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A heteroplasmic mitochondrial complex I gene mutation in adult-onset dystonia

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Abstract.

Mitochondrial DNA (mtDNA) mutations can cause rare forms of dystonia, but the role of mtDNA mutations in other types of dystonia is not well understood. We now report identification by sequencing, restriction endonuclease analyses, and clonal analyses of a heteroplasmic missense A to G base pair substitution at nucleotide position 3796 (A3796G) in the gene encoding the ND1 subunit of mitochondrial complex I in a patient with adult-onset dystonia, spasticity, and core-type myopathy. The mutation converts a highly conserved threonine to an alanine. The same mutation subsequently was identified in 2 of 74 additional unrelated adult-onset dystonia patients. A muscle biopsy was obtained from 1 of these 2 subjects and this revealed abnormalities of electron transport chain (ETC) activities. The mutation was absent in 64 subjects with early onset dystonia, 82 normal controls, and 65 subjects with Parkinson's disease or multiple system atrophy. The A3796G mutation previously has been reported in 3 of 226 subjects from mitochondrial haplogroup H. Each of the 3 subjects in our study harboring the A3796G mutation was also from haplogroup H. However, a subgroup analysis of haplogroup H subjects from our study indicates that the A3796G mutation is significantly overrepresented among haplogroup H adult-onset dystonia subjects compared with haplogroup H controls (P<0.01). This difference remains significant even after excluding the index patient (P=0.04). These data suggest that, among haplogroup H subjects, the presence of the A3796G mutation increases the risk of developing adult-onset dystonia.

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Acknowledgements.

This study was supported by the Ann B. and Norman A. Bikalis Fund for Dystonia Research (D.K.S.), the Bachmann-Strauss Dystonia Foundation (M.F.B.), and by the Medical Research Service, Department of Veteran Affairs (M.E.C.). We thank Dr. C.L. Hoppel for assistance with electron transport chain analyses.

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Authors and Affiliations

  1. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, USA

    David K. Simon, Daniel Tarsy & Donald R. Johns

  2. Harvard Medical School, Boston, USA

    David K. Simon, Daniel Tarsy & Donald R. Johns

  3. Department of Neurology, Massachusetts General Hospital, Massachusetts, USA

    Xandra O. Breakefield

  4. Department of Neurology, Baylor College of Medicine, Houston, Texas, USA

    Joseph Jankovic

  5. Mount Sinai School of Medicine, California, USA

    Mitchell F. Brin

  6. Allergan, California, USA

    Mitchell F. Brin

  7. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

    John Provias

  8. Beth Israel Medical Center, New York, USA

    Susan B. Bressman

  9. Department of Neurology, Brigham and Women's Hospital, USA

    Michael E. Charness

  10. VA Boston Healthcare System, Boston, USA

    Michael E. Charness

  11. Department of Ophthalmology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA

    Donald R. Johns

  12. Neurology and Rehabilitation, McMaster University, Hamilton, Ontario, Canada

    Mark A. Tarnopolsky

  13. Department of Neurology, Beth Israel Deaconess Medical Center, Room 856, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115, USA

    David K. Simon

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  1. David K. Simon
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  2. Jennifer Friedman
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Correspondence to David K. Simon.

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Simon, D.K., Friedman, J., Breakefield, X.O. et al. A heteroplasmic mitochondrial complex I gene mutation in adult-onset dystonia. Neurogenetics 4, 199–205 (2003). https://doi.org/10.1007/s10048-003-0150-3

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  • DOI: https://doi.org/10.1007/s10048-003-0150-3

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