Human Molecular Genetics, 2002, Vol. 11, No. 16 1797-1805
© 2002 Oxford University Press
Metabolic consequences of a novel missense mutation of the mtDNA CO I gene
1Department of Epileptology, 2Department of Neurology and 3Department of Neuropathology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany, 4Department of Neurology, University of Magdeburg Medical Center, Leipziger Strasse 44, D-39120 Magdeburg, Germany, 5Institute of Clinical Chemistry and Pathobiochemistry, Medical Center of RWTH Aachen, Pauwelsstrasse 30, D-52072 Aachen, Germany and 6Institute of Human Genetics, Wilhelmstrasse 31, D-53111 Bonn, Germany
Received February 19, 2002; Accepted June 6, 2002
We have identified a novel heteroplasmic C6489A missense mutation in the mitochondrial DNA (mtDNA) CO I gene encoding the cytochrome c oxidase (COX) subunit I in a 17-year-old girl with epilepsia partialis continua. This point mutation leads to an exchange of the highly conserved Leu196 to Ileu196. Muscle biopsy showed in single fibers decreased COX activity and lowered binding of COX antibodies, indicating decreased stability of the mutated enzyme. The analysis of blood mtDNA revealed about 30% mutant mtDNA in the patients blood but about 90% mutant mtDNA in the blood of two non-affected family members. Quantitative analysis of the mutation gene dose effect on COX activity on single muscle fiber level revealed a very high threshold—a COX deficiency was observed only in fibers containing >95% mutant mtDNA. In apparent contrast to this high mutation gene dose threshold, in vivo investigations of mitochondrial function in saponin-permeabilized muscle fibers of the index patient containing 
90% mutated mtDNA showed decreased maximal rates of respiration and an increased sensitivity of fiber respiration to cyanide. This is due to a 2-fold increase of COX flux control on muscle fiber respiration and a 30% decrease of COX metabolic threshold, supporting the concept of tight COX control of oxidative phosphorylation in skeletal muscle.
* To whom correspondence should be addressed. Tel: +49 2282875744; Fax: +49 2282876294; Email: wolfram.kunz{at}ukb.uni-bonn.de
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