Mutation in the nuclear-encoded mitochondrial isoleucyl-tRNA synthetase IARS2 in patients with cataracts, growth hormone deficiency with short stature, partial sensorineural deafness, and peripheral neuropathy or with Leigh syndrome

Hum Mutat. 2014 Nov;35(11):1285-9. doi: 10.1002/humu.22629. Epub 2014 Oct 18.


Mutations in the nuclear-encoded mitochondrial aminoacyl-tRNA synthetases are associated with a range of clinical phenotypes. Here, we report a novel disorder in three adult patients with a phenotype including cataracts, short-stature secondary to growth hormone deficiency, sensorineural hearing deficit, peripheral sensory neuropathy, and skeletal dysplasia. Using SNP genotyping and whole-exome sequencing, we identified a single likely causal variant, a missense mutation in a conserved residue of the nuclear gene IARS2, encoding mitochondrial isoleucyl-tRNA synthetase. The mutation is homozygous in the affected patients, heterozygous in carriers, and absent in control chromosomes. IARS2 protein level was reduced in skin cells cultured from one of the patients, consistent with a pathogenic effect of the mutation. Compound heterozygous mutations in IARS2 were independently identified in a previously unreported patient with a more severe mitochondrial phenotype diagnosed as Leigh syndrome. This is the first report of clinical findings associated with IARS2 mutations.

Keywords: IARS2; exome sequencing; mitochondrial disorder; mitochondrial tRNA synthetase.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Brain / pathology
  • Cataract / diagnosis
  • Cataract / genetics*
  • Consanguinity
  • DNA Mutational Analysis
  • Dwarfism, Pituitary / diagnosis
  • Dwarfism, Pituitary / genetics*
  • Female
  • Genes, Recessive
  • Hearing Loss, Sensorineural / diagnosis
  • Hearing Loss, Sensorineural / genetics*
  • Humans
  • Isoleucine-tRNA Ligase / chemistry
  • Isoleucine-tRNA Ligase / genetics*
  • Leigh Disease / diagnosis
  • Leigh Disease / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Peripheral Nervous System Diseases / diagnosis
  • Peripheral Nervous System Diseases / genetics*
  • Phenotype
  • Sequence Alignment
  • Syndrome


  • Isoleucine-tRNA Ligase