A mitochondrial tRNA aspartate mutation causing isolated mitochondrial myopathy

Abstract

Several mutations in mitochondrial transfer RNA (tRNA) genes can cause mitochondrial myopathy. We describe a young girl who presented with pronounced exercise intolerance. The anaerobic threshold and the maximal oxygen consumption were decreased. She had decreased complex I and IV enzyme activity and ragged red fibers on muscle biopsy. An A to G transition at nucleotide position 7526 in tRNA Aspartate (tRNA(Asp)) gene was heteroplasmic in several of the patient's tissues. We were unable to detect the mutation in muscle tissue from the patient's mother. This case adds a new genetic etiology for mitochondrial myopathy. It also illustrates for patients with combined deficiency of the complex I and IV enzyme activity the value of sequencing in the affected tissue muscle, and not only in blood, all mitochondrial tRNA genes including those not commonly affected, such as in this case mt tRNA(Asp).

Fluorescence imaging of mitochondria in cultured skin fibroblasts: a useful method for the detection of oxidative phosphorylation defects

“…De Paepe et al Table 3 (17)(18)(19)(20)(21)(22)(23). Diagnostic workup of the cultured skin fibroblasts consisted of spectrophotometric analysis of the activities of complex II (24), III (25), and IV (26) and activity staining of all complexes after separation by blue native-polyacrylamide gel electrophoresis (27) and immunocytochemical staining (28) ( Table 4).…”

Enzyme Histochemical Assessment of Mitochondrial Functions in Patients with Myopathic form of Limb-Girdle Syndrome

“…Mitochondrial gene polymorphism in patients with isolated mitochondrial myopathy has limited the diagnostic utility of genetic testing in these patients. On consideration of clinical, biochemical and electrophysiological findings, the patients with genetically proven isolated mitochondrial myopathies (Table 3) [4][5][6][7][8][9][10] are similar to our patients (Table 1) who turned out to be either muscular dystrophy or inflammatory myopathy on histopathology. Exercise intolerance, myalgias, elevated lactate, and creatine kinase are nonspecific features seen in muscular dystrophies, inflammatory myopathies, aminoaciduria and mitochondrial disorders.…”

Pathology-related mutation A7526G (A9G) helps in the understanding of the 3D structural core of human mitochondrial tRNAAsp

“…1), three in and between D-and T-loops, and six forming the core of the structure (Kim et al 1974;Westhof et al 1985; for review, see Giegé et al 1993;Dirheimer et al 1995). Myopathy-related mutation A7526G (Seneca et al 2005) affects nucleotide at position 9 in tRNA Asp , potentially part of the 3D network. Mutation A9G (mutant G9/ A12-U23) would break the link between residues 9 and 23 present in the wild-type triple A9/A12-U23.…”

“…It can fold into a theoretical secondary cloverleaf structure but with small D-and T-loops, and several conserved nucleotides that would be expected to induce and stabilize the 3D fold (Helm et al 2000) characteristic of classical tRNAs (Juehling et al 2009) appear to be absent. The gene for this tRNA is affected by mutation A7526G in a patient with a mitochondrial myopathy (Seneca et al 2005). The molecular impact of this mutation is unknown but raises an interesting structural question.…”