Hedrich K, Djarmati A, Schäfer N, Hering R, Wellenbrock C, Weiss P H, Hilker R, Vieregge P, Ozelius L J, Heutink P, Bonifati V, Schwinger E, Lang A E, Noth J, Bressman S B, Pramstaller P P, Riess O, Klein C
Department of Human Genetics, University of Lübeck, Germany.
Neurology. 2004 Feb 10;62(3):389-94. doi: 10.1212/01.wnl.0000113022.51739.88.
Mutations in the Parkin gene (PARK2) are the most commonly identified cause of recessively inherited early-onset Parkinson disease (EOPD) but account for only a portion of cases. DJ-1 (PARK7) was recently reported as a second gene associated with recessively inherited PD with a homozygous exon deletion and a homozygous point mutation in two families.
To investigate the frequency of DJ-1 mutations, the authors performed mutational analysis of all six coding exons of DJ-1 in 100 EOPD patients. For the detection of exon rearrangements, the authors developed a quantitative duplex PCR assay. Denaturing high performance liquid chromatography analysis was used to screen for point mutations and small deletions. Further, Parkin analysis was performed as previously described.
The authors identified two carriers of single heterozygous loss-of-function DJ-1 mutations, including a heterozygous deletion of exons 5 to 7 and an 11-base pair deletion, removing the invariant donor splice site in intron 5. Interestingly, both DJ-1 mutations identified in this study were found in the heterozygous state only. The authors also detected a polymorphism (R98Q) in 1.5% of the chromosomes in both the patient and control group. In the same patient sample, 17 cases were detected with mutations in the Parkin gene.
Mutations in DJ-1 are less frequent than mutations in Parkin in EOPD patients but should be considered as a possible cause of EOPD. The effect of single heterozygous mutations in DJ-1 on the nigrostriatal system, as described for heterozygous changes in Parkin and PARK6, remains to be elucidated.
帕金森病基因（PARK2）突变是隐性遗传早发性帕金森病（EOPD）最常见的病因，但仅占部分病例。DJ-1（PARK7）最近被报道为与隐性遗传帕金森病相关的第二个基因，在两个家族中发现了纯合外显子缺失和纯合点突变。
为了研究DJ-1突变的频率，作者对100例EOPD患者的DJ-1所有6个编码外显子进行了突变分析。为了检测外显子重排，作者开发了一种定量双链PCR检测方法。变性高效液相色谱分析用于筛选点突变和小缺失。此外，按照先前描述的方法进行帕金森病基因分析。
作者鉴定出两名携带单个杂合功能丧失性DJ-1突变的携带者，包括外显子5至7的杂合缺失和11个碱基对的缺失，去除了内含子5中不变的供体剪接位点。有趣的是，本研究中鉴定出的两个DJ-1突变仅以杂合状态存在。作者还在患者组和对照组的1.5%的染色体中检测到一种多态性（R98Q）。在同一患者样本中，检测到17例帕金森病基因突变。
在EOPD患者中，DJ-1突变的频率低于帕金森病基因的突变，但应被视为EOPD的可能病因。DJ-1单个杂合突变对黑质纹状体系统的影响，如帕金森病基因和PARK6杂合变化所描述的，仍有待阐明。
