Article (Scientific journals)
Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
Siekierska, Aleksandra; Stamberger, Hannah; Deconinck, Tine et al.
2019In Nature Communications, 10 (1), p. 708
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Keywords :
VARS; epilepsy; Aminoacyl tRNA synthetase; neurodevelopmental disease; recessive disease
Abstract :
[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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group)
ULHPC - University of Luxembourg: High Performance Computing
Disciplines :
Neurology
Biochemistry, biophysics & molecular biology
Author, co-author :
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  ;  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 ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Weckhuysen, Sarah
Francklyn, Christopher
Antonellis, Anthony
de Witte, Peter
De Jonghe, Peter
More authors (31 more) Less
External co-authors :
yes
Language :
English
Title :
Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
Publication date :
12 February 2019
Journal title :
Nature Communications
ISSN :
2041-1723
Publisher :
Nature Publishing Group, London, United Kingdom
Volume :
10
Issue :
1
Pages :
708
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
Available on ORBilu :
since 12 February 2019

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