Human Molecular Genetics Advance Access published online on March 12, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn073
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
A Functionally Dominant Mitochondrial DNA Mutation
1 Féderation des maladies neuromusculaires, CHU de Nice and INSERM U638, Nice, France 2 Clinical Genetics Unit, Dept. of Pediatrics, University of Padova, Padova, Italy 3 Hematooncology Laboratory, Dept. of Pediatrics, University of Padova, Padova, Italy 4 Dept. of Neurology, Columbia University, New York, NY, USA 5 Dept. of Genetics and Development, Columbia University, New York, NY, USA
* Corresponding Author Leonardo Salviati, MD, PhD Clinical Genetics Unit, Department of Pediatrics, University of Padova Via Giustiniani 3 35128, Padova, Italy E-mail leonardo.salviati{at}unipd.it Phone +39-049-821-3513 Fax +39-049-821-1425
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 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.
Sabrina Sacconi and Leonardo Salviati contributed equally to this work
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Poulton, S. Kennedy, P. Oakeshott, and D. Wells Preventing transmission of maternally inherited mitochondrial DNA diseases BMJ, January 30, 2009; 338(jan30_1): b94 - b94. [Full Text]
|
|