Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7)
Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7)
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DOI：
10.1002/humu.20089
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发表时间：
2004-01-01
期刊：
影响因子：
3.9
通讯作者：
Riess, O
中科院分区：
文献类型：
--
作者：
Hering, R;Strauss, KA;Riess, O
parkin基因突变已被确定为常染色体隐性遗传性帕金森病（PD）与早期疾病表现的常见原因。然而，基于连锁数据，其他基因的突变有助于早发性PD（EOPD）的遗传异质性。最近，DJ 1基因的两个突变被描述为常染色体隐性EOPD（PARK 7）的第二个原因。通过分析104例EOPD患者的PARK 7/DJ 1基因，我们发现了第三个突变，c.192G>C（p.E64D），与土耳其血统患者的EOPD相关，并表征了这种氨基酸取代的功能意义。在患者中，使用[F-18]FP-CIT和PET发现纹状体中多巴胺摄取转运蛋白（DAT）结合显著减少，表明突触前多巴胺能传入神经严重缺失。他的妹妹，E64 D纯合子，临床上未受影响，但与临床上未受影响的兄弟（E64 D杂合子）相比，多巴胺摄取减少。我们通过晶体学证明E64 D突变不会改变DJ 1蛋白的结构，但是我们观察到当在HEK 293或COS 7细胞中过表达时突变蛋白水平降低的趋势。使用免疫细胞化学在HEY，293细胞过度表达野生型DJ 1，约5%的细胞表达E64 D和高达80%的细胞表达最近描述的L166 P突变显示的突变体DJ 1蛋白的主要核定位的同质核和细胞质染色相反。(C)2004 Wiley-Liss，Inc.
Mutations in the parkin gene have been identified as a common cause of autosomal recessive inherited Parkinson disease (PD) associated with early disease manifestation. However, based on linkage data, mutations in other genes contribute to the genetic heterogeneity of early-onset PD (EOPD). Recently, two mutations in the DJ1 gene were described as a second cause of autosomal recessive EOPD (PARK7). Analyzing the PARK7/DJ1 gene in 104 EOPD patients, we identified a third mutation, c.192G>C (p.E64D), associated with EOPD in a patient of Turkish ancestry and characterized the functional significance of this amino acid substitution. In the patient, a substantial reduction of dopamine uptake transporter (DAT) binding was found in the striatum using [F-18]FP-CIT and PET, indicating a serious loss of presynaptic dopaminergic afferents. His sister, homozygous for E64D, was clinically unaffected but showed reduced dopamine uptake when compared with a clinically unaffected brother, who is heterozygous for E64D. We demonstrate by crystallography that the E64D mutation does not alter the structure of the DJ1 protein, however we observe a tendency towards decreased levels of the mutant protein when overexpressed in HEK293 or COS7 cells. Using immunocytochemistry in contrast to the homogenous nuclear and cytoplasmic staining in HEY, 293 cells overexpressing wild,type DJ1, about 5% of the cells expressing E64D and up to 80% of the cells expressing the recently described L166P mutation displayed a predominant nuclear localization of the mutant DJ1 protein. (C) 2004 Wiley-Liss, Inc.