A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle

• Published in: American journal of human genetics Vol. 60; no. 2; pp. 373 - 380
• Main Authors: WEBER, K, WILSON, J. N, TAYLOR, L, BRIERLEY, E, JOHNSON, M. A, TURNBULL, D. M, BINDOFF, L. A
• Format: Journal Article
• Language: English
• Published: Chicago, IL University of Chicago Press 01.02.1997
• Subjects: Base Sequence; Biological and medical sciences; Cells, Cultured; Cytochromes - metabolism; Diseases of striated muscles. Neuromuscular diseases; DNA, Mitochondrial - genetics; Electron Transport Complex IV - metabolism; Female; Glutamic Acid - metabolism; Humans; Medical sciences; Middle Aged; Mitochondria, Muscle - metabolism; Mitochondrial Myopathies - genetics; Mitochondrial Myopathies - metabolism; Molecular Sequence Data; Muscle Fibers, Skeletal - metabolism; Muscle, Skeletal - metabolism; Neurology; Nucleic Acid Conformation; Point Mutation; RNA, Transfer, Amino Acyl - chemistry; RNA, Transfer, Amino Acyl - genetics; Succinates - metabolism; Succinic Acid; Human; Nervous system diseases; Nucleotide sequence; Metabolic diseases; Mitochondrial DNA; Striated muscle; Enzymopathy; Congenital disease; Striated muscle disease; Mitochondria; Mitochondrial myopathy; Mutation; Molecular biology
• ISSN: 0002-9297; 1537-6605

We have identified a new mutation in mtDNA, involving tRNALeu(CUN) in a patient manifesting an isolated skeletal myopathy. This heteroplasmic A-->G transition at position 12320 affects the T psi C loop at a conserved site and was not found in 120 controls. Analysis of cultured fibroblasts, white blood cells/platelets, and skeletal muscle showed that only skeletal muscle contained the mutation and that only this tissue demonstrated a biochemical defect of respiratory-chain activity. In a series of four muscle-biopsy specimens taken over a 12-year period, there was a gradual increase, from 70% to 90%, in the overall level of mutation, as well as a marked clinical deterioration. Single-fiber PCR confirmed that the proportion of mutant mtDNA was highest in cytochrome c oxidase-negative fibers. This study, which reports a mutation involving tRNALeu(CUN), demonstrates clearly that mtDNA point mutations can accumulate over time and may be restricted in their tissue distribution. Furthermore, clinical deterioration seemed to follow the increase in the level of mutation, although, interestingly, the appearance of fibers deficient in respiratory-chain activity showed a lag period.