The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study
Wooten, G. F.
AffiliationDepartment of Neurology, Boston University School of Medicine, Boston University, Boston, MA, USA
Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School Boston, MA, USA
Department of Neurology, University of Southern California, Los Angeles, CA, USA
Departments of Clinical Neurosciences and Medical Genetics, University of Calgary, Calgary, Alberta, Canada
Department of Neurology, Medical University of Lübeck, Lübeck, Germany
Department of Neurology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
Department of Neurology, Massachusetts General Hospital, Harvard Medical School Boston, MA, USA
Department of Neurology, University of Virginia Health System, Charlottesville, VA, USA
Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA
Department of Medicine, University of Toronto, Toronto, Canada
Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA
Barrow Neurological Institute, Phoenix, AZ, USA
Sun Health Research Institute, Sun City, AZ, USA
Department of Neurology, University of Miami, Miami, FL, USA
Parkinson Institute, Istituti Clinici di Perfezionamento, Milano, Italy
Department of Biostatistics, Boston University School of Medicine, Boston University, Boston, MA, USA
Departments of Neurology and Neuroscience, Cleveland Clinic Foundation, Cleveland, OH, USA
Department of Neurology, University of Louisville School of Medicine, Louisville, KY, USA
Neurology Department, University of Sydney ANZAC Research Institute, Concord Hospital, Sydney, Australia
Struthers Parkinson's Center, Park Nicollet Clinic, Golden Valley, MN, USA
Port City Neurology, Scarborough, ME, USA
Parkinson's Disease and Movement Disorder Center of Boca Raton, Boca Raton, FL, USA
Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK
Regional Neurosciences Centre, Newcastle University, Newcastle upon Tyne, UK
Department of Neurology, General Regional Hospital Bolzano, Bolzano, Italy
Department of Neurology, University of Arkansas for Medical Sciences, AR, USA
Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
Department of Neurology, University of Arizona, Tucson, AZ, USA
Department of Neurology, Auckland City Hospital, Auckland, New Zealand
Department of Neurology, University of Kentucky College of Medicine, Lexington, KY, USA
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CitationBMC Medicine 2008, 6:32 doi:10.1186/1741-7015-6-32
Rights© 2008 Latourelle et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).
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AbstractBACKGROUND:We report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD.METHODS:A sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample.RESULTS:Thirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families.CONCLUSION:Lifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.
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Except where otherwise noted, this item's license is described as © 2008 Latourelle et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).