Human Molecular Genetics Advance Access originally published online on March 12, 2008
Human Molecular Genetics 2008 17(12):1814-1820; doi:10.1093/hmg/ddn073
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A functionally dominant mitochondrial DNA mutation
1 Féderation des maladies neuromusculaires, CHU de Nice and INSERM U638, Nice, France 2 Clinical Genetics Unit 3 Hematooncology Laboratory, Department of Pediatrics, University of Padova, Padova, Italy 4 Department of Neurology 5 Department of Genetics and Development, Columbia University, New York, NY, USA
* To whom correspondence should be addressed at: Clinical Genetics Unit, Department of Pediatrics, University of Padova, Via Giustiniani 3, Padova 35128, Italy. Tel: +39 0498213513; Fax: +39 0498211425; Email leonardo.salviati{at}unipd.it
Received January 21, 2008; Accepted March 4, 2008
Mutations in mitochondrial DNA (mtDNA) tRNA genes can be considered functionally recessive because they result in a clinical or biochemical phenotype only when the percentage of mutant molecules exceeds a critical threshold value, in the range of 70–90%. We report a novel mtDNA mutation that contradicts this rule, since it caused a severe multisystem disorder and respiratory chain (RC) deficiency even at low levels of heteroplasmy. We studied a 13-year-old boy with clinical, radiological and biochemical evidence of a mitochondrial disorder. We detected a novel heteroplasmic C>T mutation at nucleotide 5545 of mtDNA, which was present at unusually low levels (<25%) in affected tissues. The pathogenic threshold for the mutation in cybrids was between 4 and 8%, implying a dominant mechanism of action. The mutation affects the central base of the anticodon triplet of tRNATrp and it may alter the codon specificity of the affected tRNA. These findings introduce the concept of dominance in mitochondrial genetics and pose new diagnostic challenges, because such mutations may easily escape detection. Moreover, similar mutations arising stochastically and accumulating in a minority of mtDNA molecules during the aging process may severely impair RC function in cells.
These authors contributed equally to this work.
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