Lrrk2 R1628P與巴金森氏症相關性之研究

Abstract

研究背景及目的- 巴金森氏症是一種腦部神經退化性疾病，會造成動作逐漸的僵硬、顫抖與遲緩。病理學上主要是因為中腦的黑質多巴胺細胞退化與路易士體(Lewy body)堆積在細胞質中。多巴胺的缺乏生理學上造成基底核神經徑路失衡，產生對自主性動作的控制失調而產生了臨床的症狀。導致黑質多巴胺細胞退化死亡的原因到目前為止還不是很清楚，最近發現基因的突變會導致巴金森氏病。在一些家族性巴金森氏病找到了一些基因突變可能影響腦部神經元退化，目前發現了八個基因，其中最重要的一個叫做LRRK2，會造成顯性遺傳性巴金森氏病，在此基因的某些變異點的發現會增加偶發性巴金森氏病發生的機會。本研究針對LRRK2 R1628P這個變異點進行研究。 研究材料及方法- 根據UK PD Society Brain Bank Clinical Diagnostic Criteria of PD診斷巴金森氏病，共納入了484位巴金森氏病病人，健康人共341人，檢驗LRRK2 R1628P(G4883C)。這些納入的人都經過台大醫院的倫理委員會通過，每一個個案都簽署了受試者同意書。將血液萃取出染色體，利用特殊啟動子做連鎖反應後進行序列分析，比對4883的位置是否有G>C。 結果-病人組的帶因率(GC，CC)（6.6%）為正常對照組（3.2%）的兩倍。若以單條基因出現C的頻率來看，病人組為3.4%，對照組為1.6%( p=0.025)( p-value=0.025)，危險機率（odds ratio）為2.15。有R1628P突變的分別1 人為家族性，5人為早發型（＜50歲），26人為晚發型（50＞歲）。同時在台灣另一醫學中心與新加坡也同樣顯示病人C的出現頻率較高（3.0% v.s 2.2%; 2.6% v.s 1.2%）。 討論- LRRK2 R1628P目前只有在中國漢民族身上發現，包括台灣與新加坡，顯示了種族與基因演化的特殊性。目前還未有R1628P的細胞或動物模式，若可以直接證實此變異點的影響及疾病的再現，則將來對於疾病的治療可以更清楚。此基因的變異增加了巴金森氏病的機會，如果在發病前期配合目前所發現的基因突變點，設計基因晶片來偵測是否有哪些點的變異，配合神經影像如穿顱超音波與正子掃瞄，可以提早發現黑質神經元的退化，可以在早期利用特殊藥物的治療延緩疾病症狀的發生。 結論- LRRK2 R1628P 是巴金森氏病的危險因子，並特屬於中國漢民族，配合神經影像檢查可以用在遺傳諮詢。

Background and purpose- Parkinson’s disease(PD) is a neurodegenerative disease with the clinical manifestations of resting tremor, rigidity and bradykinesia. Pathologically, there is dopaminergic neurondegeneration in the substia nigra and Lewy body deposition in the cytoplasm of dying neurons. Physiologically, the dopamine deficincy causes the dysregulation of motor control in the basal gaglia and leads to clinical symptoms. The etiology of dopaminergic neuron death is still uncertain. Genetic mutations causing familial PD has been disclosed recently. There are 8 gene found related to PD. One of the most important gene naming LRRK2 caused autosomal dominant parkinsonism. Some of the polymorphism of this gene has been found to be risk factor related to the development of sporadic PD. We analyse LRRK2 R1628P in multicenter including Taiwan Singapore to see the effect on PD. Methods and material- Diagnosis of PD is accoding to UK PD Society Brain Bank Clinical Diagnostic Criteria of PD. We included 484 PD and 341 normal control. Everyone signed inform consent and National Taiwan University IRB approved the Trial. We extrated DNA and to perform polychain reaction(PCR). Then sequenced the PCR produtcs. Finally, I checked the position of 4883 to see G>C. Results- Our results show a unique LRRK2 R1628P polymorphism has assoication with PD development in Han Chinese living in Taiwan and Singapore. In our group, the carrier rate in PD(GC，CC)（6.6%）doublednormal control(3.2%）. The C allele frquency is 3.4% in PD and 1.6% in normal control. ( p-value=0.025，odds ratio為2.15). IN R1628P mutation PD, one people has family history, five people are young onset(< 50 years old), and twenty-six people are late onset(>50 years old)。Another medical center in Taiwan and in Singapore also showed higher frequency of C-allele（3.0% v.s 2.2%; 2.6%v.s 1.2%）. Discussion- LRRK2 R1628P is unique in Han Chinese(Taiwan and Singapore). It showed specific genetic evolutio. Now, it is not clear about the effect of R1628P on cell or animal model. If there is more evidence about the relationship of mutation and diseas, we can do more for PD such as therpy. R1628P increaed the risk of PD. We can design PD gene chip assoicted other found PD gene. Neuroimage such as trancranial image and functional image can detected preclinical stage. Comined gene and neuroimage, we can deinfene PD as early as possible, and give specific therapy to delay PD development. Conclusion- LRRK2 R1628P is a risk factor of PD in Han Chinese. Associated neuroimage, we can use in genetic conseling.