Cockayne Syndrome: The many challenges and approaches to understand a multifaceted disease

Abstract The striking and complex phenotype of Cockayne syndrome (CS) patients combines progeria-like features with developmental deficits. Since the establishment of the in vitro culture of skin fibroblasts derived from patients with CS in the 1970s, significant progress has been made in the understanding of the genetic alterations associated with the disease and their impact on molecular, cellular, and organismal functions. In this review, we provide a historic perspective on the research into CS by revisiting seminal papers in this field. We highlighted the great contributions of several researchers in the last decades, ranging from the cloning and characterization of CS genes to the molecular dissection of their roles in DNA repair, transcription, redox processes and metabolism control. We also provide a detailed description of all pathological mutations in genes ERCC6 and ERCC8 reported to date and their impact on CS-related proteins. Finally, we review the contributions (and limitations) of many genetic animal models to the study of CS and how cutting-edge technologies, such as cell reprogramming and state-of-the-art genome editing, are helping us to address unanswered questions.

摘要：科凯恩综合征（Cockayne Syndrome, CS）患者的表型显著且复杂，兼具早老症样特征与发育缺陷。自20世纪70年代首次建立科凯恩综合征患者皮肤成纤维细胞的体外培养体系以来，学界对该病相关遗传改变及其对分子、细胞与机体功能的影响的认知已取得长足进展。本综述通过回顾该领域的开创性研究文献，梳理科凯恩综合征研究的历史脉络；重点阐述近数十年来诸多研究者的重要贡献，涵盖科凯恩综合征致病基因的克隆与鉴定，以及这些基因在DNA修复、转录、氧化还原过程及代谢调控中功能的分子解析。本文还详细描述了目前已报道的ERCC6基因（ERCC6）与ERCC8基因（ERCC8）的全部病理性突变及其对科凯恩综合征相关蛋白的影响。最后，本文综述了各类遗传动物模型在科凯恩综合征研究中的贡献与局限性，并探讨了细胞重编程、顶尖基因组编辑等前沿技术如何助力解答尚未解决的科学问题。