A novel mitochondrial m.14430A>G (MT-ND6, p.W82R) variant causes complex I deficiency and mitochondrial Leigh syndrome

Clin Chem Lab Med. 2020 Oct 25;58(11):1809-1817. doi: 10.1515/cclm-2020-0150.


Objectives Leigh syndrome (LS) is one of the most common mitochondrial diseases and has variable clinical symptoms. However, the genetic variant spectrum of this disease is incomplete. Methods Next-generation sequencing (NGS) was used to identify the m.14430A > G (p.W82R) variant in a patient with LS. The pathogenesis of this novel complex I (CI) variant was verified by determining the mitochondrial respiration, assembly of CI, ATP, MMP and lactate production, and cell growth rate in cybrids with and without this variant. Results A novel m.14430A > G (p.W82R) variant in the NADH dehydrogenase 6 (ND6) gene was identified in the patient; the mutant loads of m.14430A > G (p.W82R) in the patient were much higher than those in his mother. Although the transmitochondrial cybrid-based study showed that mitochondrial CI assembly remains unaffected in cells with the m.14430G variant, control cells had significantly higher endogenous and CI-dependent mitochondrial respiration than mutant cells. Accordingly, mutant cells had a lower ATP, MMP and higher extracellular lactate production than control cells. Notably, mutant cells had impaired growth in a galactose-containing medium when compared to wild-type cells. Conclusions A novel m.14430A > G (p.W82R) variant in the ND6 gene was identified from a patient suspected to have LS, and this variant impaired mitochondrial respiration by decreasing the activity of mitochondrial CI.

Keywords: Leigh syndrome; complex I deficiency; m.14430A>G (MT-ND6, p.W82R); mitochondrial diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Child, Preschool
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Leigh Disease / enzymology
  • Leigh Disease / genetics*
  • Male
  • Mutation, Missense
  • NADH Dehydrogenase / deficiency*
  • NADH Dehydrogenase / genetics*


  • MT-ND6 protein, human
  • NADH Dehydrogenase

Supplementary concepts

  • Leigh Syndrome Due To Mitochondrial Complex I Deficiency