Cellular and clinical impact of haploinsufficiency for genes involved in ATR signaling
Cellular and clinical impact of haploinsufficiency for genes involved in ATR signaling
复制标题
DOI：
10.1086/518696
复制
发表时间：
2007-07-01
影响因子：
9.8
通讯作者：
Jeggo, Penny A.
中科院分区：
文献类型：
--
作者：
O'Driscoll, Mark;Dobyns, William B.;Jeggo, Penny A.
共济失调毛细血管扩张和RAD3相关(ATR)蛋白是一种调节DNA损伤反应途径的蛋白，在ATR-Seckel综合征(ATR-SS)中发生突变，ATR-SS是一种以严重小头畸形和生长迟缓为特征的疾病。在以小头畸形和生长迟缓为特征的其他疾病的细胞系中也观察到ATR信号受损，包括非ATR-SS、奈梅根断裂综合征和MCPH1(小头畸形，原发常染色体隐性遗传，1)依赖的原发小头畸形。在这里，我们研究了三种单倍体不足的邻接性基因缺失疾病的细胞株中ATR途径的功能--眼球突出症-上睑下垂-内翻综合征、Miller-Dieker无脑综合征和Williams-Beuren综合征-其中缺失区域分别包括ATR、RPA1和Rfc2。这三个基因在ATR信号转导中起作用。这些疾病的细胞系显示出受损的ATR依赖的DNA损伤反应。因此，我们将ATR信号描述为对单倍体不足异常敏感的通路，并确定了另外三种表现出缺陷的ATR依赖的DNA损伤反应的人类疾病。ATR途径功能障碍与小头畸形和生长迟缓的存在有显著的相关性，这强烈地表明了因果关系。
Ataxia telangiectasia and Rad3-related (ATR) protein, a kinase that regulates a DNA damage-response pathway, is mutated in ATR-Seckel syndrome (ATR-SS), a disorder characterized by severe microcephaly and growth delay. Impaired ATR signaling is also observed in cell lines from additional disorders characterized by microcephaly and growth delay, including non-ATR-SS, Nijmegen breakage syndrome, and MCPH1 (microcephaly, primary autosomal recessive, 1)-dependent primary microcephaly. Here, we examined ATR-pathway function in cell lines from three haploinsufficient contiguous gene-deletion disorders-a subset of blepharophimosis-ptosis-epicanthus inversus syndrome, Miller-Dieker lissencephaly syndrome, and Williams-Beuren syndrome-in which the deleted region encompasses ATR, RPA1, and RFC2, respectively. These three genes function in ATR signaling. Cell lines from these disorders displayed an impaired ATR-dependent DNA damage response. Thus, we describe ATR signaling as a pathway unusually sensitive to haploinsufficiency and identify three further human disorders displaying a defective ATR-dependent DNA damage response. The striking correlation of ATR-pathway dysfunction with the presence of microcephaly and growth delay strongly suggests a causal relationship.