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

• Published in: Clinical chemistry and laboratory medicine Vol. 58; no. 11; pp. 1809 - 1817
• Main Authors: Du, Miaomiao, Wei, Xiujuan, Xu, Pu, Xie, Anran, Zhou, Xiyue, Yang, Yanling, Li, Dongxiao, Lyu, Jianxin, Fang, Hezhi
• Format: Journal Article
• Language: English
• Published: Germany De Gruyter 01.11.2020; Walter De Gruyter & Company
• Subjects: Assembly; ATP; complex I deficiency; Cybrids; Electron transport chain; Galactose; Genetic diversity; Genetic variance; Growth rate; Lactic acid; Leigh syndrome; m.14430A>G; Mitochondria; mitochondrial diseases; Mutants; NADH; NADH dehydrogenase; ND6 gene; Next-generation sequencing; Nicotinamide adenine dinucleotide; p.W82R; Pathogenesis; Respiration; Signs and symptoms; m.14430A>G (MT-ND6, p.W82R); Leigh syndrome; complex I deficiency; mitochondrial diseases
• ISSN: 1434-6621; 1437-4331
• 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.