Generalized dystonia in a patient with a novel mutation in the GLUD1 gene
Generalized dystonia in a patient with a novel mutation in the GLUD1 gene
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DOI：
10.1002/mds.25081
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发表时间：
2012-08
影响因子：
8.6
通讯作者：
R. Miyamoto;Satoshi Goto;Wataru Sako;A. Miyashiro;Isabelle Kim;Fabienne Escande;Masafumi Harada;R. Morigaki;K. Asanuma;Y. Mizobuchi;Shinji Nagahiro;Y. Izumi;Ryuji Kaji
中科院分区：
文献类型：
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作者：
R. Miyamoto;Satoshi Goto;Wataru Sako;A. Miyashiro;Isabelle Kim;Fabienne Escande;Masafumi Harada;R. Morigaki;K. Asanuma;Y. Mizobuchi;Shinji Nagahiro;Y. Izumi;Ryuji Kaji
神经炎症可能与大多数（如果不是全部）神经退行性疾病的发病机制有关。 2 个免疫系统基因（HLA-DRB5、BST1）的多态性与帕金森病 (PD) 密切相关 (http://www.pdgene.org)。 α-突触核蛋白 (a-Syn) 激活小胶质细胞。通过 a-Syn 介导小胶质细胞激活的受体尚不清楚。诸如核苷酸结合寡聚化结构域 2 (NOD2) 之类的模式识别受体是很好的候选者。我们在之前描述的 3 个大型德国病例对照样本中使用 TaqMan 基因分型分析了 NOD2 基因中的 3 个单核苷酸多态性 (SNP)（R702W [rs2066844]、G908R [rs2066845] 和 3020insC [rs5743293]）（支持表 1）。该研究得到了当地伦理委员会的批准，并获得了所有参与者的书面知情同意书。使用PLINK进行统计分析。所有交叉表数据均使用费舍尔精确统计进行评估。所有 3 个 SNP 的检出率 > 98%，并且处于 Hardy-Weinberg 平衡 (P > .01)。功效计算表明，由于次要等位基因频率较低，需要 1755 名患者和 1450 名对照的大样本量才能可靠地检测 1.5-2.0 范围内的比值比（支持图 1）。我们没有在主导模型或等位基因模型下的组合样本（表 1）或 3 个子样本（结果未显示）中发现任何关联的证据。所有 3 个 SNP 组合的关联统计也显示患者和对照之间没有显着差异（表 1，支持表 2）。 NOD2 属于 PRR 家族，不仅识别病原体相关分子模式 (PAMP)，还识别内源性危险相关分子模式 (DAMP)。在阿尔茨海默病中，NOD2 和 TLR2（Toll 样受体 2）受体协同调节参与小胶质细胞识别淀粉样蛋白 β 1-42 (ab1-42) 的受体。 PD 和阿尔茨海默氏病具有许多共同的发病特征，包括神经炎症。 a-突触核蛋白和 ab1-42 均通过寡聚中间体形成纤维状蛋白聚集体。低聚中间体具有共同的结构特征。这些发现使我们假设 NOD2 也可能参与与 PD 相关的神经炎症。 SNP 选择取决于 (1) 先前的研究显示与 PD 相关，(2) 这些 SNP 占克罗恩病所有变异等位基因的 80% 以上的发现，以及 (3) 这些 SNP 对 NOD2 具有功能影响的先验知识。这 3 个 SNP 仅捕获 NOD2 基因中常见遗传变异的一小部分。然而，对 SNP rs2111234、rs805734、rs11647841、rs2066843、rs10521209、rs5743289、rs207675、rs574329 和 rs3135499 的分析确实涵盖了大型 GWAS 样本中整个 NOD2 基因的常见变异。 PD，在等位基因、显性或隐性模型中也没有产生任何显着的疾病关联（所有 P > .1；参考文献 7 和个人交流 T. Gasser）。我们的研究结果表明，NOD2 的遗传变异不太可能在德国患者的 PD 中发挥主要作用，但并不排除 NOD2 在 PD 发病机制中的功能作用。
Neuroinflammation might be involved in the pathogenesis of most if not all neurodegenerative disorders. Polymorphisms in 2 immune system genes (HLA-DRB5, BST1) are firmly associated with Parkinson’s disease (PD) (http:// www.pdgene.org). Alpha-synuclein (a-Syn) activates microglia. The receptors mediating microglial activation by a-Syn are unknown. Pattern recognition receptors like nucleotidebinding oligomerization domain containing 2 (NOD2) are good candidates. We analyzed 3 single-nucleotide-polymorphisms (SNPs) in the NOD2 gene (R702W [rs2066844], G908R [rs2066845], and 3020insC [rs5743293]) using TaqMan genotyping in 3 large German case–control samples that have been described previously (Supporting Table 1). The study was approved by the local ethics committees, and written informed consent was obtained from all participants. Statistical analysis was performed using PLINK. All cross-tabulated data were assessed using Fisher’s exact statistics. All 3 SNPs had a call rate > 98% and were in Hardy– Weinberg equilibrium (P > .01). Power calculations showed that because of the low minor-allele frequencies, a large sample size of 1755 patients and 1450 controls is necessary to reliably detect odds ratios in the range of 1.5–2.0 (Supporting Figure 1). We did not find any evidence for association either in the combined sample (Table 1) or in the 3 subsamples (results not shown) under the dominant model or in the allelic model. The association statistics for the combination of all 3 SNPs also showed no significant difference between patients and controls (Table 1, Supporting Table 2). NOD2 belongs to the family of PRRs that not only recognize pathogen-associated molecular patterns (PAMPs) but also endogenous danger-associated molecular patterns (DAMPs). In Alzheimer’s disease NOD2 and TLR2 (toll-like receptor 2) receptors cooperate in the regulation of a receptor involved in amyloid beta 1–42 (ab1–42) recognition by microglia. PD and Alzheimer’s disease have many pathogenetic features including neuroinflammation in common. Both, a-synuclein and ab1–42 form fibrillar protein aggregates via oligomeric intermediates. The oligomeric intermediates share structural features. These findings led us to the hypothesis that NOD2 might also be involved in neuroinflammation related to PD. SNP selection was governed by (1) a previous study showing association with PD, (2) the finding that these SNPs account for more than 80% of all variant alleles in Crohn disease, and (3) the prior knowledge that these SNPs have a functional impact on NOD2. These 3 SNPs capture only a small part of the common genetic variability in the NOD2 gene. However, analysis of SNPs rs2111234, rs805734, rs11647841, rs2066843, rs10521209, rs5743289, rs207675, rs574329, and rs3135499, which did cover common variations in the whole NOD2 gene in a large GWAS sample of PD, also did not yield any significant disease associations in allelic, dominant, or recessive models (all P > .1; ref. 7 and personal communication T. Gasser). Our findings render it unlikely that genetic variation in NOD2 plays a major role in PD in German patients but does not preclude a functional role for NOD2 in the pathogenesis of PD.