Mutations for Gaucher Disease Confer High Susceptibility to Parkinson Disease
Mutations for Gaucher Disease Confer High Susceptibility to Parkinson Disease
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DOI：
10.1001/archneurol.2009.72
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发表时间：
2009-05-01
影响因子：
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通讯作者：
Tsuji, Shoji
中科院分区：
文献类型：
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作者：
Mitsui, Jun;Mizuta, Ikuko;Tsuji, Shoji
背景资料：GBA是戈谢病的致病基因，其致病变异频率的增加被认为与帕金森病（PD）有关。目的：对GBA进行全面的重新测序，以鉴定所有序列变异，并调查这些变异与PD的关联。设计：病例对照研究。设置：多中心大学研究。参与者：534例PD患者，34个家族中有多例PD患者，以及544名对照组受试者。主要结果测量：疾病状态和GBA变异。结果：534例PD患者和544名对照组的GBA综合再测序显示27种序列变异：11种与戈谢病相关的致病性变体，11种与戈谢病无关的非同义变体和5种同义变体。50例PD患者（9.4%）在11种致病性变异中有1种处于杂合状态，而对照组仅2例（0.37%）存在此类变异（比值比，28.0）。在致病性变异中，R120W和L444P/RecNciI是高度流行的，并且每个都显示出与PD的显著关联。此外，在13例PD患者中发现了其他罕见的致病性变异，而在对照组中未发现，进一步证实了这些罕见变异在PD易感性中的作用。携带致病性变异的PD患者明显比不携带它们的患者年轻。此外，一致性的PD状态和致病性变异观察到8个多重家庭PD.Conclusion：杂合子致病性变异GBA赋予高风险的散发性PD，即使是家族聚集性，并与发病年龄显着提前。
Background: Increased frequency of pathogenic variants in GBA, the causative gene for Gaucher disease, has been suggested to be associated with Parkinson disease (PD).Objectives: To conduct comprehensive resequencing of GBA to identify all sequence variants and to investigate the association of these variants with PD.Design: Case-control study.Setting: Multicenter university-based study.Participants: Five hundred thirty-four patients with PD, 34 families in which multiple patients with PD are present, and 544 control subjects.Main Outcome Measures: Disease status and GBA variations.Results: Comprehensive resequencing of GBA in 534 patients with PD and 544 controls revealed 27 sequence variants: 11 pathogenic variants associated with Gaucher disease, 11 nonsynonymous variants not associated with Gaucher disease, and 5 synonymous variants. Fifty patients with PD (9.4%) had 1 of the 11 pathogenic variants in the heterozygous state, whereas only 2 controls (0.37%) had such variants (odds ratio, 28.0). Among the pathogenic variants, R120W and L444P/RecNciI were highly prevalent, and each showed a significant association with PD. Furthermore, other rare pathogenic variants were found in 13 patients with PD but not in the controls, further confirming the role of these rare variants in the susceptibility to PD. Patients with PD carrying pathogenic variants were significantly younger than those not carrying them. In addition, concordance of PD states and pathogenic variants was observed in 8 multiplex families with PD.Conclusion: Heterozygous pathogenic variants in GBA confer a high risk for sporadic PD, even for familial clustering, and are associated with significantly earlier age at onset of disease.