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Tissue dependent co-segregation of the novel pathogenic G12276A mitochondrial tRNALeu(CUN) mutation with the A185G D-loop polymorphism
  1. G Zsurka1,
  2. R Schröder2,
  3. C Kornblum2,
  4. J Rudolph3,*,
  5. R J Wiesner4,
  6. C E Elger1,
  7. W S Kunz1
  1. 1Department of Epileptology, University of Bonn Medical Center, Bonn, Germany
  2. 2Department of Neurology, University of Bonn Medical Center, Bonn, Germany
  3. 3Transgenomic, Inc., Gaithersburg, MD, USA
  4. 4Institute of Vegetative Physiology, Faculty of Medicine, University of Cologne, Cologne, Germany
  1. Correspondence to:
 Dr Wolfram S Kunz
 Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany;

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Most of the known disease associated point mutations in mitochondrial DNA (for overviews see Wallace1 and Shoubridge and Molnar2) affect mitochondrial tRNA genes leading to impaired translation of the mitochondrial encoded subunits of the oxidative phosphorylation complexes I, III, IV, and V. Among these, three different point mutations in the mitochondrial tRNALeu(CUN) gene have been identified so far. These rare mutations were reported only in single individuals and were found to be associated with skeletal muscle disorders, including chronic progressive external ophthalmoplegia (CPEO),3 isolated skeletal myopathy,4 and chronic fatigue syndrome.5 However, the detailed pathogenic mechanisms of these tRNA point mutations leading to mitochondrial dysfunction in skeletal muscle have remained elusive.

From a diagnostic point of view it is noteworthy that the mitochondrial genome is highly variable, which in turn leads to difficulties in proving the pathogenic role of any particular heteroplasmic mtDNA mutation.6 Therefore, it has become common practice to provide correlation between the mutation load (degree of mtDNA heteroplasmy) and the biochemical pathology (for example, cytochrome c oxidase (COX) negativity) in individual muscle fibres or cybrids.

Here, we report a novel heteroplasmic point mutation in the mitochondrial tRNALeu(CUN) gene associated with a mild form of CPEO. This mutation causes, due to its location in the highly conserved DHU-stem, a severe decrease in the steady state levels of this tRNA, explaining the impaired translation of mitochondrial encoded proteins. Interestingly, this mutation strictly co-segregates with one allele of a heteroplasmic D-loop polymorphism. This causes pseudo-correlation of the neutral polymorphism with a pathological biochemical phenotype and might be responsible for routing of the pathogenic mutation into skeletal muscle.


Case description

A 28 year old female patient presented with a history of mild exercise intolerance starting in early childhood. At the age of 13 years she developed …

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  • * Current address: NIH, Center for Scientific Review, Bethesda, MD, USA.

  • This work was supported by the University of Bonn (BONFOR) and the Deutsche Forschungsgemeinschaft (Ku 911/11-3 to WSK, Schr 562/4-1 to RS, and WSK, Wi 889/3-3 to RJW).

  • Conflict of interest: none declared.