Mutated ND2 impairs mitochondrial complex I assembly and leads to Leigh syndrome.
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.
Ugalde
Cristina
C
Nijmegen Center for Mitochondrial Disorders, Department of Pediatrics, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, 6500 HB Nijmegen, The Netherlands.
Hinttala
Reetta
R
Timal
Sharita
S
Smeets
Roel
R
Rodenburg
Richard J T
RJ
Uusimaa
Johanna
J
van Heuvel
Lambert P
LP
Nijtmans
Leo G J
LG
Majamaa
Kari
K
Smeitink
Jan A M
JA
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
D024101:Mitochondrial Proteins; D009245:NADH Dehydrogenase; C521326:NADH dehydrogenase subunit 2, human; D042967:Electron Transport Complex I