Title | Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Siekierska, 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 Authors | C4RCD Research Group, AR working group of the EuroEPINOMICS RES Consortium |
Journal | Nat Commun |
Volume | 10 |
Issue | 1 |
Pagination | 708 |
Date Published | 2019 Feb 12 |
ISSN | 2041-1723 |
Keywords | Alleles, 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 |
Abstract | 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. |
DOI | 10.1038/s41467-018-07953-w |
Alternate Journal | Nat Commun |
PubMed ID | 30755616 |
PubMed Central ID | PMC6372652 |
Grant List | R01 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 |
Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish.
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