The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study.
The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study.
复制标题
DOI：
10.1186/1741-7015-6-32
复制
发表时间：
2008-11-05
期刊：
影响因子：
9.3
通讯作者：
Myers, Richard H.
中科院分区：
文献类型：
--
作者：
Latourelle, Jeanne C.;Sun, Mei;Lew, Mark F.;Suchowersky, Oksana;Klein, Christine;Golbe, Lawrence I.;Mark, Margery H.;Growdon, John H.;Wooten, G. Frederick;Watts, Ray L.;Guttman, Mark;Racette, Brad A.;Perlmutter, Joel S.;Ahmed, Anwar;Shill, Holly A.;Singer, Carlos;Goldwurm, Stefano;Pezzoli, Gianni;Zini, Michela;Saint-Hilaire, Marie H.;Hendricks, Audrey E.;Williamson, Sally;Nagle, Michael W.;Wilk, Jemma B.;Massood, Tiffany;Huskey, Karen W.;Laramie, Jason M.;DeStefano, Anita L.;Baker, Kenneth B.;Itin, Ilia;Litvan, Irene;Nicholson, Garth;Corbett, Alastair;Nance, Martha;Drasby, Edward;Isaacson, Stuart;Burn, David J.;Chinnery, Patrick F.;Pramstaller, Peter P.;Al-hinti, Jomana;Moller, Anette T.;Ostergaard, Karen;Sherman, Scott J.;Roxburgh, Richard;Snow, Barry;Slevin, John T.;Cambi, Franca;Gusella, James F.;Myers, Richard H.
我们报告了在一个大样本的家族性帕金森病（PD）中，对与富亮氨酸重复序列激酶2（LRRK2）相关的帕金森病（PD）的年龄依赖性发病率估计。最常见的LRRK2突变Gly2019Ser（G2019S）与大约5%至6%的家族性PD病例和1%至2%的特发性病例相关，使其成为PD最常见的已知遗传原因。对LRRK2突变的突变率的研究产生了广泛的估计，可能是由于研究设计和招募的差异，特别是家族性PD与散发性PD样本之间的差异。一个样本，包括903个受影响的和58个未受影响的成员从509个家庭确定有两个或两个以上的PD受影响的成员，126个随机确定的PD患者和197个对照组，筛选五种不同的LRRK2突变。考虑到家族样本中LRRK2携带者外显率增加的固有偏倚，估计了LRRK2携带者家族的外显率。在509个多发性PD家系中，有31个（6.1%）发现有58个LRRK2突变携带者（6.4%）。31个家系中有29个有G2019S突变，2个有R1441C突变。在PD病例的对照组或未受影响的亲属中未发现突变。9名受PD影响的G2019S携带者亲属本身并不携带LRRK2突变。在90至94岁的最大观察年龄范围内，G2019 S家族的无偏估计PD率为67%，而在非LRRK2相关PD家族中观察到的基线PD风险为17%。在多重PD家族的未确定亲属中估计的LRRK2的终生突变率大于在零星确定的LRRK2病例的研究中报道的，这表明遗传易感性因素可能会改变LRRK2突变的终生突变率。此外，在LRRK2家族中存在9种PD表型，表明这些易感因素也可能增加非LRRK2相关PD的风险。男性和女性的PD发病率没有差异，这表明影响LRRK2携带者PD发病率的因素与增加男性PD发病率的因素无关。
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. 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. 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. 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.
登录
查看更多内容
影响因子：
9.9
作者：
Bower, JH;Maraganore, DM;Rocca, WA
通讯作者：
Rocca, WA
影响因子：
16.2
作者：
Paisán-Ruíz, C;Jain, S;Singleton, AB
通讯作者：
Singleton, AB
影响因子：
9.9
作者：
Orr-Urtreger, A.;Shifrin, C.;Giladi, N.
通讯作者：
Giladi, N.
影响因子：
11.2
作者：
Lesage, S;Ibanez, P;Brice, A
通讯作者：
Brice, A
影响因子：
11.2
作者：
Funayama, M;Hasegawa, K;Obata, F
通讯作者：
Obata, F