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Contrasting phenotypes in three patients with novel mutations in mitochondrial tRNA genes

We studied three patients, each harboring a novel mutation at a highly conserved position in a different mitochondrial tRNA gene. The mutation in patient 1 (T5543C) was associated with isolated mitochondrial myopathy, and occurred in the anticodon loop of tRNA Trp. In patient 2, with mitochondrial m...

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Published in:Molecular genetics and metabolism 2005-02, Vol.84 (2), p.176-188
Main Authors: Anitori, Roberto, Manning, Kara, Quan, Franklin, Weleber, Richard G., Buist, Neil R.M., Shoubridge, Eric A., Kennaway, Nancy G.
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container_title Molecular genetics and metabolism
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creator Anitori, Roberto
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description We studied three patients, each harboring a novel mutation at a highly conserved position in a different mitochondrial tRNA gene. The mutation in patient 1 (T5543C) was associated with isolated mitochondrial myopathy, and occurred in the anticodon loop of tRNA Trp. In patient 2, with mitochondrial myopathy and marked retinopathy, the mutation (G14710A) resulted in an anticodon swap (Glu to Lys) in tRNA Glu. Patient 3, who manifested mitochondrial encephalomyopathy and moderate retinal dysfunction, harbored a mutation (C3287A) in the TψC loop of tRNA Leu(UUR). The mutations were heteroplasmic in muscle in all cases, and sporadic in two cases. PCR-RFLP analysis in all patients showed much higher amounts of mutated mtDNA in affected tissue (muscle) than unaffected tissue (blood), and significantly higher levels of mutated mtDNA in cytochrome c oxidase (COX)-negative muscle fibers than in COX-positive fibers, confirming the pathogenicity of these mutations. The mutation was also detected in single hair roots from all three patients, indicating that each mutation must have arisen early in embryonic development or in maternal germ cells. This suggests that individual hair root analyses may reflect a wider tissue distribution of mutated mtDNA than is clinically apparent, and might be useful in predicting prognosis and, perhaps, the risk of transmitting the mutation to offspring. Our data suggest a correlation between clinical phenotype and distribution of mutated mtDNA in muscle versus hair roots. Furthermore, the high threshold for phenotypic expression in single muscle fibers (92–96%) suggests that therapies may only need to increase the percentage of wild-type mtDNA by a small amount to be beneficial.
doi_str_mv 10.1016/j.ymgme.2004.10.003
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subjects Adult
Animals
Complex I deficiency
Complex IV deficiency
Cytochrome c oxidase negative fibers
Female
Hair root analysis
Humans
Male
Middle Aged
Mitochondrial DNA
Mitochondrial encephalomyopathy
Mitochondrial myopathy
Mitochondrial tRNA mutation
Mutation
Pathogenesis of mitochondrial tRNA mutations
Phenotype
Pigmentary retinopathy
Polymerase Chain Reaction
Polymorphism, Restriction Fragment Length
RNA - genetics
RNA, Transfer - genetics
Sequence Homology, Nucleic Acid
title Contrasting phenotypes in three patients with novel mutations in mitochondrial tRNA genes
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