Abstract
Glycyl-tRNA synthetase (GARS; OMIM 600287) is one of thirty-seven tRNA-synthetase genes that catalyses the synthesis of glycyl-tRNA, which is required to insert glycine into proteins within the cytosol and mitochondria. To date, eighteen mutations in GARS have been reported in patients with autosomal-dominant Charcot-Marie-Tooth disease type 2D (CMT2D; OMIM 601472), and/or distal spinal muscular atrophy type V (dSMA-V; OMIM 600794). In this study, we report a patient with clinical and biochemical features suggestive of a mitochondrial respiratory chain (MRC) disorder including mild left ventricular posterior wall hypertrophy, exercise intolerance, and lactic acidosis. Using whole exome sequencing we identified compound heterozygous novel variants, c.803C>T; p.(Thr268Ile) and c.1234C>T; p.(Arg412Cys), in GARS in the proband. Spectrophotometric evaluation of the MRC complexes showed reduced activity of Complex I, III and IV in patient skeletal muscle and reduced Complex I and IV activity in the patient liver, with Complex IV being the most severely affected in both tissues. Immunoblot analysis of GARS protein and subunits of the MRC enzyme complexes in patient fibroblast extracts showed significant reduction in GARS protein levels and Complex IV. Together these studies provide evidence that the identified compound heterozygous GARS variants may be the cause of the mitochondrial dysfunction in our patient.
Highlights
Aminoacyl-tRNA synthetases (ARS) are ubiquitously expressed essential enzymes responsible for attaching amino acid residues to their cognate tRNA molecules, which is the first step of protein translation in the cytoplasm and mitochondria [1]
We report the identification of compound heterozygous GARS variants in a patient with exercise-intolerance, mild cardiomyopathy and lactic acidosis
This phenotype closely resembles those caused by autosomal dominant mutations in cytoplasmic ARS, such as AARS (OMIM: 613287), HARS (OMIM: 616625), YARS (OMIM: 608323) and MARS (OMIM: 616280), which have been associated with distal motor neuropathy or polyneuropathies in children and adults [13]
Summary
Aminoacyl-tRNA synthetases (ARS) are ubiquitously expressed essential enzymes responsible for attaching amino acid residues to their cognate tRNA molecules, which is the first step of protein translation in the cytoplasm and mitochondria [1]. For most ARS, the cytoplasmic and mitochondrial ARS for each amino acid are encoded by distinctly different nuclear genes. The cytoplasmic and mitochondrial isoforms of glycyl-tRNA synthetase, encoded by GARS, differ by a 54 amino acid N-terminal mitochondrial targeting sequence [3,4]. The human GARS belongs to the class IIA aminoacyl- tRNA synthetases, with the cytosolic isoform having 685 amino acids and the mitochondrial isoform having 739 amino acids [4]. Both isoforms include the N-terminal WHEP-TRS domain composed of the amino acid residues 62–122, a catalytic domain (124–608), and a C terminal anticodon-binding domain (602– 726) [4]
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