Department of Clinical Genetics, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
Neurogenetics. 2011 Nov;12(4):263-71. doi: 10.1007/s10048-011-0302-9. Epub 2011 Oct 13.
Early-onset Parkinson's disease (EOPD) has been associated with recessive mutations in parkin (PARK2). About half of the mutations found in parkin are genomic rearrangements, i.e., large deletions or duplications. Although many different rearrangements have been found in parkin before, the exact breakpoints involving these rearrangements are rarely mapped. In the present study, the exact breakpoints of 13 different parkin deletions/duplications, detected in 13 patients out of a total screened sample of 116 EOPD patients using Multiple Ligation Probe Amplification (MLPA) analysis, were mapped using real time quantitative polymerase chain reaction (PCR), long-range PCR and sequence analysis. Deletion/duplication-specific PCR tests were developed as a rapid and low cost tool to confirm MLPA results and to test family members or patients with similar parkin deletions/duplications. Besides several different deletions, an exon 3 deletion, an exon 4 deletion and an exon 7 duplication were found in multiple families. Haplotype analysis in four families showed that a common haplotype of 1.2 Mb could be distinguished for the exon 7 duplication and a common haplotype of 6.3 Mb for the deletion of exon 4. These findings suggest common founder effects for distinct large rearrangements in parkin.
早发性帕金森病（EOPD）与 parkin（PARK2）的隐性突变有关。在 parkin 中发现的大约一半突变是基因组重排，即大片段缺失或重复。尽管以前已经在 parkin 中发现了许多不同的重排，但这些重排的确切断点很少被映射。在本研究中，使用实时定量聚合酶链反应（PCR）、长距离 PCR 和序列分析，对 13 例 EOPD 患者的 13 种不同 parkin 缺失/重复，通过多重连接探针扩增（MLPA）分析检测到，对其确切断点进行了映射。缺失/重复特异性 PCR 测试被开发为一种快速且低成本的工具，用于确认 MLPA 结果以及测试具有类似 parkin 缺失/重复的家族成员或患者。除了几种不同的缺失外，还在多个家族中发现了一个外显子 3 缺失、一个外显子 4 缺失和一个外显子 7 重复。四个家族的单倍型分析表明，外显子 7 重复可以区分出一个常见的 1.2Mb 单倍型，外显子 4 缺失可以区分出一个常见的 6.3Mb 单倍型。这些发现表明，parkin 中不同的大片段重排存在共同的起源效应。
