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Open AccessResearch article

The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study

Jeanne C Latourelle1 email, Mei Sun2 email, Mark F Lew3 email, Oksana Suchowersky4 email, Christine Klein5 email, Lawrence I Golbe6 email, Margery H Mark6 email, John H Growdon7 email, G Frederick Wooten8 email, Ray L Watts9 email, Mark Guttman10 email, Brad A Racette11 email, Joel S Perlmutter11 email, Anwar Ahmed12 email, Holly A Shill13 email, Carlos Singer14 email, Stefano Goldwurm15 email, Gianni Pezzoli15 email, Michela Zini15 email, Marie H Saint-Hilaire1 email, Audrey E Hendricks1,16 email, Sally Williamson1 email, Michael W Nagle1 email, Jemma B Wilk1 email, Tiffany Massood1 email, Karen W Huskey1 email, Jason M Laramie1 email, Anita L DeStefano1,16 email, Kenneth B Baker17 email, Ilia Itin17 email, Irene Litvan18 email, Garth Nicholson19 email, Alastair Corbett19 email, Martha Nance20 email, Edward Drasby21 email, Stuart Isaacson22 email, David J Burn23 email, Patrick F Chinnery24 email, Peter P Pramstaller25 email, Jomana Al-hinti26 email, Anette T Moller27 email, Karen Ostergaard27 email, Scott J Sherman28 email, Richard Roxburgh29 email, Barry Snow29 email, John T Slevin30 email, Franca Cambi30 email, James F Gusella2 email and Richard H Myers1 email

1Department of Neurology, Boston University School of Medicine, Boston University, Boston, MA, USA

2Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School Boston, MA, USA

3Department of Neurology, University of Southern California, Los Angeles, CA, USA

4Departments of Clinical Neurosciences and Medical Genetics, University of Calgary, Calgary, Alberta, Canada

5Department of Neurology, Medical University of Lübeck, Lübeck, Germany

6Department of Neurology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ, USA

7Department of Neurology, Massachusetts General Hospital, Harvard Medical School Boston, MA, USA

8Department of Neurology, University of Virginia Health System, Charlottesville, VA, USA

9Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA

10Department of Medicine, University of Toronto, Toronto, Canada

11Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA

12Barrow Neurological Institute, Phoenix, AZ, USA

13Sun Health Research Institute, Sun City, AZ, USA

14Department of Neurology, University of Miami, Miami, FL, USA

15Parkinson Institute, Istituti Clinici di Perfezionamento, Milano, Italy

16Department of Biostatistics, Boston University School of Medicine, Boston University, Boston, MA, USA

17Departments of Neurology and Neuroscience, Cleveland Clinic Foundation, Cleveland, OH, USA

18Department of Neurology, University of Louisville School of Medicine, Louisville, KY, USA

19Neurology Department, University of Sydney ANZAC Research Institute, Concord Hospital, Sydney, Australia

20Struthers Parkinson's Center, Park Nicollet Clinic, Golden Valley, MN, USA

21Port City Neurology, Scarborough, ME, USA

22Parkinson's Disease and Movement Disorder Center of Boca Raton, Boca Raton, FL, USA

23Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK

24Regional Neurosciences Centre, Newcastle University, Newcastle upon Tyne, UK

25Department of Neurology, General Regional Hospital Bolzano, Bolzano, Italy

26Department of Neurology, University of Arkansas for Medical Sciences, AR, USA

27Department of Neurology, Aarhus University Hospital, Aarhus, Denmark

28Department of Neurology, University of Arizona, Tucson, AZ, USA

29Department of Neurology, Auckland City Hospital, Auckland, New Zealand

30Department of Neurology, University of Kentucky College of Medicine, Lexington, KY, USA

author email corresponding author email

BMC Medicine 2008, 6:32doi:10.1186/1741-7015-6-32

Published: 5 November 2008

Abstract

Background

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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