Functional Studies of HSPA5 Promoter Polymorphisms and Risk of Essential Tremor in Taiwan
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Date
2008-12-??
Authors
李麗卿
胡雰茹
吳逸如
羅于堯
林雅芸
陳瓊美
李桂楨
Journal Title
Journal ISSN
Volume Title
Publisher
國立臺灣師範大學生命科學學系
Department of Life Science, NTNU
Department of Life Science, NTNU
Abstract
蛋白質不正常摺疊引起的內質網壓力(ER stress)及不正常蛋白質摺疊反應(unfolded protein response; UPR)的機能失常，和神經退化性疾病的致病機制相關。70kDa熱休克蛋白5(HSPA5)為一UPR伴隨蛋白，可反應內質網壓力、抑制細胞凋零。HSPA5基因的啟動子多型性-415G/A(rs391957)、-370 C/T(rs17840761)及-180 del/G (rs3216733)可能影響其表現量。利用啟動子報告基因試驗，我們檢測了這三個多型性所暗示的功能。在神經癌SK-N-SH細胞中，帶有-415A多型性啟動子的螢光酵素報告質體表現的轉錄活性顯著低於帶有-415G者。利用個案－正常對照研究，我們分析了HSPA5基因啟動子多型性與台灣原發性顫抖症的相關性。在正常人(n=341)及原發性顫抖症患者(n=130)間，所分析的各多型性點，其基因型、等位基因與單套型頻率皆無顯著差異。我們的實驗數據顯示，HSPA5 -415 G/A多型性雖然影響其功能，但和台灣原發性顫抖症的風險無關。
Endoplasmic reticulum (ER) stress induced by misfolded proteins and a malfunction of unfolded protein response (UPR) to ER stress have been implicated in neurodegenerative disease pathogenesis. Heat shock 70 kDa protein 5 (HSPA5) is one of the UPR chaperones reactive to ER stress to block the apoptotic process. Three polymorphisms in the HSPA5 promoter region, -415 G/A (rs391957), -370 C/T (rsI7840761) and -180 del/G (rs3216733), may affect the gene expression. Using a reporter assay, we examined the functional implication of these three promoter polymorphisms. Reporter construct containing the polymorphic -415 A allele cloned into a luciferase reporter plasmid drove significantly lower transcriptional activity of HSPA5 compared with the common -415 G allele in human neuroblastoma SK-N-SH cells. The association of these polymorphisms with Taiwanese essential tremor (ET) was investigated using a case-control study. The genotype, allele or haplotype frequency distribution examined was not significantly different between the controls (n = 341) and the ET patients (n = 130). Our data suggest that while functionally, the HSPA5 -415 G/A polymorphism is unlikely to affect susceptibility to ET in Taiwanese subjects.
Endoplasmic reticulum (ER) stress induced by misfolded proteins and a malfunction of unfolded protein response (UPR) to ER stress have been implicated in neurodegenerative disease pathogenesis. Heat shock 70 kDa protein 5 (HSPA5) is one of the UPR chaperones reactive to ER stress to block the apoptotic process. Three polymorphisms in the HSPA5 promoter region, -415 G/A (rs391957), -370 C/T (rsI7840761) and -180 del/G (rs3216733), may affect the gene expression. Using a reporter assay, we examined the functional implication of these three promoter polymorphisms. Reporter construct containing the polymorphic -415 A allele cloned into a luciferase reporter plasmid drove significantly lower transcriptional activity of HSPA5 compared with the common -415 G allele in human neuroblastoma SK-N-SH cells. The association of these polymorphisms with Taiwanese essential tremor (ET) was investigated using a case-control study. The genotype, allele or haplotype frequency distribution examined was not significantly different between the controls (n = 341) and the ET patients (n = 130). Our data suggest that while functionally, the HSPA5 -415 G/A polymorphism is unlikely to affect susceptibility to ET in Taiwanese subjects.