Genetic factors influencing age at onset in LRRK2-linked Parkinson disease
Genetic factors influencing age at onset in LRRK2-linked Parkinson disease
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DOI：
10.1016/j.parkreldis.2008.10.008
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发表时间：
2009-08-01
影响因子：
4.1
通讯作者：
Fuchs, Julia
中科院分区：
文献类型：
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作者：
Golub, Yulia;Berg, Daniela;Fuchs, Julia
富亮氨酸重复激酶2 （LRRK2）相关帕金森病（PD）患者临床表现为典型的特发性PD。然而，lrrk2相关PD表现出多形性神经病理学和发病年龄（AAO）的高度变异性，这表明除突变本身外，环境和/或遗传因素影响了疾病的病程。我们研究了来自19个受影响家庭的44名患者的AAO受遗传因素的调节，包括基因编码α -突触核蛋白（SNCA）和tau （MAPT）的含突变域和PD相关多态性。利用有限数量的可用LRRK2突变载体，我们提供的证据表明，与ROC （Ras/GTPase of complex proteins）结构域的突变相比，LRRK2激酶结构域的突变显著降低了AAO。此外，在LRRK2突变个体中，MAPT的多态性变异显示与AAO有显著关联。我们的研究结果有待于在更多LRRK2突变携带者的未来研究中得到复制，但表明突变影响蛋白结构域和突变外源性遗传因素与AAO有关，并表明这些因素可能有助于解释LRRK2相关PD中观察到的表型异质性。(C) 2008 Elsevier Ltd版权所有。
Patients with Leucine-rich repeat kinase 2 (LRRK2) linked Parkinson's disease (PD) clinically present with typical idiopathic PD. However, LRRK2-linked PD displays a pleomorphic neuropathology and high variability in age at disease onset (AAO) which suggests that environmental and/or genetic factors other than the mutation itself influence the Course of the disease. We investigated the modulation of AAO by genetic factors including the mutation-containing domain and PD associated polymorphisms in the gene coding alpha-synuclein (SNCA) and tau (MAPT) in 44 patients from 19 affected families. Using this limited number of available LRRK2 mutation carriers, we provide evidence that mutations in the kinase domain of Lrrk2 significantly decrease AAO compared to mutations in the ROC (Ras/GTPase of complex proteins) domain. Furthermore, polymorphic variations in MAPT show a significant association with AAO in individuals with LRRK2 mutations. Our results await replication in future Studies with a larger number of LRRK2 mutation carriers, but indicate an association of mutation-affected protein domain and mutation-extrinsic genetic factors with AAO and suggest that these factors could Contribute to explain the phenotypic heterogeneity observed in LRRK2-linked PD. (C) 2008 Elsevier Ltd. All rights reserved.