Chromosomal instability at common fragile sites in Seckel syndrome
Chromosomal instability at common fragile sites in Seckel syndrome
复制标题
DOI：
10.1086/422701
复制
发表时间：
2004-10-01
影响因子：
9.8
通讯作者：
Glover, TW
中科院分区：
文献类型：
--
作者：
Casper, AM;Durkin, SG;Glover, TW
Seckel综合征（SCKL）是一种罕见的遗传异质性疾病，具有畸形的面部外观、生长迟缓、小头畸形、智力低下、可变染色体不稳定性和血液学疾病。迄今为止，已有三个基因座与该综合征有关，最近，编码共济失调-毛细血管扩张症和Rad 3相关蛋白（ATR）的基因被确定为SCKL 1基因座突变的基因。ATR突变影响剪接效率，导致受影响个体的ATR水平较低。在其他地方，我们报告了在缺乏复制检查点基因ATR的细胞中常见染色体脆性位点的不稳定性增加。在这里，我们测试了来自携带SCKL 1突变的患者的细胞是否会在复制应激后显示出增加的染色体断裂。我们发现，与对照组相比，有更大的染色体不稳定性，特别是在脆弱的网站，在SCKL 1受影响的患者细胞处理后，与aphidicolin，DNA聚合酶和其他聚合酶的抑制剂。对照和患者细胞之间的染色体不稳定性的差异在较高水平的阿非迪霉素治疗下增加，表明这些患者中存在的低水平ATR不足以适当地响应复制应激。这是第一个与复制应激后脆性位点染色体不稳定性增加相关的人类遗传综合征，这些发现可能与SCKL 1患者的表型发现有关。
Seckel syndrome (SCKL) is a rare, genetically heterogeneous disorder, with dysmorphic facial appearance, growth retardation, microcephaly, mental retardation, variable chromosomal instability, and hematological disorders. To date, three loci have been linked to this syndrome, and recently, the gene encoding ataxia-telangiectasia and Rad3-related protein (ATR) was identified as the gene mutated at the SCKL1 locus. The ATR mutation affects splicing efficiency, resulting in low levels of ATR in affected individuals. Elsewhere, we reported increased instability at common chromosomal fragile sites in cells lacking the replication checkpoint gene ATR. Here, we tested whether cells from patients carrying the SCKL1 mutation would show increased chromosome breakage following replication stress. We found that, compared with controls, there is greater chromosomal instability, particularly at fragile sites, in SCKL1-affected patient cells after treatment with aphidicolin, an inhibitor of DNA polymerase a and other polymerases. The difference in chromosomal instability between control and patient cells increases at higher levels of aphidicolin treatment, suggesting that the low level of ATR present in these patients is not sufficient to respond appropriately to replication stress. This is the first human genetic syndrome associated with increased chromosome instability at fragile sites following replication stress, and these findings may be related to the phenotypic findings in patients with SCKL1.