A catalytic defect in mitochondrial respiratory chain complex I due to a mutation in NDUFS2 in a patient with Leigh syndrome.
In this study, we investigated the pathogenicity of a homozygous Asp446Asn mutation in the NDUFS2 gene of a patient with a mitochondrial respiratory chain complex I deficiency. The clinical, biochemical, and genetic features of the NDUFS2 patient were compared with those of 4 patients with previously identified NDUFS2 mutations. All 5 patients presented with Leigh syndrome. In addition, 3 out of 5 showed hypertrophic cardiomyopathy. Complex I amounts in the patient carrying the Asp446Asn mutation were normal, while the complex I activity was strongly reduced, showing that the NDUFS2 mutation affects complex I enzymatic function. By contrast, the 4 other NDUFS2 patients showed both a reduced amount and activity of complex I. The enzymatic defect in fibroblasts of the patient carrying the Asp446Asn mutation was rescued by transduction of wild type NDUFS2. A 3-D model of the catalytic core of complex I showed that the mutated amino acid residue resides near the coenzyme Q binding pocket. However, the K(M) of complex I for coenzyme Q analogs of the Asp446Asn mutated complex I was similar to the K(M) observed in other complex I defects and in controls. We propose that the mutation interferes with the reduction of coenzyme Q or with the coupling of coenzyme Q reduction with the conformational changes involved in proton pumping of complex I.
Nijmegen Center for Mitochondrial Disorders, Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Lock Hock
LH
Ngu
Leo G
LG
Nijtmans
Felix
F
Distelmaier
Hanka
H
Venselaar
Sjenet E
SE
van Emst-de Vries
Mariël A M
MA
van den Brand
Berendien J M
BJ
Stoltenborg
Liesbeth T
LT
Wintjes
Peter H
PH
Willems
Lambertus P
LP
van den Heuvel
Jan A
JA
Smeitink
Richard J T
RJ
Rodenburg
D000595:Amino Acid Sequence; D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism; D002384:Catalysis; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007888:Leigh Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000235:genetics / Q000502:physiology; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000201:enzymology / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D011487:Protein Conformation; D014161:Transduction, Genetic / Q000379:methods; D014451:Ubiquinone / Q000378:metabolism
D014451:Ubiquinone; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C496411:NDUFS2 protein, human