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.
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.
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.
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.
We thank the National Natural Science Foundation of China (key program, 81830071, Funder Id: http://dx.doi.org/10.13039/501100001809) and Zhejiang Provincial Natural Science Foundation of China (LR20H200001) for supporting this work.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Research funding: This work was supported by the National Natural Science Foundation of China (key program, 81830071) and Zhejiang Provincial Natural Science Foundation of China (LR20H200001).
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: Authors state no conflict of interest.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: This study was approved by the Ethics Committee of Peking University First Hospital (No. 2017-217).
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