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.

Human Radiosensitivity and Radiosusceptibility: What Are the Differences?

“…the Li Fraumeni's syndrome (LFS), caused by the heterozygous mutations of p53 [14] is associated with cancer proneness but not with significant post-radiotherapy adverse tissue reactions [14]; • the ataxia telangiectasia (AT) caused by the homozygous mutations of ATM [15] is associated with post-radiotherapy fatal reactions and AT patients are at high risk of leukemia [15,16]; • the Cockayne's syndrome (CS) caused by the homozygous mutations of the CS genes [17] is associated with a significant tissue radiosensitivity but no cancer proneness [17,18].…”

Cockayne Syndrome Group B (CSB): The Regulatory Framework Governing the Multifunctional Protein and Its Plausible Role in Cancer

“…Cockayne syndrome (CS) is characterized by a broad spectrum of clinical features including cachectic dwarfism, cutaneous photosensitivity, microcephaly, growth and developmental abnormalities, neurological and retinal degeneration, physical impairment, deafness and premature aging (reviewed in [ 61 ]). Analyses of large cohorts of CS patients have shown that there is no definite correlation between the genotype (mutations identified) and the symptomatology (clinical manifestations) [ 62 , 63 ]. In fact, as far as CSB mutations are concerned, neither the affected region nor the nature of the mutation is linked to specific clinical manifestations or to the severity of the disease, although a tendency to more severe phenotypes has been proposed in patients with mutations downstream of the PiggyBac insertion in intron 5 [ 62 ].…”

Locked in a vicious cycle: the connection between genomic instability and a loss of protein homeostasis

“…Fibroblasts from WS patients accumulate protein aggregates and exhibit a dramatic upregulation of autophagy (Talaei et al 2013). Cockayne syndrome (CS) is another severe progeroid disorder, caused by mutations in the transcription-coupled nucleotide excision repair (TC-NER) genes CSA or CSB (Vessoni et al 2020). A recent study showed that CS patient-derived cells exhibit increased levels of misfolded proteins and ER stress, postulated to result from a reduced ribosomal translation fidelity (Alupei et al 2018).…”