Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish - Sorbonne Université Access content directly
Journal Articles Nature Communications Year : 2019

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

Patrick May
Ronen Spiegel
  • Function : Author
Sarah Weckhuysen
Christopher Francklyn
  • Function : Author
Anthony Antonellis
  • Function : Author
Peter de Witte
Peter de Jonghe
  • Function : Author
Chris Balak
  • Function : Author
Newell Belnap
  • Function : Author
Ana Claasen
  • Function : Author
Amanda Courtright
  • Function : Author
Matt de Both
  • Function : Author
Matthew J Huentelman
  • Function : Author
Marcus Naymik
  • Function : Author
Ryan Richholt
  • Function : Author
Ashley L Siniard
  • Function : Author
Szabolcs Szelinger
  • Function : Author
David W Craig
  • Function : Author
Isabelle Schrauwen
  • Function : Author
Zaid Afawi
  • Function : Author
Rudi Balling
  • Function : Author
Nina Barišić
  • Function : Author
Hande S Caglayan
  • Function : Author
Dana Craiu
  • Function : Author
Rosa Guerrero-López
  • Function : Author
Renzo Guerrini
  • Function : Author
Helle Hjalgrim
  • Function : Author
Johanna Jähn
  • Function : Author
Karl Martin Klein
  • Function : Author
Johannes R Lemke
  • Function : Author
Holger Lerche
  • Function : Author
Carla Marini
  • Function : Author
Rikke S Møller
  • Function : Author
Hiltrud Muhle
  • Function : Author
Felix Rosenow
  • Function : Author
Jose Serratosa
  • Function : Author
Arvid Suls
  • Function : Author
Ulrich Stephani
  • Function : Author
Katalin Štěrbová
  • Function : Author
Pasquale Striano
  • Function : Author
Federico Zara
  • Function : Author

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.
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hal-04423498 , version 1 (29-01-2024)

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Aleksandra Siekierska, Hannah Stamberger, Tine Deconinck, Stephanie N Oprescu, Michèle Partoens, et al.. Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish. Nature Communications, 2019, 10 (1), pp.708. ⟨10.1038/s41467-018-07953-w⟩. ⟨hal-04423498⟩
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