TY - JOUR
T1 - Contrasting phenotypes in three patients with novel mutations in mitochondrial tRNA genes
AU - Anitori, Roberto
AU - Manning, Kara
AU - Quan, Franklin
AU - Weleber, Richard G.
AU - Buist, Neil R.M.
AU - Shoubridge, Eric A.
AU - Kennaway, Nancy G.
N1 - Funding Information:
We acknowledge the following individuals who contributed to the clinical evaluation, work-up and care of these patients: Drs. B. Powell, D. Elliot, R.H. Haller, W. Johnston, T. Taivassalo, E.A. Zimmerman, and Dr. A. Penn (for 31 P MRS). We also thank Drs. K.M. Gibson, B. Popovich and their staff for sharing laboratory space and providing technical advice, and Beth Lee for measurement of respiratory chain activities. This work was supported by grants from the Muscular Dystrophy Association (to N.G.K.), Research to Prevent Blindness and The Foundation Fighting Blindness (to R.G.W.) and the Canadian Institutes of Health Research (CIHR; to E.A.S.). E.A.S. is an International Scholar of the Howard Hughes Medical Institute and a Senior Investigator of the CIHR.
PY - 2005/2
Y1 - 2005/2
N2 - 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 tRNATrp. In patient 2, with mitochondrial myopathy and marked retinopathy, the mutation (G14710A) resulted in an anticodon swap (Glu to Lys) in tRNAGlu. Patient 3, who manifested mitochondrial encephalomyopathy and moderate retinal dysfunction, harbored a mutation (C3287A) in the TψC loop of tRNALeu(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.
AB - 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 tRNATrp. In patient 2, with mitochondrial myopathy and marked retinopathy, the mutation (G14710A) resulted in an anticodon swap (Glu to Lys) in tRNAGlu. Patient 3, who manifested mitochondrial encephalomyopathy and moderate retinal dysfunction, harbored a mutation (C3287A) in the TψC loop of tRNALeu(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.
KW - Complex I deficiency
KW - Complex IV deficiency
KW - Cytochrome c oxidase negative fibers
KW - Hair root analysis
KW - Mitochondrial DNA
KW - Mitochondrial encephalomyopathy
KW - Mitochondrial myopathy
KW - Mitochondrial tRNA mutation
KW - Pigmentary retinopathy
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U2 - 10.1016/j.ymgme.2004.10.003
DO - 10.1016/j.ymgme.2004.10.003
M3 - Article
C2 - 15670724
AN - SCOPUS:12844286989
SN - 1096-7192
VL - 84
SP - 176
EP - 188
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 2
ER -