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

Jan O. Aasly, Carles Vilariño-Güell, Justus C. Dachsel, Philip J. Webber, Andrew B. West, Kristoffer Haugarvoll, Krisztina K. Johansen, Mathias Toft, John G. Nutt, Haydeh Payami, Jennifer M. Kachergus, Sarah J. Lincoln, Amela Felic, Christian Wider, Alexandra I. Soto-Ortolaza, Stephanie A. Cobb, Linda R. White, Owen A. Ross, Matthew J. Farrer

Research output: Contribution to journalArticle

77 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2156-2163
Number of pages8
JournalMovement Disorders
Volume25
Issue number13
DOIs
StatePublished - Oct 15 2010

Keywords

  • Genetic
  • Kinase
  • LRRK2
  • Parkinson's disease

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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    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., & Farrer, M. J. (2010). Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease. Movement Disorders, 25(13), 2156-2163. https://doi.org/10.1002/mds.23265