Partial tandem duplication of mtDNA–tRNAPhe impairs mtDNA translation in late-onset mitochondrial myopathy

Abstract

An 80-year-old woman (PI) has been suffering of late onset progressive weakness and wasting of lower-limb muscles, accompanied by high creatine kinase levels in blood. A muscle biopsy, performed at 63 years, showed myopathic features with partial deficiency of cytochrome c oxidase. A second biopsy taken 7 years later confirmed the presence of a mitochondrial myopathy but also of vacuolar degeneration and other morphological features resembling inclusion body myopathy. Her 46-year-old daughter (PII) and 50-year-old son (PIII) are clinically normal, but the creatine kinase levels were moderately elevated and the EMG was consistently myopathic in both. Analysis of mitochondrial DNA sequence revealed in all three patients a novel, homoplasmic 15 bp tandem duplication adjacent to the 5′ end of mitochondrial tRNAPhe gene, encompassing the first 11 nucleotides of this gene and the four terminal nucleotides of the adjacent D-loop region. Both mutant fibroblasts and cybrids showed low oxygen consumption rate, reduced mitochondrial protein synthesis, and decreased mitochondrial tRNAPhe amount. These findings are consistent with an unconventional pathogenic mechanism causing the tandem duplication to interfere with the maturation of the mitochondrial tRNAPhe transcript.

Aging-Related Diseases and Autophagy

“…Congenita (developmental delays in motor skills; skeletal and facial abnormalities are occasionally evident at birth), muscular dystrophies (progressive weakness in voluntary muscles; sometimes evident at birth), mitochondrial myopathies (such as in Kearns-Sayre syndrome, MELAS, and MERRF), glycogen storage diseases of muscle (Pompe's, Andersen's, and Cori's diseases), dermatomyositis (inflammatory myopathy of skin and muscle), myositis ossificans (bone growing in muscle tissue), polymyositis, inclusion body myositis, and related myopathies (inflammatory myopathies of skeletal muscle), neuromyotonia (alternation episodes of twitching and stiffness), tetany (characterized by prolonged spasms of the arms and legs is defined as myopathy), and major symptoms of Danon disease is linked with myopathy. There are also various autophagy-related myopathic disorders such as X-linked congenital autophagic vascular myopathy and adult onset vacuolar myopathy with multiorgan involvement that the etiology machinery has not been highlighted [187][188][189][190]. All these emphases disorders are predicted to be associated with autophagosome-lysosome fusion.…”

Mitochondrial disorders: aetiologies, models systems, and candidate therapies

“…associated with specific mitochondrial mutations. Examples include a partial tandem duplication of tRNA PHE in late-onset mitochondrial myopathy [39], causative of reduced oxygen consumption rates in cybrids, and the A3243G transition in the tRNA LEU(UUR) gene, which results in defects in respiratory chain assembly and activity, causative of MELAS, deafness, and cardiomyopathy [40]. The approach has also been adopted to evaluate the relative contribution of mitochondrial and nuclear genetic backgrounds in driving disease risk.…”