Open Access Research article

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

Jeanne C Latourelle1*, Mei Sun2, Mark F Lew3, Oksana Suchowersky4, Christine Klein5, Lawrence I Golbe6, Margery H Mark6, John H Growdon7, G Frederick Wooten8, Ray L Watts9, Mark Guttman10, Brad A Racette11, Joel S Perlmutter11, Anwar Ahmed12, Holly A Shill13, Carlos Singer14, Stefano Goldwurm15, Gianni Pezzoli15, Michela Zini15, Marie H Saint-Hilaire1, Audrey E Hendricks116, Sally Williamson1, Michael W Nagle1, Jemma B Wilk1, Tiffany Massood1, Karen W Huskey1, Jason M Laramie1, Anita L DeStefano116, Kenneth B Baker17, Ilia Itin17, Irene Litvan18, Garth Nicholson19, Alastair Corbett19, Martha Nance20, Edward Drasby21, Stuart Isaacson22, David J Burn23, Patrick F Chinnery24, Peter P Pramstaller25, Jomana Al-hinti26, Anette T Moller27, Karen Ostergaard27, Scott J Sherman28, Richard Roxburgh29, Barry Snow29, John T Slevin30, Franca Cambi30, James F Gusella2 and Richard H Myers1

Author Affiliations

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

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

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

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

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

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

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

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

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

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

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

12 Barrow Neurological Institute, Phoenix, AZ, USA

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

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

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

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

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

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

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

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

21 Port City Neurology, Scarborough, ME, USA

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

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

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

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

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

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

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

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

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

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BMC Medicine 2008, 6:32  doi: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.