LRRK2 gene in Parkinson disease -: Mutation analysis and case control association study
LRRK2 gene in Parkinson disease -: Mutation analysis and case control association study
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DOI：
10.1212/01.wnl.0000167552.79769.b3
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发表时间：
2005-09-13
期刊：
影响因子：
9.9
通讯作者：
Rogaeva, E
中科院分区：
文献类型：
--
作者：
Paisán-Ruíz, C;Lang, AE;Rogaeva, E
背景：除了与早发性帕金森病(PD)相关的四个基因(SNCA、Parkin、DJ-1和PINK1)外，最近还在常染色体显性遗传的晚发性PD家系中发现了富含亮氨酸的重复蛋白激酶2基因(LRRK2)的突变。目的：对帕金森病显性遗传家系的先证者进行LRRK2基因突变分析，并进行病例对照关联研究，以验证常见编码变异可能与帕金森病易感性增加有关的假说。方法：对23例先证者的全部51个LRRK2编码外显子进行测序，并对180例神经学正常受试者进行突变频率分析。在关联性研究中，作者对250名正常对照组和121名帕金森病患者(主要是加拿大裔白人患者)的4个编码LRRK2基因多态进行了基因分型，其中84%的患者发病年龄在50岁之前，42%的患者有阳性家族史。结果：作者鉴定出3例LRRK2杂合性突变先证者：其中2例存在已知的G2019S突变，1例先证者存在新的I1371V突变。一个大家系的突变分析显示G2019S与帕金森病完全分离。然而，在等位基因或基因水平上，PD与这四个多态中的任何一个都没有关联(p>；0.17)。此外，在帕金森病组中，作者没有检测到任何基因或APOE基因对发病年龄的影响(p>；0.20)。结论：研究结果支持LRRK2基因突变导致帕金森病的先前假设。本文报告的家系中的疾病表现出与典型帕金森病无法区分的表型。这三个家系都表现出非常不同的发病年龄，这不是APOE基因类型所能解释的。LRRK2基因中常见的编码变异既不构成强烈的帕金森病危险因素，也不会改变发病年龄；然而，适度风险影响的可能性仍有待在大数据集中评估。
Background: In addition to the four well-confirmed genes linked to early-onset Parkinson disease (PD) (SNCA, PARKIN, DJ-1, and PINK1), mutations in the leucine-rich repeat kinase 2 gene(LRRK2) have recently been identified in families with autosomal dominant late-onset PD. Objective: To perform mutation analysis of LRRK2 in probands of families showing dominant inheritance of PD and to conduct a case control association study to test the hypothesis that common coding variations might be associated with increased susceptibility to PD. Methods: All 51 LRRK2 coding exons were sequenced in 23 probands and the mutation frequencies were evaluated in 180 neurologically normal control subjects. For the association study the authors genotyped four coding LRRK2 polymorphisms in 250 normal control subjects and 121 patients with PD ( predominantly white patients of Canadian origin), 84% of whom had age at onset before 50 years and 42% had a positive family history. Results: The authors identified three probands with heterozygous LRRK2 mutations: two of them have the known G2019S substitution and one proband has a novel I1371V substitution. Mutation analysis of a large family demonstrated complete segregation of the G2019S with PD. However, there was no association between PD and any of the four polymorphisms at the allelic or genotypic levels (p > 0.17). Furthermore, the authors did not detect a modifying effect for any genotype or of APOE genotypes upon the age at onset in the PD group (p > 0.20). Conclusions: The results support the prior suggestion that LRRK2 mutations cause PD. The disease in the families reported here presents a phenotype indistinguishable from typical PD. All three families demonstrate a very variable age at onset that is not explained by APOE genotypes. The common coding variations in the LRRK2 gene neither constitute strong PD risk factors nor modify the age at onset; however, the possibility of a modest risk effect remains to be assessed in large datasets.