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Neurogenetics

, Volume 7, Issue 1, pp 27–30 | Cite as

The S18Y polymorphism in the UCHL1 gene is a genetic modifier in Huntington’s disease

  • Silke Metzger
  • Peter Bauer
  • Juergen Tomiuk
  • Franco Laccone
  • Stefano Didonato
  • Cinzia Gellera
  • Paola Soliveri
  • Herwig W. Lange
  • Helga Weirich-Schwaiger
  • Gregor K. Wenning
  • Bela Melegh
  • Victoria Havasi
  • Lazlo Balikó
  • Stefan Wieczorek
  • Larissa Arning
  • Jacek Zaremba
  • Anna Sulek
  • Dorota Hoffman-Zacharska
  • A. Nazli Basak
  • Nagehan Ersoy
  • Jana Zidovska
  • Vera Kebrdlova
  • Massimo Pandolfo
  • Pascale Ribaï
  • Ludovit Kadasi
  • Marta Kvasnicova
  • Bernhard H. F. Weber
  • Friedmar Kreuz
  • Matthias Dose
  • Manfred Stuhrmann
  • Olaf RiessEmail author
Original Article

Abstract

An expanded polyglutamine stretch in the huntingtin protein has been identified as the pathogenetic cause of Huntington's disease (HD). Although the length of the expanded polyglutamine repeat is inversely correlated with the age-at-onset, additional genetic factors are thought to modify the variance in the disease onset. As linkage analysis suggested a modifier locus on chromosome 4p, we investigated the functional relevance of S18Y polymorphism of the ubiquitin carboxy-terminal hydrolase L1 in 946 Caucasian HD patients. In this group, the allelic variation on locus S18Y is responsible for 1.1% of the variance in the HD age-at-onset, and the rare Y allele is associated with younger-aged cases.

Keywords

Huntington's disease Age-at-onset Genetic modifiers Ubiquitin carboxy-terminal hydrolase L1 (UCHL1S18Y polymorphism 

Notes

Acknowledgements

This study was supported by the GeNeMove Network for hereditary movement disorders financed by BMBF. The Polish part of the study performed in the Department of Genetics, Institute of Psychiatry and Neurology was supported by the State Committee for Scientific Research PBZ-KBN-042/P05/2001. A. Nazli Basak's research is sponsered by Bogazici University Research Funds and by Suna-Inan Kirac Foundation. Special thanks to K. Dietz, Department of Medical Biometry, University of Tübingen, Germany for statistical advice. Experiments comply with the current laws in Germany.

References

  1. 1.
    Haigh B, Huq M, Hayden MR. Huntington disease. In: GeneReviews (online). Available at:http://www.geneclinics.org/servlet/access?id=8888891&key=28UhX7Ix0tj-L&gry=&fcn=y&fw=uoW9&filename=/profiles/huntington/index.html. Cited May 25, 2004
  2. 2.
    Stine OC, Pleasant N, Franz ML, Abbott MH, Folstein SE, Ross CA (1993) Correlation between the onset age of Huntington's disease and length of the trinucleotide repeat in IT-15. Hum Mol Genet 2:1547–1549PubMedCrossRefGoogle Scholar
  3. 3.
    Brinkman RR, Mezei MM, Theilmann J, Almqvist E, Hayden MR (1997) The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. Am J Hum Genet 60:1202–1210PubMedGoogle Scholar
  4. 4.
    Nazé P, Vuillaume I, Destée A, Pasquier F, Sablonnière B (2002) Mutation analysis and association studies of the ubiquitin carboxy-terminal hydrolase L1 gene in Huntington's disease. Neurosci Lett 328:1–4CrossRefPubMedGoogle Scholar
  5. 5.
    Maraganore DM, Lesnick TG, Elbaz A, Chartier-Harlin MC, Gasser T, Krüger R, Hattori N, Mellick GD, Quattrone A, Satoh J, Toda T, Wang J, Ioannidis JP, de Andrade M, Rocca WA, the UCHL1 Global Genetics Consortium (2004) UCHL1 is a Parkinson's disease susceptibility gene. Ann Neurol 55:512–521CrossRefPubMedGoogle Scholar
  6. 6.
    Maraganore DM, Farrer MJ, Hardy JA, Lincoln SJ, McDonnell SK, Rocca WA (1999) Case-control study of the ubiquitin carboxy-terminal hydrolase L1 gene in Parkinson's disease. Neurology 53:1858–1860PubMedGoogle Scholar
  7. 7.
    Wintermeyer P, Krüger R, Kuhn W, Müller T, Woitalla D, Berg D, Becker G, Leroy E, Polymeropoulos M, Berger K, Przuntek H, Schöls L, Epplen JT, Riess O (2000) Mutation analysis and association studies of the UCHL1 gene in German Parkinson's disease patients. Neuroreport 14:2079–2082CrossRefGoogle Scholar
  8. 8.
    Li J-L, Hayden MR, Almqvist EW, Brinkman RR, Durr A, Dodé C, Morrison PJ, Sochowersky O, Ross CA, Margolis RL, Rosenblatt A, Gómez-Tortosa E, Cabrero DM, Novelletto A, Frontali M, Nance M, Trent RJA, McCusker E, Jones R, Paulsen JS, Harrison M, Zanko A, Abramson RA, Russ AL, Knowlton B, Djoussé L, Mysore JS, Tariot S, Gusella MF, Wheeler VC, Atwood LD, Cupples LA, Saint-Hilaire M, Cha J-HJ, Hersch SM, Koroshetz WJ, Gusella JF, MacDonald ME, Myers RH (2003) A genome scan for modifiers of age at onset in Huntington disease: the HD MAPS study. Am J Hum Genet 73:682–687CrossRefPubMedGoogle Scholar
  9. 9.
    Djoussé L, Knowlton B, Hayden MR, Almqvist EW, Brinkman RR, Ross CA, Margolis RL, Rosenblatt A, Durr A, Dode C, Morrison PJ, Novelletto A, Frontali M, Trent RJA, McCusker E, Gómez-Tortosa E, Cabrero DM, Jones R, Zanko A, Nance M, Abramson RA, Suchowersky O, Paulsen JS, Harrison MB, Yang Q, Cupples LA, Mysore J, Gusella JF, MacDonald ME, Myers RH (2004) Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16. Neurogenetics 5:109–114CrossRefPubMedGoogle Scholar
  10. 10.
    Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT Jr (2002) The UCH-L1 gene encodes two opposing enzymatic activities that affect á-synuclein degradation and Parkinson's disease susceptibility. Cell 111:209–218CrossRefPubMedGoogle Scholar
  11. 11.
    Spillantini MG, Goedert M (2000) The á-synucleinopathies: Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Ann NY Acad Sci 920:16–27PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Silke Metzger
    • 1
  • Peter Bauer
    • 1
  • Juergen Tomiuk
    • 1
  • Franco Laccone
    • 2
  • Stefano Didonato
    • 3
  • Cinzia Gellera
    • 3
  • Paola Soliveri
    • 3
  • Herwig W. Lange
    • 4
  • Helga Weirich-Schwaiger
    • 5
  • Gregor K. Wenning
    • 6
  • Bela Melegh
    • 7
  • Victoria Havasi
    • 7
  • Lazlo Balikó
    • 7
    • 8
  • Stefan Wieczorek
    • 9
  • Larissa Arning
    • 9
  • Jacek Zaremba
    • 10
  • Anna Sulek
    • 10
  • Dorota Hoffman-Zacharska
    • 10
  • A. Nazli Basak
    • 11
  • Nagehan Ersoy
    • 11
  • Jana Zidovska
    • 12
  • Vera Kebrdlova
    • 12
  • Massimo Pandolfo
    • 13
  • Pascale Ribaï
    • 13
  • Ludovit Kadasi
    • 14
  • Marta Kvasnicova
    • 15
  • Bernhard H. F. Weber
    • 16
  • Friedmar Kreuz
    • 17
  • Matthias Dose
    • 18
  • Manfred Stuhrmann
    • 19
  • Olaf Riess
    • 1
    Email author
  1. 1.Department of Medical GeneticsUniversity of TübingenTübingenGermany
  2. 2.Institute of Human GeneticsUniversity of GöttingenGöttingenGermany
  3. 3.National Institute of Neurology Carlo BestaMilanoItaly
  4. 4.air-RehazentrumDüsseldorfGermany
  5. 5.Department of Medical Genetics, Molecular and Clinical PharmacologyMedical University of InnsbruckInnsbruckAustria
  6. 6.Department of NeurologyMedical University of InnsbruckInnsbruckAustria
  7. 7.Department of Medical Genetics and Child DevelopmentUniversity of PécsPécsHungary
  8. 8.Department of NeurologyCsolnoky Ferenc County HospitalVeszpremHungary
  9. 9.Department of Human GeneticsUniversity of BochumBochumGermany
  10. 10.Department of GeneticsInstitute of Psychiatry and NeurologyWarsawPoland
  11. 11.Department of Molecular Biology and GeneticsBogazici University Bebek IstanbulIstanbulTurkey
  12. 12.Institute of Biology and Medical Genetics1st Medical Faculty of Charles University and Teaching HospitalPragueCzech Republic
  13. 13.Department of NeurologyErasme HospitalBrusselsBelgium
  14. 14.Institute of Molecular Physiology and GeneticsSlovak Academy of SciencesBratislavaSlovakia
  15. 15.Department of Clinical GeneticsBanska BystricaSlovakia
  16. 16.Institute of Human GeneticsUniversity of RegensburgRegensburgGermany
  17. 17.Klinikum für PsychiatrieKlinikum ChemnitzChemnitzGermany
  18. 18.BKH-TaufkirchenTaufkirchenGermany
  19. 19.Institute of Human GeneticsUniversity of HannoverHannoverGermany

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