Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Australia.
J Exp Med. 2021 Mar 1;218(3). doi: 10.1084/jem.20200622.
ERCC1-XPF is a multifunctional endonuclease involved in nucleotide excision repair (NER), interstrand cross-link (ICL) repair, and DNA double-strand break (DSB) repair. Only two patients with bi-allelic ERCC1 mutations have been reported, both of whom had features of Cockayne syndrome and died in infancy. Here, we describe two siblings with bi-allelic ERCC1 mutations in their teenage years. Genomic sequencing identified a deletion and a missense variant (R156W) within ERCC1 that disrupts a salt bridge below the XPA-binding pocket. Patient-derived fibroblasts and knock-in epithelial cells carrying the R156W substitution show dramatically reduced protein levels of ERCC1 and XPF. Moreover, mutant ERCC1 weakly interacts with NER and ICL repair proteins, resulting in diminished recruitment to DNA damage. Consequently, patient cells show strongly reduced NER activity and increased chromosome breakage induced by DNA cross-linkers, while DSB repair was relatively normal. We report a new case of ERCC1 deficiency that severely affects NER and considerably impacts ICL repair, which together result in a unique phenotype combining short stature, photosensitivity, and progressive liver and kidney dysfunction.
ERCC1-XPF 是一种多功能内切核酸酶，参与核苷酸切除修复 (NER)、链间交联 (ICL) 修复和 DNA 双链断裂 (DSB) 修复。仅报道过两名具有双等位基因 ERCC1 突变的患者，均具有 Cockayne 综合征的特征，并在婴儿期死亡。在这里，我们描述了两名具有双等位基因 ERCC1 突变的青少年兄弟姐妹。基因组测序确定 ERCC1 内的缺失和错义变体 (R156W)，破坏 XPA 结合口袋下方的盐桥。携带 R156W 取代的患者衍生成纤维细胞和敲入上皮细胞显示 ERCC1 和 XPF 的蛋白水平显著降低。此外，突变型 ERCC1 与 NER 和 ICL 修复蛋白的弱相互作用导致其向 DNA 损伤的募集减少。因此，患者细胞显示出强烈降低的 NER 活性和由 DNA 交联剂诱导的染色体断裂增加，而 DSB 修复相对正常。我们报告了一种新的 ERCC1 缺乏症病例，该病例严重影响 NER，并对 ICL 修复产生重大影响，这共同导致了一种独特的表型，包括身材矮小、光敏感性和进行性肝肾功能障碍。
