Neurogenetics

, Volume 1, Issue 3, pp 197–204

Novel mutations of mitochondrial complex I in pathologically proven Parkinson disease

  • Siegfried Kösel
  • E. M. Grasbon-Frodl
  • Ulrike Mautsch
  • Rupert Egensperger
  • U. von Eitzen
  • Dimitrij Frishman
  • Sabine Hofmann
  • Klaus-Dieter Gerbitz
  • Parviz Mehraein
  • Manuel B. Graeber
Original article

DOI: 10.1007/s100480050029

Cite this article as:
Kösel, S., Grasbon-Frodl, E., Mautsch, U. et al. Neurogenetics (1998) 1: 197. doi:10.1007/s100480050029

ABSTRACT

Complete sequence analysis of all mitochondrial complex I genes was performed in 22 cases of neuropathologically confirmed idiopathic Parkinson disease (PD). DNA from the substantia nigra was used as a template for polymerase chain reaction-based genomic sequencing. Seven novel mutations causing the exchange of amino acids were detected in subunit genes ND1 (3992 C/T, 4024 A/G), ND4 (11253 T/C, 12084 C/T), ND5 (13711 G/A, 13768 T/C), and ND6 (14582 T/C). In addition, five known missense mutations affecting the ND1 (3335 T/C, 3338 T/C), ND2 (5460 G/A), ND3 (10398 A/G), and ND5 (13966 A/G) genes as well as three secondary LHON mutations (4216 T/C, 4917 A/G, 13708 G/A) were found in the PD group. Among the novel mutations, the 11253 T/C transition which changes a conserved isoleucine residue into threonine is most likely to be of functional relevance. Furthermore, 43 synonymous polymorphisms were detected in PD brains, including 20 novel sequence variants. Haplogroup analysis revealed that most unique missense mutations were found in PD cases belonging to the Dc haplogroup. Our data are in line with the view that PD is not a single disease entity but comprises a genetically heterogeneous group of disorders. The results of our study further suggest that 90% or more of all idiopathic PD cases are not due to sequence variation of mitochondrial complex I, but that mitochondrial mutations may play a pathogenic role in a subset of PD patients.

Key words Genetic heterogeneityMitochondrial haplogroupsNADH dehydrogenaseSusceptibility genes

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • Siegfried Kösel
    • 1
  • E. M. Grasbon-Frodl
    • 1
  • Ulrike Mautsch
    • 1
  • Rupert Egensperger
    • 2
  • U. von Eitzen
    • 1
  • Dimitrij Frishman
    • 3
  • Sabine Hofmann
    • 4
  • Klaus-Dieter Gerbitz
    • 4
  • Parviz Mehraein
    • 1
  • Manuel B. Graeber
    • 1
  1. 1.Molecular Neuropathology Laboratory, Institute of Neuropathology, Ludwig-Maximilians-University, D-80337 Munich, GermanyDE
  2. 2.Molecular Neuropathology Laboratory, Institute of Neuropathology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, GermanyDE
  3. 3.Institute for Protein Sequences, Max-Planck-Institute for Biochemistry, Am Klopferspitz 18a, D-82152 Martinsried, GermanyDE
  4. 4.Institutes of Clinical Chemistry and Diabetes Research, Academic Hospital Schwabing, Kölner Platz 1, D-80804 Munich, GermanyDE
  5. 5.Molecular Neuropathology Laboratory, Department of Neuromorphology, Max-Planck-Institute of Psychiatry, Am Klopferspitz 18a, D-82152 Martinsried, GermanyDE