Analysis of CYP2D6 gene haplotype in patients of juvenile onset Parkinson disease

青少年发病帕金森病患者CYP2D6基因单倍型分析

• 批准号: 06670658
• 负责人: FURUYA Hirokazu
• 金额: $ 1.41万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06670658/
• 关键词: Parkinson disease; Cytochrome P450; polymorphism; haplotype analysis; debrisoquine hydroxylase (CYP2D6); CytochromeP450; debrisoquine hydroxylase (CYP2D6); Cytochrome P450; Parkinson disease(Juvenile onset); PCR

Juvenile onset Parkinson disease (YOPD) is one of subtype of Parkinson disease (PD), but its onset age of symptom is below 40 and some cases have a genetic background. Since its symptoms are homogenous, it is considered to be suitable for analysis of genetic background. Cytochrome P450 debrisoquine hydroxylase (CYP2D6) has been regarded as one of the main genetic factor in PD.So, we analyze relationships between YOPD and CYP2D6 by determing haplotype of CYP2D6 gene polymorphisms.Genomic DNA samples are extracted from 8 YOPD, 18 PD and 55 age matched normal control. The B mutation in CYP2D6 are detected with the method by Smith et al and Hha I RFLP in exon 6 by Tuneoka et al. In Caucasian populatiopn, it is reported that the frequency of B mutation homozygous genotype (poor metabolizer of debrisoquine hydroxylase) is quite high in PD.But on the contrary, we found that its frequency is quite low in Japanese population and is not useful for genetic marker.Next, we use Hha I RFLP, which is rather high frequency in Japanese population. In conclusion, there is no mutation homozygous type, which is reported to be rather high frequency in Caucasian PD, is not found in Japanese YOPD and PD sample. Furthermore, there are no different allele frequency of Hha I RFLP between YOPD, PD and normal control. These results indicate that there is a possibility that CYP2D6 is not the risk factor of PD or YOPD.

青少年型帕金森病（juvenile onset Parkinson disease，YOPD）是帕金森病（Parkinson disease，PD）的一种亚型，但其发病年龄多在40岁以下，且部分病例有遗传背景。由于其症状是同质的，它被认为是适合于遗传背景的分析。细胞色素P450异喹羟化酶（CYP2D6）被认为是帕金森病的主要遗传因素之一，因此，本研究通过测定CYP2D6基因多态性单倍型，分析CYP2D6与帕金森病的关系。用Smith等的方法和Tuneoka等的Hha Ⅰ RFLP方法检测了CYP2D6基因B突变，在高加索人群中，B突变纯合基因型的频率明显高于其他人群，异喹胍羟化酶（debrisoquine hydroxylase）的弱代谢产物在PD中的比例很高，但相反，我们发现它在日本人群中的频率很低，不适合作为遗传标记。我们使用Hha I RFLP，这在日本人群中是相当高的频率。总之，不存在突变纯合型，这在白人PD中报告频率较高，在日本YOPD和PD样本中未发现。Hha Ⅰ RFLP基因频率在青少年PD组、PD组和正常对照组之间无显著性差异。这些结果表明，CYP2D6可能不是PD或YOPD的危险因素。

项目成果

Yokota H: "cDNA cloning and chromosome mapping of human dihydropyrimidine dehydrogenase, an enzyme associated with 5-fluorouracil toxicity and congenital thymine uraciluria" J Biol Chem. 269. 23192-23196 (1994)

Yokota H：“人二氢嘧啶脱氢酶的 cDNA 克隆和染色体图谱，一种与 5-氟尿嘧啶毒性和先天性胸腺嘧啶尿嘧啶尿症相关的酶”J Biol Chem。

Yasutake T: "Molecular analysis of X-linked adrenoleukodystrophy patients" J Neurol Sci. 131. 58-64 (1995)

Yasutake T：“X连锁肾上腺脑白质营养不良患者的分子分析”J Neurol Sci。

Furuya H: "Genetic polymorphism CYP2C9 and its effect on warfarin maintenance dose repuirement in patients undergoing anticoagulation therapy" Pharmacogenetics. (in press).

Furuya H：“CYP2C9 基因多态性及其对接受抗凝治疗的患者华法林维持剂量需求的影响”药物遗传学。

Yokota H, Fernandez-Salguero P, Furuya H, et al.: "cDNA cloning and chromosome mapping of human dihydropyrimidine dchydrogenase, an enzyme associated with 5-fluorouracil toxicity and congenital thymine uraciluria." J Biol Chem. 269. 23192-23196 (1994)

Yokota H、Fernandez-Salguero P、Furuya H 等人：“人二氢嘧啶脱氢酶的 cDNA 克隆和染色体图谱，这是一种与 5-氟尿嘧啶毒性和先天性胸腺嘧啶尿嘧啶尿症相关的酶。”

Yasutake T, Yamada T, et al.: "Molecular analysis of X-linked adrenoleukodystrophy patients." J Neurol Sci. 131. 58-64 (1995)

Yasutake T、Yamada T 等人：“X 连锁肾上腺脑白质营养不良患者的分子分析。”