Research Article

Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease†

  1. Jan O. Aasly MD, PhD1,2,
  2. Carles Vilariño-Güell PhD3,
  3. Justus C. Dachsel PhD3,
  4. Philip J. Webber PhD4,
  5. Andrew B. West PhD4,
  6. Kristoffer Haugarvoll MD, PhD1,3,
  7. Krisztina K. Johansen MD2,
  8. Mathias Toft MD, PhD2,3,
  9. John G. Nutt MD5,
  10. Haydeh Payami PhD6,
  11. Jennifer M. Kachergus BS3,
  12. Sarah J. Lincoln MSc3,
  13. Amela Felic MSc2,3,
  14. Christian Wider MD3,
  15. Alexandra I. Soto-Ortolaza BS3,
  16. Stephanie A. Cobb BA3,
  17. Linda R. White PhD1,2,
  18. Owen A. Ross PhD3,
  19. Matthew J. Farrer PhD3,*

Article first published online: 28 JUL 2010

DOI: 10.1002/mds.23265

Issue

Movement Disorders

Movement Disorders

Volume 25, Issue 13, pages 2156–2163, 15 October 2010

Additional Information

How to Cite

Aasly, J. O., Vilariño-Güell, C., Dachsel, J. C., Webber, P. J., West, A. B., Haugarvoll, K., Johansen, K. K., Toft, M., Nutt, J. G., Payami, H., Kachergus, J. M., Lincoln, S. J., Felic, A., Wider, C., Soto-Ortolaza, A. I., Cobb, S. A., White, L. R., Ross, O. A. and Farrer, M. J. (2010), Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease. Mov. Disord., 25: 2156–2163. doi: 10.1002/mds.23265

Author Information

  1. 1

    Department of Neurology, St. Olav's Hospital, Trondheim, Norway

  2. 2

    Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway

  3. 3

    Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA

  4. 4

    Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA

  5. 5

    Department of Neurology, Oregon Health and Science University, Parkinson Disease Research, Education and Clinical Center, Portland VA, Oregon, USA

  6. 6

    Division of Genetic Disorders, New York State Department of Health, Wadsworth Center, Albany, New York, USA

*Department of Neuroscience, Morris K. Udall Parkinson's Disease Research Center of Excellence, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224

  1. †

    Potential conflict of interest: Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 NS40256). MJF and OAR are supported by the Michael J. Fox Foundation. JOA is supported by the Research Council of Norway. Additional support for ABW was from an NIH R00NS058111 award, for HP from an NIH R01NS36960, and for PJW an American Parkinson's Disease Association fellowship. CVG, JCD, KH, KKJ, MT, JGN, JMK, SJL, AF, CW, AIS, SAC, LRW have no financial disclosures to make.

Publication History

  1. Issue published online: 28 JUL 2010
  2. Article first published online: 28 JUL 2010
  3. Manuscript Accepted: 27 APR 2010
  4. Manuscript Revised: 28 FEB 2010
  5. Manuscript Received: 13 NOV 2009

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Keywords:

  • LRRK2;
  • Parkinson's disease;
  • genetic;
  • kinase

Abstract

Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) that co-segregates with disease manifestation (LOD = 3.15, θ = 0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1 of 692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP-binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2-linked parkinsonism. © 2010 Movement Disorder Society

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