Mutations in NR4A2 associated with familial Parkinson disease
Mutations in NR4A2 associated with familial Parkinson disease
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DOI：
10.1038/ng1066
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发表时间：
2003-01-01
期刊：
影响因子：
30.8
通讯作者：
Vassilatis, DK
中科院分区：
文献类型：
--
作者：
Le, WD;Xu, PY;Vassilatis, DK
编码核受体超家族1成员的NR 4A 2对于黑质多巴胺能神经元的分化是必需的（2-4）。为了确定NR 4A 2是否是帕金森病的易感基因，我们对201名帕金森病患者和221名年龄匹配的未受影响的对照者进行了遗传分析。我们鉴定了与帕金森病相关的NR 4A 2中的两个突变（-291Tdel和-245T-->G），其映射到NR 4A 2的第一外显子，并且影响107个家族性帕金森病个体中的10个的一个等位基因，但不影响任何散发性帕金森病个体（n = 94）或未受影响的对照（n = 221）。这10名患者的发病年龄和临床特征与典型帕金森病患者没有差异。突变导致NR 4A 2 mRNA水平在转染细胞系和受影响的个人的淋巴细胞显着下降。此外，NR 4A 2的突变会影响编码酪氨酸羟化酶的基因的转录。这些数据表明，NR 4A 2突变可导致多巴胺能功能障碍，与帕金森病相关。
NR4A2, encoding a member of nuclear receptor superfamily 1, is essential for the differentiation of the nigral dopaminergic neurons(2-4). To determine whether NR4A2 is a susceptibility gene for Parkinson disease, we carried out genetic analyses in 201 individuals affected with Parkinson disease and 221 age-matched unaffected controls. We identified two mutations in NR4A2 associated with Parkinson disease (-291Tdel and -245T-->G), which map to the first exon of NR4A2 and affect one allele in 10 of 107 individuals with familial Parkinson disease but not in any individuals with sporadic Parkinson disease (n = 94) or in unaffected controls (n = 221). The age at onset of disease and clinical features of these ten individuals were not different from those of individuals with typical Parkinson disease. The mutations resulted in a marked decrease in NR4A2 mRNA levels in transfected cell lines and in lymphocytes of affected individuals. Additionally, mutations in NR4A2 affect transcription of the gene encoding tyrosine hydroxylase. These data suggest that mutations in NR4A2 can cause dopaminergic dysfunction, associated with Parkinson disease.