Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish.

TitleBiallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish.
Publication TypeJournal Article
Year of Publication2019
AuthorsSiekierska, A, Stamberger, H, Deconinck, T, Oprescu, SN, Partoens, M, Zhang, Y, Sourbron, J, Adriaenssens, E, Mullen, P, Wiencek, P, Hardies, K, Lee, J-S, Giong, H-K, Distelmaier, F, Elpeleg, O, Helbig, KL, Hersh, J, Isikay, S, Jordan, E, Karaca, E, Kecskes, A, Lupski, JR, Kovacs-Nagy, R, May, P, Narayanan, V, Pendziwiat, M, Ramsey, K, Rangasamy, S, Shinde, DN, Spiegel, R, Timmerman, V, von Spiczak, S, Helbig, I, Weckhuysen, S, Francklyn, C, Antonellis, A, de Witte, P, De Jonghe, P
Corporate AuthorsC4RCD Research Group, AR working group of the EuroEPINOMICS RES Consortium
JournalNat Commun
Date Published2019 Feb 12
KeywordsAlleles, Animals, Brain Diseases, Cell Line, Disease Models, Animal, Epilepsy, Female, Fibroblasts, Gene Knockout Techniques, Genetic Predisposition to Disease, Humans, Loss of Function Mutation, Male, Microcephaly, Models, Molecular, Neurodevelopmental Disorders, Pedigree, Prosencephalon, Valine-tRNA Ligase, Zebrafish

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.

Alternate JournalNat Commun
PubMed ID30755616
PubMed Central IDPMC6372652
Grant ListR01 GM054899 / GM / NIGMS NIH HHS / United States
R01 GM118647 / GM / NIGMS NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States

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