Genomic instability in the PARK2 locus is associated with Parkinson's disease.
Genomic instability in the PARK2 locus is associated with Parkinson's disease.
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DOI：
10.1007/s13353-015-0282-9
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发表时间：
2015-11
影响因子：
2.4
通讯作者：
Hoffman-Zacharska D
中科院分区：
文献类型：
--
作者：
Ambroziak W;Koziorowski D;Duszyc K;Górka-Skoczylas P;Potulska-Chromik A;Sławek J;Hoffman-Zacharska D
帕金森病（Parkinson's disease，PD）是一种常见的神经退行性疾病，主要累及老年人，但也有一部分患者发展为早发性PD（early-onset PD，EOPD）。PARK 2基因突变是常染色体隐性EOPD的常见原因。PARK 2属于非常大的人类基因家族，其通常位于基因组常见脆性位点（CFS）中并表现出总体不稳定性。PARK 2位于FRA 6 E的中心，FRA 6 E是人类基因组中第三大最易突变的CFS。该基因包含一个1.3 Mbp的区域，在其突变中，单个或多个外显子的大重排约占50%。我们对一组344名患有EOPD和经典型疾病的PD患者的PARK 2基因进行了分析。首先使用多重连接探针扩增（MLPA）鉴定拷贝数变化，其范围通过阵列比较基因组杂交（aCGH）表征。使用直接测序绘制精确的断点。在8名受试者中发现了重排，包括5名缺失和3名重复。重排大多是非经常性的，没有重复序列或扩展的同源性被确定在侧翼断裂点连接的区域。然而，在大多数情况下，存在1-3 bp的微同源性，强烈表明微同源性介导的机制，特别是非同源末端连接（NHEJ）和叉停滞和模板转换（FoSTeS）/微同源性介导的断裂诱导复制（MMBIR），主要参与该基因组区域的重排过程。
Parkinson’s disease (PD) is a common neurodegenerative disorder affecting mostly elderly people, although there is a group of patients developing so-called early-onset PD (EOPD). Mutations in the PARK2 gene are a common cause of autosomal recessive EOPD. PARK2 belongs to the family of extremely large human genes which are often localised in genomic common fragile sites (CFSs) and exhibit gross instability. PARK2 is located in the centre of FRA6E, the third most mutation-susceptible CFS of the human genome. The gene encompasses a region of 1.3 Mbp and, among its mutations, large rearrangements of single or multiple exons account for around 50 %. We performed an analysis of the PARK2 gene in a group of 344 PD patients with EOPD and classical form of the disease. Copy number changes were first identified using multiplex ligation probe amplification (MLPA), with their ranges characterised by array comparative genomic hybridisation (aCGH). Exact breakpoints were mapped using direct sequencing. Rearrangements were found in eight subjects, including five deletions and three duplications. Rearrangements were mostly non-recurrent and no repetitive sequences or extended homologies were identified in the regions flanking breakpoint junctions. However, in most cases, 1–3 bp microhomologies were present, strongly suggesting that microhomology-mediated mechanisms, specifically non-homologous end joining (NHEJ) and fork stalling and template switching (FoSTeS)/microhomology-mediated break-induced replication (MMBIR), are predominantly involved in the rearrangement processes in this genomic region.