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Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease |
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| Authors: | Jan O. Aasly MD PhD Carles Vilariño‐Güell PhD Justus C. Dachsel PhD Philip J. Webber PhD Andrew B. West PhD Kristoffer Haugarvoll MD PhD Krisztina K. Johansen MD Mathias Toft MD PhD John G. Nutt MD Haydeh Payami PhD Jennifer M. Kachergus BS Sarah J. Lincoln MSc Amela Felic MSc Christian Wider MD Alexandra I. Soto‐Ortolaza BS Stephanie A. Cobb BA Linda R. White PhD Owen A. Ross PhD Matthew J. Farrer PhD |
| Affiliation: | 1. Department of Neurology, St. Olav's Hospital, Trondheim, Norway;2. Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway;3. Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA;4. Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA;5. Department of Neurology, Oregon Health and Science University, Parkinson Disease Research, Education and Clinical Center, Portland VA, Oregon, USA;6. Division of Genetic Disorders, New York State Department of Health, Wadsworth Center, Albany, New York, USA |
| 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 |
| Keywords: | LRRK2 Parkinson's disease genetic kinase |