng, Liyong ; LeDuc, Charles A. ; Wang, Jiayao ; Hanner, Ashleigh ; Mirmira, Raghu ; Park, Myung Hee ; Mastracci, Teresa L. ; Chung, Wendy K. / Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder. In: American Journal of Human Genetics. 2019 ; Vol. 104, No. 2. pp. 287-298.
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AU - Ganapathi, Mythily

AU - Padgett, Leah R.

AU - Yamada, Kentaro

AU - Devinsky, Orrin

AU - Willaert, Rebecca

AU - Person, Richard

AU - Au, Ping Yee Billie

AU - Tagoe, Julia

AU - McDonald, Marie

AU - Karlowicz, Danielle

AU - Wolf, Barry

AU - Lee, Joanna

AU - Shen, Yufeng

AU - Okur, Volkan

AU - Deng, Liyong

AU - LeDuc, Charles A.

AU - Wang, Jiayao

AU - Hanner, Ashleigh

AU - Mirmira, Raghu

AU - Park, Myung Hee

AU - Mastracci, Teresa L.

AU - Chung, Wendy K.

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N2 - 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.

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