Loss of polycystin-1 causes centrosome amplification and genomic instability
Loss of polycystin-1 causes centrosome amplification and genomic instability
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DOI：
10.1093/hmg/ddn180
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发表时间：
2008-09-15
影响因子：
3.5
通讯作者：
Gusella, G. Luca
中科院分区：
文献类型：
--
作者：
Battini, Lorenzo;Macip, Salvador;Gusella, G. Luca
常染色体显性遗传性多囊肾病（ADPKD）是最常见的单基因遗传病，主要由PKD 1基因改变或失调引起，该基因编码多囊蛋白-1（PC 1）。这种疾病的特征是双侧充满液体的肾囊肿进行性扩张，最终导致肾功能衰竭。个别囊肿，即使在生殖系突变的患者，是遗传异质性，显示不同的染色体异常。迄今为止，这种遗传异质性的分子机制仍然未知。使用慢病毒介导的siRNA表达模型的Pkd 1亚型，我们表明，PC 1功能的丧失足以产生中心体扩增和多极纺锤体形成。这些事件导致基因组的不稳定性，其特征在于总多倍体和有丝分裂灾难。这些戏剧性的早期变化后，细胞群体迅速收敛到一个稳定的倍性，中心体扩增显着减少，虽然细胞学异常，如微核，染色质桥和非整倍性仍然很常见。与我们的体外研究结果一致，我们提供了第一个体内证据表明，在疾病进展的早期和晚期以及人类ADPKD患者中，条件性Pkd 1敲除小鼠的肾脏中发生了显著的中心体扩增。这些发现建立了一个新的功能，PC 1在ADPKD的发病机制和遗传机制，可能是ADPKD进展的家族内变异。
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic disease predominantly caused by alteration or dysregulation of the PKD1 gene, which encodes polycystin-1 (PC1). The disease is characterized by the progressive expansion of bilateral fluid-filled renal cysts that ultimately lead to renal failure. Individual cysts, even within patients with germline mutations, are genetically heterogeneous, displaying diverse chromosomal abnormalities. To date, the molecular mechanisms responsible for this genetic heterogeneity remain unknown. Using a lentiviral-mediated siRNA expression model of Pkd1 hypomorphism, we show that loss of PC1 function is sufficient to produce centrosome amplification and multipolar spindle formation. These events lead to genomic instability characterized by gross polyploidism and mitotic catastrophe. Following these dramatic early changes, the cell population rapidly converges toward a stable ploidy in which centrosome amplification is significantly decreased, though cytological abnormalities such as micronucleation, chromatin bridges and aneuploidy remain common. In agreement with our in vitro findings, we provide the first in vivo evidence that significant centrosome amplification occurs in kidneys from conditional Pkd1 knockout mice at early and late time during the disease progression as well as in human ADPKD patients. These findings establish a novel function of PC1 in ADPKD pathogenesis and a genetic mechanism that may underlie the intrafamilial variability of ADPKD progression.