Deep sequencing unearths nuclear mitochondrial sequences under Leber's hereditary optic neuropathy-associated false heteroplasmic mitochondrial DNA variants

Hum Mol Genet. 2012 Sep 1;21(17):3753-64. doi: 10.1093/hmg/dds182. Epub 2012 May 15.


Leber's hereditary optic neuropathy (LHON) is associated with mitochondrial DNA (mtDNA) ND mutations that are mostly homoplasmic. However, these mutations are not sufficient to explain the peculiar features of penetrance and the tissue-specific expression of the disease and are believed to be causative in association with unknown environmental or other genetic factors. Discerning between clear-cut pathogenetic variants, such as those that appear to be heteroplasmic, and less penetrant variants, such as the homoplasmic, remains a challenging issue that we have addressed here using next-generation sequencing approach. We set up a protocol to quantify MTND5 heteroplasmy levels in a family in which the proband manifests a LHON phenotype. Furthermore, to study this mtDNA haplotype, we applied the cybridization protocol. The results demonstrate that the mutations are mostly homoplasmic, whereas the suspected heteroplasmic feature of the observed mutations is due to the co-amplification of Nuclear mitochondrial Sequences.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Adolescent
  • Adult
  • Cell Nucleus / genetics*
  • DNA, Mitochondrial / genetics*
  • Electron Transport Complex I / genetics
  • Energy Metabolism
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Male
  • Middle Aged
  • Mitochondria / genetics*
  • Mitochondrial Proteins / genetics
  • Mutation / genetics*
  • Optic Atrophy, Hereditary, Leber / genetics*
  • Pedigree
  • Temperature
  • Young Adult


  • DNA, Mitochondrial
  • Mitochondrial Proteins
  • Adenosine Triphosphate
  • MT-ND5 protein, human
  • Electron Transport Complex I