Impaired Complex I Assembly in a Leigh Syndrome Patient with a Novel Missense Mutation in the ND6 Gene

University of Oulu, Uleoborg, Northern Ostrobothnia, Finland
Annals of Neurology (Impact Factor: 9.98). 11/2003; 54(5):665-9. DOI: 10.1002/ana.10734
Source: PubMed


We describe a novel mutation in the ND6 gene (T14487C) in a patient with Leigh syndrome. Biochemical analyses indicated a low complex I activity in the patient's fibroblasts but normal values in muscle and liver. Cybrid clones showed a specific complex I defect that correlates with the mutant heteroplasmy levels. Additionally, we demonstrate an altered mobility and a decrease in the levels of fully assembled complex I in the patient's fibroblasts and cybrids, suggesting that the mutation has a profound effect on complex I assembly and/or stability.

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    • "Mimicking other mutations common to LHON also significantly altered the rates of ETC assembly (Pello et al., 2008). Another consequence of altered mtDNA sequence is the interdependency of the ETC Complexes for their stability within the mitochondrial membrane (Lamantea et al., 2002; Ugalde et al., 2003; Acin-Perez et al., 2004; Edgar et al., 2009). Collectively these studies point to the critical role of mtDNA fidelity has on the mitochondrial function within the myocardium. "
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    • "Lethal infantile mitochondrial disease Calvo et al. (2010) c.1158C>G Leukoencephalopathy Breningstall et al. (2008) c.1294G>C + c.989- 990del-2 LS Benit et al. (2001) c.86C>T NDUFV2 Encephalomyopathy NADH-dehydrogenase module Hinttala et al. (2005) IVS2 + 5 + 8delGTTA Hypertrophic Cardiomyopathy and Encephalopathy Bénit et al. (2003a,b), Pagniez-Mammeri et al. (2009) a All the listed mutations induce a CI disassembly except for c.1336G>A/NDUFS2 (Ngu et al., 2012). of subcomplexes in patient-derived cell cultures (Solano et al., 2003; Ugalde et al., 2003). Moreover, a partial CI disassembly has been described in cells harboring LS pathogenic mutations , namely m.10158T>C, m.10191T>C and m.10197G>A in MT-ND3 (Kirby et al., 2004a; McFarland et al., 2004). "
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