Large-Scale Deletion and Point Mutations of the Nuclear NDUFV1 and NDUFS1 Genes in Mitochondrial Complex I Deficiency

Abstract

Reduced nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase (complex I) is the largest complex of the mitochondrial respiratory chain and complex I deficiency accounts for approximately 30% cases of respiratory-chain deficiency in humans. Only seven mitochondrial DNA genes, but >35 nuclear genes encode complex I subunits. In an attempt to elucidate the molecular bases of complex I deficiency, we studied the six most-conserved complex I nuclear genes (NDUFV1, NDUFS8, NDUFS7, NDUFS1, NDUFA8, and NDUFB6) in a series of 36 patients with isolated complex I deficiency by denaturing high-performance liquid chromatography and by direct sequencing of the corresponding cDNA from cultured skin fibroblasts. In 3/36 patients, we identified, for the first time, five point mutations (del222, D252G, M707V, R241W, and R557X) and one large-scale deletion in the NDUFS1 gene. In addition, we found six novel NDUFV1 mutations (Y204C, C206G, E214K, IVS 8+41, A432P, and del nt 989-990) in three other patients. The six unrelated patients presented with hypotonia, ataxia, psychomotor retardation, or Leigh syndrome. These results suggest that screening for complex I nuclear gene mutations is of particular interest in patients with complex I deficiency, even when normal respiratory-chain-enzyme activities in cultured fibroblasts are observed.

Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage

“…Anti-NDUFS1 was chosen here instead of anti-NDUFB8 because it produced better results (stronger signal) in immunofluorescent staining. NDUFS1 is a core subunit considered essential for complex I function [5]. Sections were deparaffinised in Histoclear and rehydrated in graded ethanol.…”

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

“…The clinical presentation of CI disorders can range from the neonatal period to adult onset, with symptoms including cardiomyopathy, liver disease and neurological disorders [55][56][57][58]. The most common clinical presentations include Leigh Syndrome, a multiple organ disorder with degeneration of the muscular, peripheral and central nervous systems [55,[59][60][61], fatal infantile lactic acidosis and other infancy/early childhood onset neuropathological disorders [44].…”

Whole Exome Sequencing Identifies the Genetic Basis of Late-Onset Leigh Syndrome in a Patient with MRI but Little Biochemical Evidence of a Mitochondrial Disorder

“…Clinical hallmark signs of Leigh syndrome are brainstem dysfunction, symmetrical spongiform lesions in the brain, dystonia, spasticity, movement disorders, visual disturbances, nystagmus, ophthalmoparesis, ptosis, cerebellar ataxia, seizures, scoliosis, bulbar dysfunction and peripheral neuropathy that lead to biochemical signs of mitochondrial dysfunction including lactate elevation in different body fluids, Krebs cycle intermediates in urine and dysfunction of the mitochondrial respiratory chain in different tissues (Lake et al 2015). Mutations in the nuclear-encoded mitochondrial CI gene NDUFV1 [MIM 161015] have previously been reported by Schuelke et al (1999) in a patient with seizures, followed by a report by Benit et al (2001) in a patient with the same mutations as reported here and a clinical phenotype of Leigh syndrome and CI deficiency (Benit et al 2001;Schuelke et al 1999). This gene encodes a 51 kDa subunit of the flavoprotein portion of CI, containing NADH, flavin mononucleotide (FMN) and Fe-S-binding sites (Mimaki et al 2012).…”