The LRRK2 G2019S mutation in Ashkenazi Jews with Parkinson disease -: Is there a gender effect?
The LRRK2 G2019S mutation in Ashkenazi Jews with Parkinson disease -: Is there a gender effect?
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DOI：
10.1212/01.wnl.0000277637.33328.d8
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发表时间：
2007-10-16
期刊：
影响因子：
9.9
通讯作者：
Giladi, N.
中科院分区：
文献类型：
--
作者：
Orr-Urtreger, A.;Shifrin, C.;Giladi, N.
背景：富含亮氨酸的重复蛋白激酶2(LRRK2)基因突变是迄今为止发现的帕金森病(PD)最常见的遗传决定因素，并与家族性和散发性帕金森病有关。LRRK2外显子41的G2019S突变与亚洲、欧洲、北美和北非人群中不同频率的疾病有关，在德系犹太人中尤为普遍。方法：我们评估了LRRK2 G2019S、I2012T、I2020T和R1441G/C/H突变在我们的犹太以色列PD患者队列中的出现情况，并利用6个跨越全基因的微卫星标记确定了76名G2019S携带者和50名非携带者德裔患者的LRRK2单倍型。结果：仅在我们的帕金森病患者中发现G2019S突变，在德裔患者中为14.8%，在非德裔患者中为2.7%26%和10.6%的德裔家族性病例和明显的散发性病例。在德系和非德系系对照样本中，携带者频率分别为2.4%和0.4%。除两名外，在所有非德系克肯纳兹人和半德系克尼人携带者以及所有被测试的完全德系克肯纳兹人携带者中都检测到一种共同的单倍型。在G2019S突变携带者中，女性和有帕金森病阳性家族史的患者比例明显偏高。携带者和非携带者的发病年龄相似。结论：LRRK2 G2019S突变在以色列家族性和散发性帕金森病(PD)的病因中起着重要作用，性别影响其在患者中的频率。尽管检测有症状的患者可能有助于建立帕金森病的诊断，但在更准确地评估这种突变的外显性和年龄相关风险并提供特定的疾病预防或修改干预措施之前，筛查无症状个体的价值仍然值得怀疑。
Background: Mutations in the leucine-rich repeat kinase 2(LRRK2) gene are the most common genetic determinant of Parkinson disease (PD) identified to date, and have been implicated in both familial and sporadic forms of the disease. The G2019S change in LRRK2 exon 41 has been associated with disease at varying frequencies in Asian, European, North American, and North African populations, and is particularly prevalent among Ashkenazi Jews.Methods: We assessed the occurrence of the LRRK2 G2019S, I2012T, I2020T, and R1441G/C/H mutations in our cohort of Jewish Israeli patients with PD, and determined the LRRK2 haplotypes in 76 G2019S-carriers detected and in 50 noncarrier Ashkenazi patients, using six microsatellite markers that span the entire gene.Results: Only the G2019S mutation was identified among our patients with PD, 14.8% in the Ashkenazi and 2.7% in the non-Ashkenazi patients, and in 26% and 10.6% of the Ashkenazi familial and apparently sporadic cases. The carrier frequencies in the Ashkenazi and non-Ashkenazi control samples were 2.4% and 0.4%. A common shared haplotype was detected in all non-Ashkenazi and half-Ashkenazi carriers and in all full-Ashkenazi carriers tested, except two. Women and patients with a positive family history of PD were significantly over-represented among the G2019S mutation carriers. Age at disease onset was similar in carriers and noncarriers.Conclusions: Our data suggest that the LRRK2 G2019S mutation plays an important role in the causality of familial and sporadic Parkinson disease (PD) in Israel and that gender affects its frequency among patients. Although testing symptomatic patients may help establish the diagnosis of PD, the value of screening asymptomatic individuals remains questionable until the penetrance and age-dependent risk of this mutation are more accurately assessed, and specific disease prevention or modifying interventions become available.