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Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy

Nature Genetics volume 21, pages 260–261 (1999)Cite this article

Complex I is a multi-subunit protein structure at the inner mitochondrial membrane that serves as a 'gateway' for electrons that are transferred from NADH to molecular oxygen through the respiratory chain1. The free energy of this transfer is the main driving force behind mitochondrial ATP production2. At least 35 complex I subunits are encoded by nuclear genes3. Of these, the 51-kD subunit (encoded by NDUFV1; MIM 161015) carries the NADH-binding site4; its high degree of conservation underlines its functional importance5. Previous work on the bovine 51-kD subunit enabled us to determine the human NDUFV1 sequence6,7. As in the bovine gene, consensus motifs for NADH-, FMN- and Fe-S-binding sites are present8.

Disturbances of mitochondrial energy metabolism occur with an estimated incidence of 1 in 10,000 live births and are often caused by isolated mitochondrial complex I (NADH:ubiquinone oxidoreductase) deficiency9. As mitochondrial DNA (mtDNA) mutations are rarely reported to be causative, the genetic defects are thought to be mainly of nuclear origin, especially if symptoms begin during infancy1. We detected mutations in NDUFV1 in 3 of 20 patients with isolated complex I deficiency.

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Figure 1: NDUFV1 mutations in patients with isolated complex I deficiency.
Figure 2: Alignment of NADH dehydrogenases of different species.

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Acknowledgements

We thank the patients and their families for participation; and A. Janssen and M. Bakker. The study was supported by the Deutsche Forschungsgemeinschaft (Schu 1187/1-1), the Parents' action group "Helft dem muskelkranken Kind" (Hamburg), the "Prinses Beatrix Fonds", the Stichting "Kinderen die wel willen maar niet kunnen" and the "Fonds Bevordering Wetenschapsbeoefening" from the Department of Pediatrics, University Hospital Nijmegen (to J.S. and L.v.d.H.).

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  1. Markus Schuelke

    Present address: Department of Neuropediatrics, Virchow-Charité University Hospital, Augustenburger Platz 1, D-13353, Berlin, Germany

Authors and Affiliations

  1. Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, University Hospital Nijmegen, Nijmegen, The Netherlands

    Markus Schuelke, Jan Smeitink, Jan Loeffen, Frans Trijbels & Lambert van den Heuvel

  2. Department of Human Genetics, Nijmegen Center for Mitochondrial Disorders, University Hospital Nijmegen, Nijmegen, The Netherlands

    Edwin Mariman

  3. Universitätsklinik für Kinder- und Jugendheilkunde, Universität Graz, Austria

    Barbara Plecko

  4. Department of Pediatrics, University of Vienna, Austria

    Sylvia Stöckler-Ipsiroglu

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Correspondence to Jan Smeitink.

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Schuelke, M., Smeitink, J., Mariman, E. et al. Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy. Nat Genet 21, 260–261 (1999). https://doi.org/10.1038/6772

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