Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome

Abstract

BackgroundLeigh syndrome is an early onset, progressive, neurodegenerative disorder with developmental and motor skills regression. Characteristic magnetic resonance imaging abnormalities consist of focal bilateral lesions in the basal ganglia and/or the brainstem. The main cause is a deficiency in oxidative phosphorylation due to mutations in an mtDNA or nuclear oxidative phosphorylation gene.Methods and resultsA consanguineous Moroccan family with Leigh syndrome comprise 11 children, three of which are affected. Marker analysis revealed a homozygous region of 11.5 Mb on chromosome 20, containing 111 genes. Eight possible mitochondrial candidate genes were sequenced. Patients were homozygous for an unclassified variant (p.P193L) in the cardiolipin synthase gene (CRLS1). As this variant was present in 20% of a Moroccan control population and enzyme activity was only reduced to 50%, this could not explain the rare clinical phenotype in our family. Patients were also homozygous for an amino acid substitution (p.L159F) in C20orf7, a new complex I assembly factor. Parents were heterozygous and unaffected sibs heterozygous or homozygous wild type. The mutation affects the predicted S-adenosylmethionine (SAM) dependent methyltransferase domain of C20orf7, possibly involved in methylation of NDUFB3 during the assembly process. Blue native gel electrophoresis showed an altered complex I assembly with only 30–40% of mature complex I present in patients and 70–90% in carriers.ConclusionsA new cause of Leigh syndrome can be a defect in early complex I assembly due to C20orf7 mutations.

MidA is a putative methyltransferase that is required for mitochondrial complex I function

“…CI is formed by a large number of subunits (up to 45 subunits in humans). The assembly and stability of such a large multiprotein complex requires specific chaperone and assembly factors, six of which have been implicated in human CI deficiency, including NDUFAF1-NDUFAF4 Ogilvie et al, 2005;Saada et al, 2009;Vogel et al, 2005), C8ORF38 and C20ORF7 (Gerards et al, 2009;Sugiana et al, 2008). Others such as Ecsit (Vogel et al, 2007), AIF (Vahsen et al, 2004) and IndI (Bych et al, 2008) are required for CI assembly, but have not yet been implicated in human disease.…”

“…The functional similarities between Dictyostelium MidA and its human homologue strongly suggest that both proteins are orthologous proteins that contain a methyltransferase domain and required for mitochondrial CI function. Another putative methyltransferase has recently been described to function in CI assembly or stability (Gerards et al, 2009;Sugiana et al, 2008), highlighting the potentially important but poorly understood role of methylation in CI function.…”

TIMMDC1/C3orf1 Functions as a Membrane-Embedded Mitochondrial Complex I Assembly Factor through Association with the MCIA Complex

“…The early assembly factor C20orf7 promotes incorporation of the membrane arm MT-ND1 subunit into the membrane (23,36), which then joins with a soluble arm subcomplex containing NDUFS2, NDUFS3, NDUFS7, NDUFS8, and NDUFA9 (37) with the assistance of the NDUFAF3-NDUFAF4 assembly complex to produce an ϳ0.4-MDa complex (38) (Fig. 6D).…”

A Mutation in the Flavin Adenine Dinucleotide-Dependent Oxidoreductase FOXRED1 Results in Cell-Type-Specific Assembly Defects in Oxidative Phosphorylation Complexes I and II

“…The assembly pathway of complex I initiates with the formation of two independent subcomplexes, one membrane module containing the mitochondrially encoded subunit ND1 and the assembly factor NDUFAF5 (7,9,30,32) and another containing the soluble proteins NDUFS2 and NDUFS3 and assembly factors NUBPL, NDUFAF3, NDUFAF4, NDUFAF6, and NDUFAF7 (7,30,31,33). Next, subunits NDUFS7 and NDUFS8, and probably NDUFA9, join the soluble module, forming a 200-kDa subcomplex.…”