Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy

Hum Mutat. 2019 Oct;40(10):1826-1840. doi: 10.1002/humu.23799. Epub 2019 Jun 18.


Mutations in genes encoding aminoacyl-tRNA synthetases have been reported in several neurological disorders. KARS is a dual localized lysyl-tRNA synthetase and its cytosolic isoform belongs to the multiple aminoacyl-tRNA synthetase complex (MSC). Biallelic mutations in the KARS gene were described in a wide phenotypic spectrum ranging from nonsyndromic deafness to complex impairments. Here, we report on a patient with severe neurological and neurosensory disease investigated by whole-exome sequencing and found to carry biallelic mutations c.683C>T (p.Pro228Leu) and c.871T>G (p.Phe291Val), the second one being novel, in the KARS gene. The patient presented with an atypical clinical presentation with an optic neuropathy not previously reported. At the cellular level, we show that cytoplasmic KARS was expressed at a lower level in patient cells and displayed decreased interaction with MSC. In vitro, these two KARS variants have a decreased aminoacylation activity compared with wild-type KARS, the p.Pro228Leu being the most affected. Our data suggest that dysfunction of cytoplasmic KARS resulted in a decreased level of translation of the nuclear-encoded lysine-rich proteins belonging to the respiratory chain complex, thus impairing mitochondria functions.

Keywords: aaRS; deafness; lysyl-tRNA synthetase; mitochondrial respiratory chain defect; neurological disorder; optic neuropathy; translation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Amino Acyl-tRNA Synthetases / chemistry
  • Amino Acyl-tRNA Synthetases / genetics*
  • Amino Acyl-tRNA Synthetases / metabolism
  • Electron Transport Complex I / genetics
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex IV / metabolism
  • Fibroblasts / metabolism
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Lysine-tRNA Ligase / chemistry
  • Lysine-tRNA Ligase / genetics*
  • Lysine-tRNA Ligase / metabolism
  • Magnetic Resonance Imaging
  • Models, Molecular
  • Mutation*
  • Nervous System Diseases / complications*
  • Nervous System Diseases / diagnosis
  • Nervous System Diseases / genetics*
  • Optic Nerve Diseases / complications*
  • Optic Nerve Diseases / diagnosis
  • Pedigree
  • Protein Binding
  • Protein Conformation
  • Sensation Disorders / complications*
  • Sensation Disorders / diagnosis
  • Sensation Disorders / genetics*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Electron Transport Complex IV
  • p38 Mitogen-Activated Protein Kinases
  • Amino Acyl-tRNA Synthetases
  • Lysine-tRNA Ligase
  • Electron Transport Complex I
  • NDUFB6 protein, human