De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Am J Hum Genet. 2020 Aug 6;107(2):311-324. doi: 10.1016/j.ajhg.2020.06.016. Epub 2020 Jul 31.


Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.

Keywords: aminoacyl-tRNA synthetase; developmental delay; epilepsy; neurodevelopment; neuropathy; next generation sequencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acyl-tRNA Synthetases / genetics
  • Aspartate-tRNA Ligase / genetics*
  • Cell Line
  • Female
  • Gain of Function Mutation / genetics*
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Loss of Function Mutation / genetics*
  • Male
  • Neurodevelopmental Disorders / genetics*
  • Pedigree
  • RNA, Transfer / genetics
  • RNA, Transfer, Amino Acyl / genetics*
  • Stem Cells / physiology


  • RNA, Transfer, Amino Acyl
  • RNA, Transfer
  • Amino Acyl-tRNA Synthetases
  • Aspartate-tRNA Ligase
  • asparaginyl-tRNA synthetase