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Further pitfalls in the diagnosis of mtDNA mutations: homoplasmic mt-tRNA mutations
  1. H A L Tuppen1,
  2. F Fattori2,
  3. R Carrozzo2,
  4. M Zeviani3,
  5. S DiMauro4,
  6. S Seneca5,
  7. J E Martindale6,
  8. S E Olpin7,
  9. E P Treacy8,
  10. R McFarland1,
  11. F M Santorelli2,
  12. R W Taylor1
  1. 1
    Mitochondrial Research Group, Department of Neurology, Medical School, Newcastle University, Newcastle-upon-Tyne, UK
  2. 2
    IRCCS-Bambino Gesu Hospital, Rome, Italy
  3. 3
    Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Centre for the Study of Children’s Mitochondrial Disorders, National Neurological Institute ‘C.Besta’, Milan, Italy
  4. 4
    Department of Neurology, Columbia University Medical Center, New York, USA
  5. 5
    Centre for Medical Genetics, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
  6. 6
    North Trent Molecular Genetics Service, Sheffield Children’s Hospital, Western Bank, Sheffield, UK
  7. 7
    Neonatal Screening Laboratory, Sheffield Children’s Hospital, Western Bank, Sheffield, UK
  8. 8
    National Centre for Inherited Metabolic Disorders, The Children’s University Hospital, Dublin, Ireland
  1. Professor R W Taylor, Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK; r.w.taylor{at}


Background: Mitochondrial DNA (mtDNA) mutations are important causes of human genetic disease, with mutations in tRNA genes particularly prevalent. In many patients, mutations are heteroplasmic, affecting a population of mtDNA molecules. Establishing the pathogenicity of homoplasmic mitochondrial tRNA (mt-tRNA) mutations, in which the mutation is present in every mtDNA molecule, is extremely difficult. These mutations must conform to specific pathogenic criteria, documenting unequivocally a functional defect of the mutant mt-tRNA.

Aims: To investigate the pathogenic nature of two homoplasmic mt-tRNAThr deletions, m.15940delT (previously reported as pathogenic) and m.15937delA, by assessing the steady state levels of the mutant mt-tRNA in tissue and cell-line samples from six unrelated families, in which affected individuals were thoroughly investigated for mitochondrial DNA disease on the basis of clinical presentations. Rates of de novo mitochondrial protein synthesis were also examined in control and m.15937delA mutant fibroblasts.

Results: Our data strongly suggest that both single nucleotide deletions are neutral polymorphisms; no obvious defects were apparent in either steady state mt-tRNAThr levels or rates of mitochondrial protein synthesis.

Conclusions: These findings have important implications for the investigation of other families with suspected mtDNA disease, in particular the requirement to fulfil strict and established pathogenic criteria in order to avoid misattribution of pathogenicity to mt-tRNA variants.

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  • Funding: Funded by the Italian Ministry of Health (FMS), a Fellowship from the Bambino Gesù-Roma3 University joint PhD program (FF), Fondazione Pierfranco e Luisa Mariani (MZ), MITOCIRCLE (MZ), the Marriott Mitochondrial Disorder Clinical Research Fund (SD), the Medical Research Council, UK (RM) and the Wellcome Trust (RWT).

  • Competing interests: None declared.

  • Ethics approval: This study was performed under the ethical guidelines issued by each of our institutions for clinical studies.