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

被引：81

作者：

Latourelle, Jeanne C. ^{[1
]}

Sun, Mei ^{[2
]}

Lew, Mark F. ^{[3
]}

Suchowersky, Oksana ^{[4
,5
]}

Klein, Christine ^{[6
]}

Golbe, Lawrence I. ^{[7
]}

Mark, Margery H. ^{[7
]}

Growdon, John H. ^{[8
]}

Wooten, G. Frederick ^{[9
]}

Watts, Ray L. ^{[10
]}

Guttman, Mark ^{[11
]}

Racette, Brad A. ^{[12
]}

Perlmutter, Joel S. ^{[12
]}

Ahmed, Anwar ^{[13
]}

Shill, Holly A. ^{[14
]}

Singer, Carlos ^{[15
]}

Goldwurm, Stefano ^{[16
]}

Pezzoli, Gianni ^{[16
]}

Zini, Michela ^{[16
]}

Saint-Hilaire, Marie H. ^{[1
]}

Hendricks, Audrey E. ^{[1
,17
]}

Williamson, Sally ^{[1
]}

Nagle, Michael W. ^{[1
]}

Wilk, Jemma B. ^{[1
]}

Massood, Tiffany ^{[1
]}

Huskey, Karen W. ^{[1
]}

Laramie, Jason M. ^{[1
]}

DeStefano, Anita L. ^{[1
,17
]}

Baker, Kenneth B. ^{[18
,19
]}

Itin, Ilia ^{[18
,19
]}

Litvan, Irene ^{[20
]}

Nicholson, Garth ^{[21
]}

Corbett, Alastair ^{[21
]}

Nance, Martha ^{[22
]}

Drasby, Edward ^{[23
]}

Isaacson, Stuart ^{[24
]}

Burn, David J. ^{[25
]}

Chinnery, Patrick F. ^{[26
]}

Pramstaller, Peter P. ^{[27
]}

Al-hinti, Jomana ^{[28
]}

Moller, Anette T. ^{[29
]}

Ostergaard, Karen ^{[29
]}

Sherman, Scott J. ^{[30
]}

Roxburgh, Richard ^{[31
]}

Snow, Barry ^{[31
]}

Slevin, John T. ^{[32
]}

Cambi, Franca ^{[32
]}

Gusella, James F. ^{[2
]}

Myers, Richard H. ^{[1
]}

机构：

[1] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[2] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurogenet Unit,Ctr Human Genet Res, Boston, MA USA

[3] Univ So Calif, Dept Neurol, Los Angeles, CA USA

[4] Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada

[5] Univ Calgary, Dept Med Genet, Calgary, AB, Canada

[6] Med Univ Lubeck, Dept Neurol, D-23538 Lubeck, Germany

[7] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurol, New Brunswick, NJ 08903 USA

[8] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA

[9] Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA USA

[10] Univ Alabama, Dept Neurol, Birmingham, AL 35294 USA

[11] Univ Toronto, Dept Med, Toronto, ON, Canada

[12] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

[13] Barrow Neurol Inst, Phoenix, AZ 85013 USA

[14] Sun Hlth Res Inst, Sun City, AZ USA

[15] Univ Miami, Dept Neurol, Miami, FL USA

[16] Ist Clinici Perfezionamento, Parkinson Inst, Milan, Italy

[17] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02118 USA

[18] Cleveland Clin Fdn, Dept Neurol, Cleveland, OH 44195 USA

[19] Cleveland Clin Fdn, Dept Neurosci, Cleveland, OH 44195 USA

[20] Univ Louisville, Sch Med, Dept Neurol, Louisville, KY 40292 USA

[21] Univ Sydney, Dept Neurol, ANZAC Res Inst, Concord Hosp, Sydney, NSW 2006, Australia

[22] Struthers Parkinsons Ctr, Pk Nicollet Clin, Golden Valley, MN USA

[23] Port City Neurol, Scarborough, ME USA

[24] Parkinsons Dis & Movement Disorder Ctr Boca Raton, Boca Raton, FL USA

[25] Univ Newcastle, Inst Ageing & Hlth, Newcastle Upon Tyne, Tyne & Wear, England

[26] Univ Newcastle, Reg Neurosci Ctr, Newcastle Upon Tyne, Tyne & Wear, England

[27] Gen Reg Hosp Bolzano, Dept Neurol, Bolzano, Italy

[28] Univ Arkansas Med Sci, Dept Neurol, Little Rock, AR 72205 USA

[29] Aarhus Univ Hosp, Dept Neurol, DK-8000 Aarhus, Denmark

[30] Univ Arizona, Dept Neurol, Tucson, AZ USA

[31] Auckland City Hosp, Dept Neurol, Auckland, New Zealand

[32] Univ Kentucky, Coll Med, Dept Neurol, Lexington, KY USA

来源：

BMC MEDICINE | 2008年 / 6卷 / 1期

关键词：

D O I：

10.1186/1741-7015-6-32

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页数：7

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