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

dc.contributor.authorGanapathi, Mythily
dc.contributor.authorPadgett, Leah R.
dc.contributor.authorYamada, Kentaro
dc.contributor.authorDevinsky, Orrin
dc.contributor.authorWillaert, Rebecca
dc.contributor.authorPerson, Richard
dc.contributor.authorAu, Ping-Yee Billie
dc.contributor.authorTagoe, Julia
dc.contributor.authorMcDonald, Marie
dc.contributor.authorKarlowicz, Danielle
dc.contributor.authorWolf, Barry
dc.contributor.authorLee, Joanna
dc.contributor.authorShen, Yufeng
dc.contributor.authorOkur, Volkan
dc.contributor.authorDeng, Liyong
dc.contributor.authorLeDuc, Charles A.
dc.contributor.authorWang, Jiayao
dc.contributor.authorHanner, Ashleigh
dc.contributor.authorMirmira, Raghavendra G.
dc.contributor.authorPark, Myung Hee
dc.contributor.authorMastracci, Teresa L.
dc.contributor.authorChung, Wendy K.
dc.contributor.departmentPediatrics, School of Medicineen_US
dc.date.accessioned2019-10-04T20:25:17Z
dc.date.available2019-10-04T20:25:17Z
dc.date.issued2019-02-07
dc.description.abstractHypusine 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.en_US
dc.identifier.citationGanapathi, M., Padgett, L. R., Yamada, K., Devinsky, O., Willaert, R., Person, R., … Chung, W. K. (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, 104(2), 287–298. doi:10.1016/j.ajhg.2018.12.017en_US
dc.identifier.urihttps://hdl.handle.net/1805/21060
dc.language.isoen_USen_US
dc.publisherElsevieren_US
dc.relation.isversionof10.1016/j.ajhg.2018.12.017en_US
dc.relation.journalAmerican Journal of Human Geneticsen_US
dc.rightsPublisher Policyen_US
dc.sourcePMCen_US
dc.subjectDHPSen_US
dc.subjectDOHHen_US
dc.subjectDeoxyhypusine synthaseen_US
dc.subjecteIF5Aen_US
dc.subjectExome sequencingen_US
dc.subjectHypusinationen_US
dc.subjectHypusineen_US
dc.subjectInborn errors of metabolismen_US
dc.subjectNeurodevelopmental disorderen_US
dc.subjectPolyamine pathwayen_US
dc.titleRecessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorderen_US
dc.typeArticleen_US
ul.alternative.fulltexthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369575/en_US
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