Reference : Biallelic VARS variants cause developmental encephalopathy with microcephaly that is ...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Human health sciences : Neurology
Systems Biomedicine
Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
Siekierska, Aleksandra []
Stamberger, Hannah []
Deconinck, Tine []
Oprescu, Stephanie N. []
Partoens, Michèle []
Sourbron, Jo []
Zhang, Yifan []
Adriaenssens, Elias []
Mullen, Patrick []
Wiencek, Patrick []
Hardies, Katja []
Lee, Jeong-Soo []
Giong, Hoi-Khoanh []
Distelmaier, Felix []
Elpeleg, Orly []
Helbig, Katherine L. []
Hersh, Joseph []
Isikay, Sedat []
Jordan, Elizabeth []
Karaca, Ender []
Kecskes, Angela []
Lupski, James R. []
Kovacs-Nagy, Reka []
May, Patrick mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Narayanan, Vinodh []
Pendziwiat, Manuela []
Ramsey, Keri []
Rangasamy, Sampathkumar []
Shinde, Deepali []
Spiegel, Ronan []
Timmerman, Vincent []
Von Spiczak, Sarah []
Helbig, Ingo []
CARCD Research Group []
EuroEPINOMICS RES AR working group []
Balling, Rudi mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Weckhuysen, Sarah []
Francklyn, Christopher []
Antonellis, Anthony []
de Witte, Peter []
De Jonghe, Peter []
Nature Communications
Nature Publishing Group
Yes (verified by ORBilu)
United Kingdom
[en] VARS ; epilepsy ; Aminoacyl tRNA synthetase ; neurodevelopmental disease ; recessive disease
[en] 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.
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) ; University of Luxembourg: High Performance Computing - ULHPC

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