title: Mutated ND2 impairs mitochondrial complex I assembly and leads to Leigh syndrome.
abstract: We describe a novel mitochondrial ND2 mutation (T4681C) in a patient presenting with Leigh Syndrome. Biochemical analyses revealed a low isolated complex I activity in patient's fibroblasts, blood and skeletal muscle. Mutant transmitochondrial cybrid clones retained the specific complex I defect, demonstrating the mitochondrial genetic origin of the disease. The mutation leads to a L71P substitution at an evolutionary conserved amino acid stretch. By two-dimensional blue native electrophoresis (2D-BN-SDS-PAGE), decreased complex I levels were observed together with an accumulation of specific assembly intermediates, suggesting that the mutation disturbs the complex I assembly pathway.
authors.affiliation: Nijmegen Center for Mitochondrial Disorders, Department of Pediatrics, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, 6500 HB Nijmegen, The Netherlands.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ugalde
authors.forename: Reetta
authors.initials: R
authors.lastname: Hinttala
authors.forename: Sharita
authors.initials: S
authors.lastname: Timal
authors.forename: Roel
authors.initials: R
authors.lastname: Smeets
authors.forename: Richard J T
authors.initials: RJ
authors.lastname: Rodenburg
authors.forename: Johanna
authors.initials: J
authors.lastname: Uusimaa
authors.forename: Lambert P
authors.initials: LP
authors.lastname: van Heuvel
authors.forename: Leo G J
authors.initials: LG
authors.lastname: Nijtmans
authors.forename: Kari
authors.initials: K
authors.lastname: Majamaa
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007888:Leigh Disease / Q000201:enzymology* / Q000209:etiology / Q000235:genetics*; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009245:NADH Dehydrogenase / Q000235:genetics* / Q000502:physiology
chemical_list: D024101:Mitochondrial Proteins; D009245:NADH Dehydrogenase; C521326:NADH dehydrogenase subunit 2, human; D042967:Electron Transport Complex I