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De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

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dc.contributor.authorManole, Andreea
dc.contributor.authorEfthymiou, Stephanie
dc.contributor.authorO'Connor, Emer
dc.contributor.authorMendes, Marisa
dc.contributor.authorJennings, Matthew
dc.contributor.authorMaroofian, Reza
dc.contributor.authorDavagnanam, Indran
dc.contributor.authorMankad, Kshitij
dc.contributor.authorLopez, Maria Rodriguez
dc.contributor.authorSalpietro, Vincenzo
dc.contributor.authorHarripaul, Ricardo
dc.contributor.authorBadalato, Lauren
dc.contributor.authorWalia, Jagdeep
dc.contributor.authorFrancklyn, Christopher S.
dc.contributor.authorAthanasiou-Fragkouli, Alkyoni
dc.contributor.authorSullivan, Roisin
dc.contributor.authorDesai, Sonal
dc.contributor.authorBaranano, Kristin
dc.contributor.authorZafar, Faisal
dc.contributor.authorRana, Nuzhat
dc.contributor.authorIlyas, Muhammed
dc.contributor.authorHorga, Alejandro
dc.contributor.authorKara, Majdi
dc.contributor.authorMattioli, Francesca
dc.contributor.authorGoldenberg, Alice
dc.contributor.authorGriffin, Helen
dc.contributor.authorPiton, Amelie
dc.contributor.authorHenderson, Lindsay B.
dc.contributor.authorKara, Benyekhlef
dc.contributor.authorASLANGER, Ayça Dilruba
dc.contributor.authorRaaphorst, Joost
dc.contributor.authorPfundt, Rolph
dc.contributor.authorPortier, Ruben
dc.contributor.authorShinawi, Marwan
dc.contributor.authorKirby, Amelia
dc.contributor.authorChristensen, Katherine M.
dc.contributor.authorWang, Lu
dc.contributor.authorRosti, Rasim O.
dc.contributor.authorParacha, Sohail A.
dc.contributor.authorSarwar, Muhammad T.
dc.contributor.authorJenkins, Dagan
dc.contributor.authorAhmed, Jawad
dc.contributor.authorSantoni, Federico A.
dc.contributor.authorRanza, Emmanuelle
dc.contributor.authorIwaszkiewicz, Justyna
dc.contributor.authorCytrynbaum, Cheryl
dc.contributor.authorWeksberg, Rosanna
dc.contributor.authorWentzensen, Ingrid M.
dc.contributor.authorSacoto, Maria J. Guillen
dc.contributor.authorSi, Yue
dc.contributor.authorTelegrafi, Aida
dc.contributor.authorAndrews, Marisa
dc.contributor.authorBaldridge, Dustin
dc.contributor.authorGabriel, Heinz
dc.contributor.authorMohr, Julia
dc.contributor.authorOehl-Jaschkowitz, Barbara
dc.contributor.authorDebard, Sylvain
dc.contributor.authorSenger, Bruno
dc.contributor.authorFischer, Frederic
dc.contributor.authorvan Ravenwaaij, Conny
dc.contributor.authorFock, Annemarie J. M.
dc.contributor.authorStevens, Servi J. C.
dc.contributor.authorBahler, Jurg
dc.contributor.authorNasar, Amina
dc.contributor.authorMantovani, John F.
dc.contributor.authorManzur, Adnan
dc.contributor.authorSarkozy, Anna
dc.contributor.authorSmith, Desiree E. C.
dc.contributor.authorSalomons, Gajja S.
dc.contributor.authorAhmed, Zubair M.
dc.contributor.authorRiazuddin, Shaikh
dc.contributor.authorRiazuddin, Saima
dc.contributor.authorUsmani, Muhammad A.
dc.contributor.authorSeibt, Annette
dc.contributor.authorAnsar, Muhammad
dc.contributor.authorAntonarakis, Stylianos E.
dc.contributor.authorVincent, John B.
dc.contributor.authorAyub, Muhammad
dc.contributor.authorGrimmel, Mona
dc.contributor.authorJelsig, Anne Marie
dc.contributor.authorHjortshoj, Tina Duelund
dc.contributor.authorKarstensen, Helena Gasdal
dc.contributor.authorHummel, Marybeth
dc.contributor.authorHaack, Tobias B.
dc.contributor.authorJamshidi, Yalda
dc.contributor.authorDistelmaier, Felix
dc.contributor.authorHorvath, Rita
dc.contributor.authorGleeson, Joseph G.
dc.contributor.authorBecker, Hubert
dc.contributor.authorMandel, Jean-Louis
dc.contributor.authorKoolen, David A.
dc.contributor.authorHoulden, Henry
dc.contributor.institutionauthorASLANGER, AYÇA DILRUBA
dc.date.accessioned2020-10-22T15:59:00Z
dc.date.available2020-10-22T15:59:00Z
dc.date.issued2020-08-01T00:00:00Z
dc.description.abstractAminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.
dc.identifier.citationManole A., Efthymiou S., O-Connor E., Mendes M., Jennings M., Maroofian R., Davagnanam I., Mankad K., Lopez M. R. , Salpietro V., et al., -De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects-, AMERICAN JOURNAL OF HUMAN GENETICS, cilt.107, ss.311-324, 2020
dc.identifier.doi10.1016/j.ajhg.2020.06.016
dc.identifier.pubmed32738225
dc.identifier.scopus85088934445
dc.identifier.trdizintrdizin
dc.identifier.urihttp://hdl.handle.net/20.500.12645/23787
dc.identifier.urihttps://pubmed.ncbi.nlm.nih.gov/32738225/
dc.identifier.wosWOS:000558491800011
dc.subjectAminoacyl-tRNA synthetase
dc.subjectDevelopmental delay
dc.subjectEpilepsy
dc.titleDe Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects
dc.typeArticle
dspace.entity.typePublication
local.avesis.id5d16532b-9b4a-477b-84f6-f91f14c14402
local.publication.isinternational1
relation.isAuthorOfPublicatione8905b02-3184-49da-a603-fd2991619d0a
relation.isAuthorOfPublication.latestForDiscoverye8905b02-3184-49da-a603-fd2991619d0a
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