Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy

Hum Mutat. 2017 Oct;38(10):1348-1354. doi: 10.1002/humu.23250. Epub 2017 Jun 23.


Aminoacyl-transfer RNA (tRNA) synthetases ligate amino acids to specific tRNAs and are essential for protein synthesis. Although alanyl-tRNA synthetase (AARS) is a synthetase implicated in a wide range of neurological disorders from Charcot-Marie-Tooth disease to infantile epileptic encephalopathy, there have been limited data on their pathogenesis. Here, we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy, and spasticity. Whole-exome sequencing identified that the affected individuals were compound heterozygous for mutations in AARS gene, c.2067dupC (p.Tyr690Leufs*3) and c.2738G>A (p.Gly913Asp). A lymphoblastoid cell line developed from one of the affected individuals showed a strong reduction in AARS abundance. The mutations decrease aminoacylation efficiency by 70%-90%. The p.Tyr690Leufs*3 mutation also abolished editing activity required for hydrolyzing misacylated tRNAs, thereby increasing errors during aminoacylation. Our study has extended potential mechanisms underlying AARS-related disorders to include destabilization of the protein, aminoacylation dysfunction, and defective editing activity.

Keywords: AARS; aminoacylation defect; hypomyelination; microcephaly; transfer RNA.

MeSH terms

  • Alanine-tRNA Ligase / genetics*
  • Amino Acid Sequence / genetics
  • Aminoacylation / genetics
  • Charcot-Marie-Tooth Disease / genetics
  • Charcot-Marie-Tooth Disease / pathology
  • Child, Preschool
  • Electroencephalography
  • Exome Sequencing
  • Female
  • Humans
  • Infant
  • Lennox Gastaut Syndrome / complications
  • Lennox Gastaut Syndrome / diagnosis
  • Lennox Gastaut Syndrome / genetics*
  • Lennox Gastaut Syndrome / pathology
  • Microcephaly / diagnostic imaging
  • Microcephaly / genetics*
  • Microcephaly / pathology
  • Mutation / genetics
  • Protein Biosynthesis / genetics
  • Siblings
  • Spasms, Infantile / complications
  • Spasms, Infantile / diagnostic imaging
  • Spasms, Infantile / genetics*
  • Spasms, Infantile / pathology
  • Spastic Paraplegia, Hereditary / complications
  • Spastic Paraplegia, Hereditary / genetics*
  • Spastic Paraplegia, Hereditary / pathology


  • Alanine-tRNA Ligase

Supplementary concepts

  • Infantile Epileptic-Dyskinetic Encephalopathy