ZFIN ID: ZDB-PUB-190214-3
Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
Siekierska, A., Stamberger, H., Deconinck, T., Oprescu, S.N., 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, K.L., Hersh, J., Isikay, S., Jordan, E., Karaca, E., Kecskes, A., Lupski, J.R., Kovacs-Nagy, R., May, P., Narayanan, V., Pendziwiat, M., Ramsey, K., Rangasamy, S., Shinde, D.N., Spiegel, R., Timmerman, V., von Spiczak, S., Helbig, I., C4RCD Research Group, AR working group of the EuroEPINOMICS RES Consortium, Weckhuysen, S., Francklyn, C., Antonellis, A., de Witte, P., De Jonghe, P.
Date: 2019
Source: Nature communications   10: 708 (Journal)
Registered Authors: de Witte, Peter, Zhang, Yifan
Keywords: none
MeSH Terms:
  • Alleles
  • Animals
  • Brain Diseases/enzymology
  • Brain Diseases/genetics*
  • Brain Diseases/pathology
  • Cell Line
  • Disease Models, Animal
  • Epilepsy/enzymology
  • Epilepsy/genetics
  • Epilepsy/pathology
  • Female
  • Fibroblasts
  • Gene Knockout Techniques
  • Genetic Predisposition to Disease
  • Humans
  • Loss of Function Mutation
  • Male
  • Microcephaly/enzymology
  • Microcephaly/genetics*
  • Microcephaly/pathology
  • Models, Molecular
  • Neurodevelopmental Disorders/enzymology
  • Neurodevelopmental Disorders/genetics
  • Neurodevelopmental Disorders/pathology
  • Pedigree
  • Prosencephalon/pathology
  • Valine-tRNA Ligase/genetics*
  • Zebrafish
PubMed: 30755616 Full text @ Nat. Commun.
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.