Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity

Am J Hum Genet. 2013 May 2;92(5):774-80. doi: 10.1016/j.ajhg.2013.04.006.


Inherited white-matter disorders are a broad class of diseases for which treatment and classification are both challenging. Indeed, nearly half of the children presenting with a leukoencephalopathy remain without a specific diagnosis. Here, we report on the application of high-throughput genome and exome sequencing to a cohort of ten individuals with a leukoencephalopathy of unknown etiology and clinically characterized by hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL), as well as the identification of compound-heterozygous and homozygous mutations in cytoplasmic aspartyl-tRNA synthetase (DARS). These mutations cause nonsynonymous changes to seven highly conserved amino acids, five of which are unchanged between yeast and man, in the DARS C-terminal lobe adjacent to, or within, the active-site pocket. Intriguingly, HBSL bears a striking resemblance to leukoencephalopathy with brain stem and spinal cord involvement and elevated lactate (LBSL), which is caused by mutations in the mitochondria-specific DARS2, suggesting that these two diseases might share a common underlying molecular pathology. These findings add to the growing body of evidence that mutations in tRNA synthetases can cause a broad range of neurologic disorders.

Publication types

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

MeSH terms

  • Aspartate-tRNA Ligase / chemistry
  • Aspartate-tRNA Ligase / genetics*
  • Brain Stem / pathology
  • Crystallography, X-Ray
  • Humans
  • Leg / pathology
  • Leukoencephalopathies / genetics*
  • Leukoencephalopathies / pathology
  • Models, Molecular*
  • Muscle Spasticity / genetics*
  • Mutation / genetics
  • Protein Conformation*
  • Spinal Cord / pathology


  • Aspartate-tRNA Ligase