A catalytic defect in mitochondrial respiratory chain complex I due to a mutation in NDUFS2 in a patient with Leigh syndrome |
| |
Authors: | Lock Hock Ngu,Leo G. Nijtmans,Felix DistelmaierHanka Venselaar,Sjenet E. van Emst-de VriesMarië l A.M. van den Brand,Berendien J.M. StoltenborgLiesbeth T. Wintjes,Peter H. WillemsLambertus P. van den Heuvel,Jan A. SmeitinkRichard J.T. Rodenburg |
| |
Affiliation: | a Nijmegen Center for Mitochondrial Disorders, Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlandsb Centre for Molecular and Biomolecular Informatics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlandsc Department of Biochemistry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlandsd Laboratory for Genetic, Endocrine, and Metabolic Disorders, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlandse Division of Clinical Genetics, Department of Genetics, Kuala Lumpur Hospital, Kuala Lumpur, Malaysiaf Department of General Pediatrics, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany |
| |
Abstract: | 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 KM of complex I for coenzyme Q analogs of the Asp446Asn mutated complex I was similar to the KM 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. |
| |
Keywords: | BN-PAGE, blue native-PAGE CoQ, coenzyme Q CS, citrate synthase OXPHOS, oxidative phosphorylation |
本文献已被 ScienceDirect 等数据库收录! |
|