Neurogenetics

, Volume 4, Issue 4, pp 199–205

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

  • David K. Simon
  • Jennifer Friedman
  • Xandra O. Breakefield
  • Joseph Jankovic
  • Mitchell F. Brin
  • John Provias
  • Susan B. Bressman
  • Michael E. Charness
  • Daniel Tarsy
  • Donald R. Johns
  • Mark A. Tarnopolsky
Original Article

DOI: 10.1007/s10048-003-0150-3

Cite this article as:
Simon, D.K., Friedman, J., Breakefield, X.O. et al. Neurogenetics (2003) 4: 199. doi:10.1007/s10048-003-0150-3

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.

Keywords

GeneticsMitochondriaHaplogroupND1

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • David K. Simon
    • 1
    • 2
    • 13
  • Jennifer Friedman
  • Xandra O. Breakefield
    • 3
  • Joseph Jankovic
    • 4
  • Mitchell F. Brin
    • 5
    • 6
  • John Provias
    • 7
  • Susan B. Bressman
    • 8
  • Michael E. Charness
    • 9
    • 10
  • Daniel Tarsy
    • 1
    • 2
  • Donald R. Johns
    • 1
    • 2
    • 11
  • Mark A. Tarnopolsky
    • 12
  1. 1.Department of NeurologyBeth Israel Deaconess Medical CenterBostonUSA
  2. 2.Harvard Medical SchoolBostonUSA
  3. 3.Department of NeurologyMassachusetts General HospitalUSA
  4. 4.Department of NeurologyBaylor College of MedicineHoustonUSA
  5. 5.Mount Sinai School of MedicineUSA
  6. 6.AllerganUSA
  7. 7.Department of Pathology and Molecular MedicineMcMaster UniversityHamiltonCanada
  8. 8.Beth Israel Medical CenterNew YorkUSA
  9. 9.Department of NeurologyBrigham and Women's HospitalUSA
  10. 10.VA Boston Healthcare SystemBostonUSA
  11. 11.Department of OphthalmologyBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUSA
  12. 12.Neurology and RehabilitationMcMaster UniversityHamiltonCanada
  13. 13.Department of NeurologyBeth Israel Deaconess Medical CenterBostonUSA