Neurogenetics

, 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

Abstract

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.

Keywords

CADASIL mtDNA DNA sequence analysis Genetic variation NOTCH3 

References

  1. 1.
    Tournier-Lasserve E, Joutel A, Melki J et al (1993) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet 3:256–259PubMedCrossRefGoogle Scholar
  2. 2.
    Chabriat H, Vahedi K, Iba-Zizen MT et al (1995) Clinical spectrum of CADASIL: a study of 7 families. Lancet 346:934–939PubMedCrossRefGoogle Scholar
  3. 3.
    Dichgans M, Mayer M, Uttner I et al (1998) The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol 44:731–739PubMedCrossRefGoogle Scholar
  4. 4.
    Joutel A, Corpechot C, Ducros A et al (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383:707–710PubMedCrossRefGoogle Scholar
  5. 5.
    Dotti MT, De Stefano N, Bianchi S et al (2004) A novel Notch3 frameshift deletion and mitochondrial abnormalities in a patient with CADASIL. Arch Neurol 61:942–945PubMedCrossRefGoogle Scholar
  6. 6.
    Joutel A, Monet M, Domenga V, Riant F, Tournier-Lasserve E (2004) Pathogenic mutations associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy differently affect Jagged1 binding and Notch3 activity via the RBP/JK signaling pathway. Am J Hum Genet 74:338–347PubMedCrossRefGoogle Scholar
  7. 7.
    Okeda R, Arima K, Kawai M (2002) Arterial changes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in relation to pathogenesis of diffuse myelin loss of cerebral white matter: examination of cerebral medullary arteries by reconstruction of serial sections of an autopsy case. Stroke 33:2565–2569PubMedCrossRefGoogle Scholar
  8. 8.
    Uchino M, Hirano T, Uyama E, Hashimoto Y (2002) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and CADASIL-like disorders in Japan. Ann N Y Acad Sci 977:273–278PubMedCrossRefGoogle Scholar
  9. 9.
    Mazzei R, Conforti FL, Lanza PL et al (2004) A novel Notch3 gene mutation not involving a cysteine residue in an Italian family with CADASIL. Neurology 63:561–564PubMedGoogle Scholar
  10. 10.
    Finnilä S, Tuisku S, Herva R, Majamaa K (2001) A novel mitochondrial DNA mutation and a mutation in the Notch3 gene in a patient with myopathy and CADASIL. J Mol Med 79:641–647PubMedCrossRefGoogle Scholar
  11. 11.
    de la Peña P, Bornstein B, del Hoyo P et al (2001) Mitochondrial dysfunction associated with a mutation in the Notch3 gene in a CADASIL family. Neurology 57:1235–1238PubMedGoogle Scholar
  12. 12.
    Malandrini A, Albai F, Palmeri S et al (2002) Asymptomatic cores and paracrystalline mitochondrial inclusions in CADASIL. Neurology 59:617–620PubMedGoogle Scholar
  13. 13.
    DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348:2656–2668PubMedCrossRefGoogle Scholar
  14. 14.
    Sickmann A, Reinders J, Wagner Y et al (2003) The proteome of Saccharomyces cerevisiae mitochondria. Proc Natl Acad Sci USA 100:13207–13212PubMedCrossRefGoogle Scholar
  15. 15.
    Ohlmeier S, Kastaniotis AJ, Hiltunen JK, Bergmann U (2004) The yeast mitochondrial proteome, a study of fermentative and respiratory growth. J Biol Chem 6:3954–3979Google Scholar
  16. 16.
    Mykkänen K, Savontaus M-L, Juvonen V et al (2004) Detection of the founder effect in Finnish CADASIL families. Eur J Hum Genet 12:813–819PubMedCrossRefGoogle Scholar
  17. 17.
    Finnilä S, Lehtonen MS, Majamaa K (2001) Phylogenetic network for European mtDNA. Am J Hum Genet 68:1475–1484PubMedCrossRefGoogle Scholar
  18. 18.
    Finnilä S, Hassinen IE, Ala-Kokko L, Majamaa K (2000) Phylogenetic network of the mtDNA haplogroup U in Northern Finland based on sequence analysis of the complete coding region by conformation-sensitive gel electrophoresis. Am J Hum Genet 66:1017–1026PubMedCrossRefGoogle Scholar
  19. 19.
    Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N (1999) Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet 23:147PubMedCrossRefGoogle Scholar
  20. 20.
    Lehtonen M, Moilanen J, Majamaa K (2003) Increased variation in mtDNA in patients with familial sensorineural hearing impairment. Hum Genet 113:220–227PubMedCrossRefGoogle Scholar
  21. 21.
    Loogväli EL, Roostalu U, Malyarchuk BA et al (2004) Disuniting uniformity: a pied cladistic canvas of mtDNA haplogroup H in Eurasia. Mol Biol Evol 21:2012–2021CrossRefGoogle Scholar
  22. 22.
    Rost B (1996) PHD: predicting one-dimensional protein structure by profile-based neural networks. Methods Enzymol 266:525–539PubMedCrossRefGoogle Scholar
  23. 23.
    Berman HM, Westbrook J, Feng Z et al (2000) The protein data bank. Nucleic Acids Res 28:235–242PubMedCrossRefGoogle Scholar
  24. 24.
    Martz E (2002) Protein explorer: easy yet powerful macromolecular visualization. Trends Biochem Sci 27:107–109PubMedCrossRefGoogle Scholar
  25. 25.
    Tajima F (1983) Evolutionary relationship of DNA sequences in finite populations. Genetics 105:437–460PubMedGoogle Scholar
  26. 26.
    Watterson GA (1975) On the number of segregating sites in genetical models without recombination. Theor Popul Biol 7:256–276PubMedCrossRefGoogle Scholar
  27. 27.
    Fu YX, Li WH (1993) Statistical tests of neutrality of mutations. Genetics 133:693–709PubMedGoogle Scholar
  28. 28.
    Parsons TJ, Muniec DS, Sullivan K et al (1997) A high observed substitution rate in the human mitochondrial DNA control region. Nat Genet 15:363–368PubMedCrossRefGoogle Scholar
  29. 29.
    Cavelier L, Jazin E, Jalonen P, Gyllensten U (2000) MtDNA substitution rate and segregation of heteroplasmy in coding and noncoding regions. Hum Genet 107:45–50PubMedCrossRefGoogle Scholar
  30. 30.
    Rousset F, Raymond M (1995) Testing heterozygote excess and deficiency. Genetics 140:1413–1419PubMedGoogle Scholar
  31. 31.
    Schneider S, Roessli D, Excoffier L (2000) Arlequin ver. 2.000: a software for population genetics data analysis. Genetics and Biometry Laboratory, University of GenevaGoogle Scholar
  32. 32.
    Bandelt HJ, Lahermo P, Richards M, Macaulay V (2001) Detecting errors in mtDNA data by phylogenetic analysis. Int J Legal Med 115:64–69PubMedCrossRefGoogle Scholar
  33. 33.
    Schröder JM, Zuchner S, Dichgans M, Nagy Z, Molnar MJ (2005) Peripheral nerve and skeletal muscle involvement in CADASIL. Acta Neuropathol (Berl) 110:587–599CrossRefGoogle Scholar
  34. 34.
    Vilmi T, Moilanen JS, Finnilä S, Majamaa K (2005) Sequence variation in the tRNA genes of human mitochondrial DNA. J Mol Evol 60:587–597PubMedCrossRefGoogle Scholar
  35. 35.
    McFarland R, Elson JL, Taylor RW, Howell N, Turnbull DM (2004) Assigning pathogenicity to mitochondrial tRNA mutations: when “definitely maybe” is not good enough. Trends Genet 20:591–596PubMedCrossRefGoogle Scholar
  36. 36.
    Niemi A-K, Hervonen A, Hurme M, Karhunen PJ, Jylhä M, Majamaa K (2003) Mitochondrial DNA polymorphisms associated with longevity in a Finnish population. Hum Genet 112:29–33PubMedCrossRefGoogle Scholar
  37. 37.
    Moilanen JS, Finnilä S, Majamaa K (2003) Lineage-specific selection in human mtDNA: lack of polymorphisms in a segment of MTND5 gene in haplogroup J. Mol Biol Evol 20:2132–2142PubMedCrossRefGoogle Scholar
  38. 38.
    Howell N, Kubacka I, Halvorson S, Howell B, McCullough DA, Mackey D (1995) Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees. Genetics 140:285–302PubMedGoogle Scholar
  39. 39.
    Howell N, Kubacka I, Mackey DA (1996) How rapidly does the human mitochondrial genome evolve? Am J Hum Genet 59:501–509PubMedGoogle Scholar
  40. 40.
    Howell N, Bogolin Smejkal C, Mackey DA, Chinnery PF, Turnbull DM, Herrnstadt C (2003) The pedigree rate of sequence divergence in the human mitochondrial genome: there is a difference between phylogenetic and pedigree rates. Am J Hum Genet 72:659–670PubMedCrossRefGoogle Scholar
  41. 41.
    Sigurðardóttir S, Helgason A, Gulcher JR, Stefansson J, Donelly P (2000) The mutation rate in the human mtDNA control region. Am J Hum Genet 66:1599–1609CrossRefGoogle Scholar
  42. 42.
    Moilanen JS, Majamaa K (2003) Phylogenetic network and physicochemical properties of nonsynonymous mutations in the protein-coding genes of human mitochondrial DNA. Mol Biol Evol 20:1195–1210PubMedCrossRefGoogle Scholar
  43. 43.
    Kraytsberg Y, Schwartz M, Brown TA et al (2004) Recombination of human mitochondrial DNA. Science 304:981PubMedCrossRefGoogle Scholar
  44. 44.
    Sato A, Nakada K, Akimoto M et al (2005) Rare creation of recombinant mtDNA haplotypes in mammalian tissues. Proc Natl Acad Sci USA 102:6057–6062PubMedCrossRefGoogle Scholar
  45. 45.
    Zsurka G, Kraytsberg Y, Kudina T et al (2005) Recombination of mitochondrial DNA in skeletal muscle of individuals with multiple mitochondrial DNA heteroplasmy. Nat Genet 37:873–877PubMedCrossRefGoogle Scholar
  46. 46.
    Battersby B, Loredo-Osti J, Shoubridge E (2003) Nuclear genetic control of mitochondrial DNA segregation. Nat Genet 33:183–186PubMedCrossRefGoogle Scholar

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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