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针对 E200K 致病性突变的家族性克雅氏病保护机制的生物网络推断。

Biological network inferences for a protection mechanism against familial Creutzfeldt-Jakob disease with E200K pathogenic mutation.

机构信息

Division of Zoonoses, Center for Immunology and Pathology, National Institute of Health, Korea Center for Disease Control and Prevention, Cheongju-si 363-700, Korea.

出版信息

BMC Med Genomics. 2014 Aug 22;7:52. doi: 10.1186/1755-8794-7-52.

Abstract

BACKGROUND

Human prion diseases are caused by abnormal accumulation of misfolded prion protein in the brain tissue. Inherited prion diseases, including familial Creutzfeldt-Jakob disease (fCJD), are associated with mutations of the prion protein gene (PRNP). The glutamate (E)-to-lysine (K) substitution at codon 200 (E200K) in PRNP is the most common pathogenic mutation causing fCJD, but the E200K pathogenic mutation alone is regarded insufficient to cause prion diseases; thus, additional unidentified factors are proposed to explain the penetrance of E200K-dependent fCJD. Here, exome differences and biological network analysis between fCJD patients with E200K and healthy individuals, including a non-CJD individual with E200K, were analysed to gain new insights into possible mechanisms for CJD in individuals carrying E200K.

METHODS

Exome sequencing of the three CJD patients with E200K and 11 of the family of one patient (case1) were performed using the Illumina HiSeq 2000. The exome sequences of 24 Healthy Koreans were used as control. The bioinformatic analysis of the exome sequences was performed using the CLC Genomics Workbench v5.5. Sanger sequencing for variants validation was processed using a BigDye Terminator Cycle Sequencing Kit and an ABI 3730xl automated sequencer. Biological networks were created using Cytoscape (v2.8.3 and v3.0.2) and Pathway Studio 9.0 software.

RESULTS

Nineteen sites were only observed in healthy individuals. Four proteins (NRXN2, KLKB1, KARS, and LAMA3) that harbour rarely observed single-nucleotide variants showed biological interactions that are associated with prion diseases and/or prion protein in our biological network analysis.

CONCLUSION

Through this study, we confirmed that individuals can have a CJD-free life, even if they carry a pathogenic E200K mutation. Our research provides a possible mechanism that involves a candidate protective factor; this could be exploited to prevent fCJD onset in individuals carrying E200K.

摘要

背景

人类朊病毒病是由脑组织中异常折叠的朊病毒蛋白积累引起的。遗传性朊病毒病,包括家族性克雅氏病(fCJD),与朊病毒蛋白基因(PRNP)的突变有关。PRNP 密码子 200 位的谷氨酸(E)到赖氨酸(K)取代(E200K)是导致 fCJD 的最常见致病性突变,但单独的 E200K 致病性突变被认为不足以引起朊病毒病;因此,提出了其他未识别的因素来解释依赖于 E200K 的 fCJD 的外显率。在这里,对携带 E200K 的 fCJD 患者与健康个体之间的外显子差异和生物网络进行了分析,包括一名携带 E200K 的非 CJD 个体,以深入了解携带 E200K 的个体发生 CJD 的可能机制。

方法

使用 Illumina HiSeq 2000 对 3 名携带 E200K 的 CJD 患者和 1 名患者(病例 1)的 11 名家族成员进行外显子组测序。24 名健康韩国人的外显子组序列用作对照。使用 CLC Genomics Workbench v5.5 对外显子组序列进行生物信息学分析。使用 BigDye Terminator Cycle Sequencing Kit 和 ABI 3730xl 自动化测序仪对变体进行 Sanger 测序验证。使用 Cytoscape(v2.8.3 和 v3.0.2)和 Pathway Studio 9.0 软件创建生物网络。

结果

仅在健康个体中观察到 19 个位点。在我们的生物网络分析中,携带罕见单核苷酸变异的 4 种蛋白质(NRXN2、KLKB1、KARS 和 LAMA3)具有与朊病毒病和/或朊病毒蛋白相关的生物相互作用。

结论

通过这项研究,我们证实即使携带致病性 E200K 突变,个体也可以拥有无 CJD 的生活。我们的研究提供了一种可能的机制,涉及候选保护因素;这可以用来防止携带 E200K 的个体发生 fCJD。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/457e/4151374/d1cfa61dcc12/1755-8794-7-52-1.jpg

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