, Volume 7, Issue 3, pp 185–194 | Cite as

Mitochondrial DNA sequence variation and mutation rate in patients with CADASIL

  • Johanna Annunen-Rasila
  • Saara Finnilä
  • Kati Mykkänen
  • Jukka S. Moilanen
  • Johanna Veijola
  • Minna Pöyhönen
  • Matti Viitanen
  • Hannu Kalimo
  • Kari Majamaa
Original Article


Mutations in the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is clinically characterised by recurrent ischemic strokes, migraine with aura, psychiatric symptoms, cognitive decline and dementia. We have previously described a patient with CADASIL caused by a R133C mutation in the NOTCH3 gene and with a concomitant myopathy caused by a 5650G>A mutation in the MTTA gene in mitochondrial DNA (mtDNA). We assume that the co-occurrence of the two mutations is not coincidental and that mutations in the NOTCH3 gene may predispose the mtDNA to mutations. We therefore examined the nucleotide variation in the mtDNA coding region sequences in 20 CADASIL pedigrees with 77 affected patients by conformation-sensitive gel electrophoresis and sequencing. The sequence variation in mtDNA was then compared with that among 192 healthy Finns. A total of 180 mtDNA coding region sequence differences were found relative to the revised Cambridge reference sequence, including five novel synonymous substitutions, two novel nonsynonymous substitutions and one novel tRNA substitution. We found that maternal relatives in two pedigrees differed from each other in their mtDNA. Furthermore, the average number of pairwise differences in sequences from the 41 unrelated maternal lineages with CADASIL was higher than that expected among haplogroup-matched controls. The numbers of polymorphic sites and polymorphisms that were present in only one sequence were also higher among the CADASIL sequences than among the control sequences. Our results show that mtDNA sequence variation is increased within CADASIL pedigrees. These findings suggest a relationship between NOTCH3 and mtDNA.


CADASIL mtDNA DNA sequence analysis Genetic variation NOTCH3 



The expert technical assistance of Ms. Irma Vuoti and Ms. Pirjo Keränen is acknowledged. This study was supported by grants from the Council for the Health Sciences of the Academy of Finland (project numbers 79843, 107174 and 203953 to K.M. and 107490 and 108953 to J.S.M.) and by the Sigrid Juselius Foundation and the National Graduate School of Clinical Investigation. The study complies with the current laws in Finland.


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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Johanna Annunen-Rasila
    • 1
    • 2
  • Saara Finnilä
    • 1
    • 2
  • Kati Mykkänen
    • 3
  • Jukka S. Moilanen
    • 1
    • 4
    • 5
  • Johanna Veijola
    • 1
    • 2
  • Minna Pöyhönen
    • 6
    • 7
  • Matti Viitanen
    • 8
    • 9
  • Hannu Kalimo
    • 10
    • 11
    • 12
  • Kari Majamaa
    • 1
    • 2
    • 13
  1. 1.Department of NeurologyUniversity of OuluOuluFinland
  2. 2.Clinical Research CenterOulu University HospitalOuluFinland
  3. 3.Department of Medical GeneticsUniversity of TurkuTurkuFinland
  4. 4.Department of Clinical GeneticsOulu University HospitalOuluFinland
  5. 5.Institute of Medical TechnologyUniversity of TampereTampereFinland
  6. 6.Department of Medical GeneticsUniversity of HelsinkiHelsinkiFinland
  7. 7.Department of Clinical GeneticsHelsinki University Central HospitalHelsinkiFinland
  8. 8.Department of Geriatric MedicineUniversity of TurkuTurkuFinland
  9. 9.Division of Clinical GeriatricsKarolinska Institute, Karolinska University HospitalStockholmSweden
  10. 10.Department of PathologyUniversity of HelsinkiHelsinkiFinland
  11. 11.Department of PathologyHelsinki University Central HospitalHelsinkiFinland
  12. 12.Department of PathologyUniversity of TurkuTurkuFinland
  13. 13.Department of NeurologyUniversity of TurkuTurkuFinland

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