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Increased risk of sensorineural hearing loss and migraine in patients with a rare mitochondrial DNA variant 4336A>G in tRNAGln
  1. Saara Finniläa,b,c,
  2. Jaana Autered,
  3. Maarit Lehtovirtad,
  4. Päivi Hartikainend,
  5. Arto Mannermaae,
  6. Hilkka Soininend,
  7. Kari Majamaaa,b,c
  1. aDepartment of Neurology, University of Oulu, PO Box 5000, FIN-90014 University of Oulu, Oulu, Finland, bDepartment of Medical Biochemistry, University of Oulu, Oulu, Finland, cBiocenter, University of Oulu, Oulu, Finland, dDepartment of Neurology, University of Kuopio, Kuopio, Finland, eDNA and Chromosome Laboratory, Kuopio University Hospital, Kuopio, Finland
  1. Dr Majamaa, kari.majamaa{at}

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Editor—Selectively neutral polymorphisms in mitochondrial DNA (mtDNA) have accumulated during human evolution along mtDNA lineages that correlate with ethnic and geographical origin. By contrast, deleterious mutations have arisen repeatedly and occur against various genomic backgrounds. Since they reduce the fitness of carriers, however, the affected maternal lineages eventually become extinct. Mutations of intermediate severity also occur along mtDNA lineages and have become fixed in the population.1Although they do not substantially reduce fitness, they may interact with nuclear or environmental factors, predisposing people to an increased risk of developing neurodegenerative diseases later in life.1

1555A>G in the 12S rRNA gene may be considered a mutation of intermediate severity. It has been shown to predispose carriers to maternally transmitted sensorineural hearing impairment, the expression of which requires additional environmental or genetic factors.2 Similarly, 14484T>C and 11778G>A have been shown to cause Leber's hereditary optic neuropathy, but expression of the disease phenotype is significantly higher when 14484T>C occurs in mtDNA belonging to haplogroup J3 and a preferential association with this haplogroup has also been observed for the 11778G>A mutation.4 The homoplasmic transition A to G at nt 4336 (4336A>G) in the mtDNA tRNAGln gene has been found at low frequency in populations of European origin. This nucleotide connects the amino acid acceptor stem with the TψC stem of tRNAGln and is moderately conserved between species.5 It is thought to entail an increased risk of Alzheimer's disease (AD) and Parkinson's disease (PD),1 ,5-7 but its possible role in diseases manifesting in middle life has not been evaluated. We therefore set out to study the frequency of this mutation among middle aged patients with various clinical phenotypes and in healthy, age matched controls (group 1), and also in patients with late onset …

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