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帕金森氏症(PD)為僅次於阿茲海默氏症常見的神經退化性疾病。臨床症狀包括四肢及軀體顫抖、行動緩慢等現象,主要的病理特徵是多巴胺神經元在基底核與其他腦幹神經核有退化死亡的現象,尤其以黑質之緻密區與路易氏體(Lewy body)存在的神經元最為嚴重。LRRK2基因為目前引起顯性遺傳帕金森氏症病患重要的基因。近年來研究發現LRRK2基因上的G2385R與R1628P變異為亞洲人種所特有的危險因子。本研究經定序PD患者的LRRK2 cDNA,找到一個已報導的R1441H、兩個未被報導過的R767H與S885N突變,及5個改變胺基酸、8個未改變胺基酸的多型性或變異。進一步針對R1398H、G2385R與M2397T多型性,進行病例-對照組研究,發現G2385R多型性異型合子在PD患者的頻率要高於正常人(8.4 vs. 4.2%, odds ratio = 2.08, 95% CI: 1.05-4.41, P = 0.044),且M2397T多型性同基因型會加重G2385R異基因型對PD的感受性(4.2 vs. 0.4%, odds ratio = 10.63, 95% CI: 2.08-194.26, P = 0.024)。由於近年研究發現GRN基因突變與額顳葉型失智症(FTD)相關,本研究亦針對41位病人的GRN基因做定序分析,發現兩個未被報導的突變L57M、T487I及兩個已被報導的多型性D128、3’ UTR C>T。本研究結果可提供臨床上診斷及諮詢的參考。
Abstract Parkinson’s disease (PD), the second most common neurodegenerative disorder, is characterized by resting tremor, rigidity, bradykinesia, and postural instability. The symptoms of PD in pathology are neuronal loss in the basal ganglia, especially in the substantia nigra pars compacta, and presence of intracellular Lewy body inclusions in surviving neurons. Mutations in leucine-rich repeat kinase 2 (LRRK2, encoding dardarin) are the most frequent genetic cause of PD known nowadays. Mutations in different functional regions of LRRK2 have been reported. Studies from China, Singapore, and Japan indicate that the G2385R polymorphism is an ancient and common risk factor for sporadic PD in the Asian population. In this study, we screened LRRK2 mutations in PD patients and identified a reported (R1441H) and two novel (R767H and S885N) mutations, in addition to 5 nonsynonymous and 8 synonymous amino acid substitutions. In the case-control study, the frequency of the heterozygous G2385R genotype was higher in PD compared to controls (8.4 vs. 4.2%, odds ratio = 2.08, 95% CI: 1.05-4.41, P = 0.044). Moreover, M2397T acting synergistically with G2385R to play role in PD susceptibility (4.2 vs. 0.4%, odds ratio = 10.63, 95% CI: 2.08-194.26, P = 0.024). Granulin (GRN) has been identified as one of the gene responsible for frontotemporal dementia (FTD) and mutations in GRN have been reported. Using cDNA sequencing, we found two novel mutations L57M and T487I, additionally to a synonymous D128 and a C>T variation in 3’UTR. The studies may provide a tool for clinical diagnosis and counseling.



LRRK2基因, GRN基因, 帕金森氏症, 額顳葉型失智症, LRRK2, GRN, Parkinson's Disease, Frontotemporal Dementia