Rare recessive loss-of-function methionyl-tRNA synthetase mutations presenting as a multi-organ phenotype

BMC Med Genet. 2013 Oct 8;14:106. doi: 10.1186/1471-2350-14-106.


Background: Methionyl-tRNA synthetase (MARS) catalyzes the ligation of methionine to its cognate transfer RNA and therefore plays an essential role in protein biosynthesis.

Methods: We used exome sequencing, aminoacylation assays, homology modeling, and immuno-isolation of transfected MARS to identify and characterize mutations in the methionyl-tRNA synthetase gene (MARS) in an infant with an unexplained multi-organ phenotype.

Results: We identified compound heterozygous mutations (F370L and I523T) in highly conserved regions of MARS. The parents were each heterozygous for one of the mutations. Aminoacylation assays documented that the F370L and I523T MARS mutants had 18 ± 6% and 16 ± 6%, respectively, of wild-type activity. Homology modeling of the human MARS sequence with the structure of E. coli MARS showed that the F370L and I523T mutations are in close proximity to each other, with residue I523 located in the methionine binding pocket. We found that the F370L and I523T mutations did not affect the association of MARS with the multisynthetase complex.

Conclusion: This infant expands the catalogue of inherited human diseases caused by mutations in aminoacyl-tRNA synthetase genes.

Publication types

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

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Bone Marrow / pathology
  • Brain / diagnostic imaging
  • Exons
  • Female
  • Heterozygote
  • Humans
  • Infant
  • Liver Diseases / genetics
  • Liver Diseases / pathology
  • Magnetic Resonance Imaging
  • Methionine / metabolism
  • Methionine-tRNA Ligase / chemistry
  • Methionine-tRNA Ligase / genetics*
  • Molecular Sequence Data
  • Mutation
  • Phenotype
  • Protein Structure, Tertiary
  • Radiography
  • Sequence Analysis, DNA


  • Methionine
  • Methionine-tRNA Ligase