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A frameshift mitochondrial complex I gene mutation in a patient with dystonia and cataracts: is the mutation pathogenic?
  1. DAVID K SIMON*,
  2. MARK A TARNOPOLSKY†,
  3. J TIMOTHY GREENAMYRE‡,
  4. DONALD R JOHNS*,§
  1. *Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, 77 Avenue Louis Pasteur, Room HIM847, Boston, MA 02115, USA
  2. †Department of Neurology and Rehabilitation, McMaster University, Hamilton, Ontario, Canada
  3. ‡Department of Neurology, Emory University, Atlanta, GA, USA
  4. §Department of Ophthalmology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
  1. Dr Simon, dsimon1{at}caregroup.harvard.edu

https://doi.org/10.1136/jmg.38.1.58

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    Editor—Mitochondrial DNA (MtDNA) is highly polymorphic. Each person is estimated to differ from another on average at about 25 base pairs among the 16 569 that comprise the mitochondrial genome.1 Thus, only a small fraction of mtDNA variants are likely to be of pathogenic significance. Criteria currently used for determining the likelihood that a missense mutation is pathogenic include heteroplasmy (the percentage of mtDNA molecules within a cell or tissue harbouring a mutation), evolutionary conservation of the altered amino acid, a maternal inheritance pattern, absence of the mutation in controls, clinical features commonly linked to known pathogenic mtDNA mutations, and defects in mitochondrial morphologies and enzyme activities.1 However, these criteria are inadequate for several reasons. Many mitochondrial missense mutations are homoplasmic. Pathogenic mtDNA mutations are typically characterised by incomplete penetrance, even when homoplasmic, presumably reflecting interactions with environmental and genetic factors.2 As a result, inherited mtDNA mutations may manifest as “sporadic” disorders rather than with the classical maternal inheritance pattern. Biochemical assays may also be inconclusive, as the expression of a defect in mitochondrial function depends on the nuclear background and tissue type in which the mutation is studied.3 ,4 As a result, mtDNA mutations identified in rare families or subjects with a putative mitochondrial genetic disorder are often of uncertain pathogenic significance.

    Over 100 point mutations have been identified in mitochondrial genes in association with human disease, at least 45 of which are missense mutations in protein encoding genes.5 However, frameshift mtDNA mutations are exceedingly rare. An acquired frameshift 4 bp deletion mutation was identified in the cytochrome b gene at nucleotide position (np) 14 787-14 790 in a patient with parkinsonism-MELAS overlap syndrome6 and somatic mutations including frameshift mutations have been found in human cancers.7 ,8In contrast, inherited frameshift …

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