Copyright © 2005 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 76, Issue 4, 672-680, 1 April 2005
doi:10.1086/429256
Report
Identification of a Novel LRRK2 Mutation Linked to Autosomal Dominant Parkinsonism: Evidence of a Common Founder across European Populations
Jennifer Kachergus1, *, Ignacio F. Mata1, *, Mary Hulihan1, Julie P. Taylor1, Sarah Lincoln1, Jan Aasly3, J. Mark Gibson5, Owen A. Ross1, 6, Timothy Lynch7, 8, Joseph Wiley7, 8, Haydeh Payami9, John Nutt10, Demetrius M. Maraganore11, Krzysztof Czyzewski12, Maria Styczynska13, Zbigniew K. Wszolek2, Matthew J. Farrer1, 
, 
and Mathias Toft1, 4
1 Department of Neuroscience, Jacksonville, FL
2 Department of Neurology, Mayo Clinic, Jacksonville, FL
3 Department of Neurology, St. Olav’s Hospital, Trondheim, Norway
4 Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway
5 Department of Neurology, Royal Victoria Hospital, Belfast
6 School of Biology and Biochemistry, Queens University of Belfast, Belfast
7 Department of Neurology, Mater Misericordiae University Hospital, Dublin
8 Conway Institute of Biomolecular and Biomedical Research, Dublin
9 Wadsworth Center, New York State Department of Health, Albany
10 Department of Neurology, Oregon Health Sciences University, Portland
11 Department of Neurology, Mayo Clinic, Rochester, MN
12 Department of Neurodegenerative Disorders, Medical Research Centre of the Polish Academy of Sciences, Warsaw
13 Department of Neurology, Ministerstwo Spraw Wewnetrznych i Administracji Hospital, Warsaw
Address for correspondence and reprints: Dr. Matthew J. Farrer, Department of Neuroscience, Mayo Clinic, Birdsall Building, 4500 San Pablo Road, Jacksonville, FL 32224* These two authors contributed equally to this work.
Abstract
Autosomal dominant parkinsonism has been attributed to pathogenic amino acid substitutions in leucine-rich repeat kinase 2 (LRRK2). By sequencing multiplex families consistent with a PARK8 assignment, we identified a novel heterozygous LRRK2 mutation. A referral sample of 248 affected probands from families with autosomal dominant parkinsonism was subsequently assessed; 7 (2.8%) were found to carry a heterozygous LRRK2 6055G→A transition (G2019S). These seven patients originate from the United States, Norway, Ireland, and Poland. In samples of patients with idiopathic Parkinson disease (PD) from the same populations, further screening identified six more patients with LRRK2 G2019S; no mutations were found in matched control individuals. Subsequently, 42 family members of the 13 probands were examined; 22 have an LRRK2 G2019S substitution, 7 with a diagnosis of PD. Of note, all patients share an ancestral haplotype indicative of a common founder, and, within families, LRRK2 G2019S segregates with disease (multipoint LOD score 2.41). Penetrance is age dependent, increasing from 17% at age 50 years to 85% at age 70 years. In summary, our study demonstrates that LRRK2 G2019S accounts for parkinsonism in several families within Europe and North America. Our work highlights the fact that a proportion of clinically typical, late-onset PD cases have a genetic basis.
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