Mutations in the mitochondrial tRNA(Ser(AGY)) gene are associated with deafness, retinal degeneration, myopathy and epilepsy

  1. Lookup NU author(s)
  2. Dr Helen Tuppen
  3. John Yarham
  4. Professor Robert Taylor
  5. Dr Bobby McFarland
Author(s)Tuppen HA, Naess K, Kennaway NG, Al-Dosary M, Lesko N, Yarham JW, Bruhn H, Wibom R, Nennesmo I, Weleber RG, Blakely EL, Taylor RW, McFarland R
Publication type Article
JournalEuropean Journal of Human Genetics
Year2012
Volume20
Issue
Pages897-904
ISSN (print)1018-4813
ISSN (electronic)1476-5438
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
Although over 200 pathogenic mitochondrial DNA (mtDNA) mutations have been reported to date, determining the genetic aetiology of many cases of mitochondrial disease is still not straightforward. Here, we describe the investigations undertaken to uncover the underlying molecular defect(s) in two unrelated Caucasian patients with suspected mtDNA disease, who presented with similar symptoms of myopathy, deafness, neurodevelopmental delay, epilepsy, marked fatigue and, in one case, retinal degeneration. Histochemical and biochemical evidence of mitochondrial respiratory chain deficiency was observed in the patient muscle biopsies and both patients were discovered to harbour a novel heteroplasmic mitochondrial tRNA (mt-tRNA)Ser(AGY) (MTTS2) mutation (m.12264C>T and m.12261T>C, respectively). Clear segregation of the m.12261T>C mutation with the biochemical defect, as demonstrated by single-fibre radioactive RFLP, confirmed the pathogenicity of this novel variant in patient 2. However, unusually high levels of m.12264C>T mutation within both COX-positive (98.4±1.5%) and COX-deficient (98.2 ±2.1%) fibres in patient 1 necessitated further functional investigations to prove its pathogenicity. Northern blot analysis demonstrated the detrimental effect of the m.12264C>T mutation on mt-tRNASer(AGY) stability, ultimately resulting in decreased steady-state levels of fully assembled complexes I and IV, as shown by blue-native polyacrylamide gel electrophoresis. Our findings expand the spectrum of pathogenic mutations associated with the MTTS2 gene and highlight MTTS2 mutations as an important cause of retinal and syndromic auditory impairment.
PublisherNature Publishing Group
URLhttp://dx.doi.org/10.1038/ejhg.2012.44
DOI10.1038/ejhg.2012.44
Actions    Link to this publication
Share