Vissing et al. (1998) identified a heteroplasmic 4409T-C transition in the MTTM gene in a 30-year-old woman with growth retardation, muscle weakness, severe exercise intolerance since age 10 years, and lactic acidosis. Other features included decreased IQ (verbal, 81; performance, 82) and diffuse muscle atrophy. Muscle biopsy showed unusually severe dystrophic features with internal nuclei, variation in fiber type, and ragged red fibers. Electron microscopy showed giant mitochondria with abnormal cristae structure and crystalloid inclusions. There was 77% mutation load in muscle and 8% in leukocytes; presence of the mutation in muscle correlated with decreased oxidative capacity. The mutation was not present in maternal relatives or 25 healthy subjects.
Jones et al. (2008) found that the 4409T-C transition results in a drastic disruption of the structure of the tRNA-Met, causing loss of stable structure at physiologic temperatures and improper folding. This significantly reduces its aminoacylation. The small fraction of tRNA-Met that can be aminoacylated is not formylated by the mitochondrial Met-tRNA transformylase (MTFMT; 611766), preventing its function in initiation. It is also unable to form a stable ternary complex with elongation factor EF-Tu (TUFM; 602389), preventing any participation in chain elongation. Further studies indicated that the 4409T-C mutation disrupts a critical Mg(2+)-binding site on the tRNA required for formation of the biologically active structure.
