A Novel NDUFS3 mutation in a Chinese patient with severe Leigh syndrome

Abstract

Leigh syndrome is one of the most common subtypes of mitochondrial disease. Mutations in encoding genes of oxidative phosphorylation complexes have been frequently reported, of which, MTATP6 was one of the most frequently reported genes for Leigh syndrome. In this study, by using next-generation sequencing targeted to MitoExome in a patient with clinical manifestations of Leigh syndrome, two missense mutations of NDUFS3 (c.418 C > T/p.R140W and c.595 C > T/p.R199W) were identified, of which c.418 C > T was novel. Functionally, the patient derived lymphoblastoid cells showed decreased amount of NDUFS3 and complex I assembly when compared with two control cells. Although NDUFS3 mutations have been related to late onset Leigh syndrome, we found that the patient carrying these two mutations developed an early onset Leigh syndrome. To our knowledge, this is the second study on patient carrying NDUFS3 mutations. In conclusion, we identified a novel Leigh syndrome causing NDUFS3 mutation and expanded the clinical spectrum caused by NDUFS3 mutations in this study.

Molecular basis of Leigh syndrome: a current look

“…Previous descriptions for complex I include early-onset presentation displaying muscle hypotonia, spastic diplegia, oculomotor disfunction, ataxia, lethargy, without leukodystrophy in brain imaging. Lou X. et al presented an early-onset case in a 7-month-old boy with torticollis, brain MRI compatible with LS, who evolved to metabolic crisis and progressive lesions in basal ganglia in imaging studies [26]. Whole Exome Sequencing (WES) identified missense variants c.418 C > T (p.Arg140Try)new variant -and c.595 C > T (p.Arg199Try) in NDUFS3 confirmed by Sanger sequencing and tested in B-lymphocytes of the trio.…”

Leigh Syndrome: A Tale of Two Genomes

“…Mutations in nuclear genes encoding structural and assembly subunits ( Supplementary Table 1 ) of ETC enzymes have also been described. The most common of these are mutations in the NDUF ( Budde et al, 2000 ; Bugiani et al, 2004 ; Hoefs et al, 2008 , 2011 ; Tuppen et al, 2010b ; Uehara et al, 2014 ; Lou et al, 2018 ; Sofou et al, 2018 ) and SURF1 ( Tiranti et al, 1999 ; Sonam et al, 2014 ; Li et al, 2018 )genes. Mutations in nuclear genes resulting in CI or CIV deficiencies ( Supplementary Table 1 ) account for a large percentage of the nuclear mutations associated with LS ( Koene et al, 2012 ; Gerards et al, 2016 ).…”

Metformin delays neurological symptom onset in a mouse model of neuronal complex I deficiency

“…Despite reports that metformin inhibits complex I activity, our findings did not show worsening a complex I defect nor increases in lactic acid, suggesting that metformin should be further evaluated for use in patients with mitochondrial encephalopathies. and R199W) has been associated with early-onset Leigh syndrome and severe reduction in CI levels (23,24). In homozygosity, the R199W mutation caused developmental delay, encephalopathy, myopathy, and lactic acidosis (22).…”