title: Compound heterozygous mutations in glycyl-tRNA synthetase are a proposed cause of systemic mitochondrial disease.
abstract: BACKGROUND
  Glycyl-tRNA synthetase (GARS) is an aminoacyl-tRNA synthetase (ARS) that links the amino acid glycine to its corresponding tRNA prior to protein translation and is one of three bifunctional ARS that are active within both the cytoplasm and mitochondria. Dominant mutations in GARS cause rare forms of Charcot-Marie-Tooth disease and distal spinal muscular atrophy.
  
  
  METHODS
  We report a 12-year old girl who presented with clinical and biochemical features of a systemic mitochondrial disease including exercise-induced myalgia, non-compaction cardiomyopathy, persistent elevation of blood lactate and alanine and MRI evidence of mild periventricular leukomalacia. Using exome sequencing she was found to harbor compound heterozygous mutations within the glycyl-tRNA synthetase (GARS) gene; c.1904C > T; p.Ser635Leu and c.1787G > A; p.Arg596Gln. Each mutation occurred at a highly conserved site within the anticodon binding domain.
  
  
  CONCLUSIONS
  Our findings suggest that recessive mutations in GARS may cause systemic mitochondrial disease. This phenotype is distinct from patients with previously reported dominant mutations in this gene, thereby expanding the spectrum of disease associated with GARS dysregulation.
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, 401 Smyth Rd, Ottawa, ON K1H 8 L1, Canada. hmcmillan@cheo.on.ca.
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: McMillan
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.forename: Amanda
authors.initials: A
authors.lastname: Smith
authors.forename: Suzie
authors.initials: S
authors.lastname: Lee
authors.forename: Pranesh
authors.initials: P
authors.lastname: Chakraborty
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Bulman
authors.forename: Chandree L
authors.initials: CL
authors.lastname: Beaulieu
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.forename: Michael T
authors.initials: MT
authors.lastname: Geraghty
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D017079:Exercise Tolerance / Q000235:genetics; D005260:Female; D006032:Glycine-tRNA Ligase / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007969:Leukomalacia, Periventricular / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D025202:Molecular Diagnostic Techniques; D020125:Mutation, Missense; D063806:Myalgia / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D010375:Pedigree
chemical_list: D006032:Glycine-tRNA Ligase