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Novel mitochondrial tRNAIle m.4282A>G gene mutation leads to chronic progressive external ophthalmoplegia plus phenotype
  1. Christopher B Jackson1,2,3,
  2. Christoph Neuwirth4,
  3. Dagmar Hahn2,
  4. J-M Nuoffer2,
  5. Stephan Frank5,
  6. Sabina Gallati1,
  7. André Schaller1
  1. 1Division of Human Genetics, Departments of Pediatrics and Clinical Research, Inselspital, University of Berne, Berne, Switzerland
  2. 2Institute of Clinical Chemistry, Inselspital, University of Berne, Berne, Switzerland
  3. 3Graduate School for Cellular and Biomedical Sciences, University of Berne, Berne, Switzerland
  4. 4Neuromuscular Diseases Centre, Cantonal Hospital St.Gallen, St.Gallen, Switzerland
  5. 5Division of Neuropathology, Institute of Pathology, Basle University Hospital, Basle, Switzerland
  1. Correspondence to Dr André Schaller, Division of Human Genetics, Departments of Pediatrics and Clinical Research, Inselspital, University of Berne, Freiburgstrasse, Berne CH-3010, Switzerland andre.schaller{at}


Background/aim To investigate the underlying pathomechanism in a 33-year-old female Caucasian patient presenting with chronic progressive external ophthalmoplegia (CPEO) plus symptoms.

Methods Histochemical anaylsis of skeletal muscle and biochemical measurements of individual oxidative phosphorylation (OXPHOS) complexes. Genetic analysis of mitochondrial DNA in various tissues with subsequent investigation of single muscle fibres for correlation of mutational load.

Results The patient’s skeletal muscle showed 20% of cytochrome c oxidase-negative fibres and 8% ragged-red fibres. Genetic analysis of the mitochondrial DNA revealed a novel point mutation in the mitochondrial tRNAIle (MTTI) gene at position m.4282G>A. The heteroplasmy was determined in blood, buccal cells and muscle by restriction fragment length polymorphism (RFLP) combined with a last fluorescent cycle. The total mutational load was 38% in skeletal muscle, but was not detectable in blood or buccal cells of the patient. The phenotype segregated with the mutational load as determined by analysis of single cytochrome c oxidase-negative/positive fibres by laser capture microdissection and subsequent LFC-RFLP.

Conclusions We describe a novel MTTI transition mutation at nucleotide position m.4282G>A associated with a CPEO plus phenotype. The novel variant at position m.4282G>A disrupts the middle bond of the D-stem of the tRNAIle and is highly conserved. The conservation and phenotype-genotype segregation strongly suggest pathogenicity and is in good agreement with the MTTI gene being frequently associated with CPEO. This novel variant broadens the spectrum of MTTI mutations causing CPEO.

  • Genetics
  • Muscles
  • Eye Lids

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