The New p.F1700L LRRK2 Variant Causes Parkinson's Disease by Extensively Increasing Kinase Activity.
The New p.F1700L LRRK2 Variant Causes Parkinson's Disease by Extensively Increasing Kinase Activity.
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新的 p.F1700L LRRK2 变体通过大幅增加激酶活性导致帕金森病。
DOI：
10.1002/mds.29385
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Borsche M
中科院分区：
文献类型：
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作者：
Borsche M
LRRK2基因变异是临床上经典单基因帕金森病(PD)最常见的原因。1改变的LRRK2蛋白功能促进神经炎症，损害囊泡运输，并影响纹状体内的纤毛发生。2由于1000多个已鉴定的LRRK2变异体3中的相关部分不是致病的，确定单个变异体的致病性至关重要，特别是因为LRRK2激酶抑制剂已经进入第三阶段试验。4值得注意的是，我们已经建立了一种分析工作流程，以确定KK活性并破译单个LRRK2变体在体外和体内的致病性。6在这封信中，我们报告了一位来自德国北部的74岁男性患者，他患有晚期典型帕金森病(统一帕金森病评定量表III：33/108分，Hoehn和Yahr分期3-4分)，没有相关的震颤。发病年龄67岁。病程进展缓慢，他对多巴胺治疗有良好的反应，没有痴呆。家族史提示常染色体显性遗传，父亲和两个兄弟也被诊断为帕金森病。然而，父亲已经去世，一名兄弟无法接受检查，第二名兄弟在献血进行基因调查后早早死亡。两兄弟都携带了一辆新的P.F1700L(NM_198578)。4：LRRK2中的C.5098T>；C)变异，最初通过基因面板分析在死者兄弟中检测到，并通过Sanger测序进行进一步研究。根据美国医学遗传学学会的标准(由Franklin：https://franklin.评估)，该变体被评为具有不确定意义的变体基诺克斯。Com/)，并且未在gnomAD(https://gnomad.)中列出博大学院。Org/)。在计算机预测中，基于联合注释依赖耗竭评分(https://cadd.)提示致病性GS.华盛顿。Edu/)27.3。该变异体位于复合蛋白B支架结构域的RAS的C末端。5.
Variants in LRRK2 represent the most frequent cause of clinically classical monogenic Parkinson’s disease (PD). 1 Altered LRRK2 protein function boosts neuroinflammation, impairs vesicle trafficking, and affects ciliogenesis within the striatum. 2 Because a relevant fraction of the more than 1000 identified LRRK2 variants3 is not pathogenic, determining pathogenicity for single variants is crucial, particularly because LRRK2 kinase inhibitors have entered phase 3 trials. 4 Notably, we have already established an analytic workflow to determine kinase activity and decipher the pathogenicity of single LRRK2 variants in vitro5 and in vivo. 6 In this letter, we report on a 74-year-old male patient from northern Germany with advanced typical PD (Unified Parkinson’s Disease Rating Scale Part III: 33/108 points, Hoehn and Yahr stage 3–4) without relevant tremor. The age at onset was 67 years. The disease course was slowly progressive, he experienced a good response to dopaminergic therapy, and dementia was absent. Family history was suggestive of autosomal dominant inheritance, with the father and two brothers also diagnosed with PD. However, the father was already deceased, one brother was not available for examination, and the second brother died early after giving blood for genetic investigation. Both brothers carried a new p. F1700L (NM_198578. 4: c. 5098T> C) variant in LRRK2, initially detected by gene panel analysis in the deceased brother and further investigated by Sanger sequencing. The variant is rated as a variant of uncertain significance according to the criteria of the American College of Medical Genetics (assessed byFranklin: https://franklin. genoox. com/) and is not listed in gnomAD (https://gnomad. broadinstitute. org/). In silico prediction suggested pathogenicity based on a Combined Annotation Dependent Depletion (CADD) score (https://cadd. gs. washington. edu/) of 27.3. The variant is located within the C terminus of the Ras of complex protein B scaffolding domain. 5