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Ageing Research Reviews Jan 2017Cockayne syndrome (CS) is a disorder characterized by a variety of clinical features including cachectic dwarfism, severe neurological manifestations including... (Review)
Review
Cockayne syndrome (CS) is a disorder characterized by a variety of clinical features including cachectic dwarfism, severe neurological manifestations including microcephaly and cognitive deficits, pigmentary retinopathy, cataracts, sensorineural deafness, and ambulatory and feeding difficulties, leading to death by 12 years of age on average. It is an autosomal recessive disorder, with a prevalence of approximately 2.5 per million. There are several phenotypes (1-3) and two complementation groups (CSA and CSB), and CS overlaps with xeroderma pigmentosum (XP). It has been considered a progeria, and many of the clinical features resemble accelerated aging. As such, the study of CS affords an opportunity to better understand the underlying mechanisms of aging. The molecular basis of CS has traditionally been ascribed to defects in transcription and transcription-coupled nucleotide excision repair (TC-NER). However, recent work suggests that defects in base excision DNA repair and mitochondrial functions may also play key roles. This opens up the possibility for molecular interventions in CS, and by extrapolation, possibly in aging.
Topics: Aging; Aging, Premature; Animals; Cockayne Syndrome; Cognition; DNA Repair; Humans; Mitochondria; Models, Biological; Symptom Assessment; Transcriptional Activation
PubMed: 27507608
DOI: 10.1016/j.arr.2016.08.002 -
Annual Review of Biochemistry Jun 2023Ultraviolet (UV) irradiation and other genotoxic stresses induce bulky DNA lesions, which threaten genome stability and cell viability. Cells have evolved two main... (Review)
Review
Ultraviolet (UV) irradiation and other genotoxic stresses induce bulky DNA lesions, which threaten genome stability and cell viability. Cells have evolved two main repair pathways to remove such lesions: global genome nucleotide excision repair (GG-NER) and transcription-coupled nucleotide excision repair (TC-NER). The modes by which these subpathways recognize DNA lesions are distinct, but they converge onto the same downstream steps for DNA repair. Here, we first summarize the current understanding of these repair mechanisms, specifically focusing on the roles of stalled RNA polymerase II, Cockayne syndrome protein B (CSB), CSA and UV-stimulated scaffold protein A (UVSSA) in TC-NER. We also discuss the intriguing role of protein ubiquitylation in this process. Additionally, we highlight key aspects of the effect of UV irradiation on transcription and describe the role of signaling cascades in orchestrating this response. Finally, we describe the pathogenic mechanisms underlying xeroderma pigmentosum and Cockayne syndrome, the two main diseases linked to mutations in NER factors.
Topics: Humans; Cockayne Syndrome; DNA Repair Enzymes; Transcription, Genetic; DNA Repair; DNA Damage; DNA; Carrier Proteins
PubMed: 37040775
DOI: 10.1146/annurev-biochem-052621-091205 -
Neurological Sciences : Official... Nov 2019Basal ganglia calcifications could be incidental findings up to 20% of asymptomatic patients undergoing CT or MRI scan. The presence of neuropsychiatric symptoms... (Review)
Review
Basal ganglia calcifications could be incidental findings up to 20% of asymptomatic patients undergoing CT or MRI scan. The presence of neuropsychiatric symptoms associated with bilateral basal ganglia calcifications (which could occur in other peculiar brain structures, such as dentate nuclei) identifies a clinical picture defined as Fahr's Disease. This denomination mainly refers to idiopathic forms in which no metabolic or other underlying causes are identified. Recently, mutations in four different genes (SLC20A2, PDGFRB, PDGFB, and XPR1) were identified, together with novel mutations in the Myogenic Regulating Glycosylase gene, causing the occurrence of movement disorders, cognitive decline, and psychiatric symptoms. On the other hand, secondary forms, also identified as Fahr's syndrome, have been associated with different conditions: endocrine abnormalities of PTH, such as hypoparathyroidism, other genetically determined conditions, brain infections, or toxic exposure. The underlying pathophysiology seems to be related to an abnormal calcium/phosphorus homeostasis and transportation and alteration of the blood-brain barrier.
Topics: Autoimmune Diseases of the Nervous System; Basal Ganglia Diseases; Calcinosis; Cockayne Syndrome; Humans; Hypoparathyroidism; Lupus Vasculitis, Central Nervous System; Mitochondrial Diseases; Nervous System Malformations; Neurodegenerative Diseases; Neurotoxicity Syndromes; Pseudohypoparathyroidism; Xenotropic and Polytropic Retrovirus Receptor
PubMed: 31267306
DOI: 10.1007/s10072-019-03998-x -
Cell Mar 2020In response to transcription-blocking DNA damage, cells orchestrate a multi-pronged reaction, involving transcription-coupled DNA repair, degradation of RNA polymerase...
In response to transcription-blocking DNA damage, cells orchestrate a multi-pronged reaction, involving transcription-coupled DNA repair, degradation of RNA polymerase II (RNAPII), and genome-wide transcription shutdown. Here, we provide insight into how these responses are connected by the finding that ubiquitylation of RNAPII itself, at a single lysine (RPB1 K), is the focal point for DNA-damage-response coordination. K ubiquitylation affects DNA repair and signals RNAPII degradation, essential for surviving genotoxic insult. RNAPII degradation results in a shutdown of transcriptional initiation, in the absence of which cells display dramatic transcriptome alterations. Additionally, regulation of RNAPII stability is central to transcription recovery-persistent RNAPII depletion underlies the failure of this process in Cockayne syndrome B cells. These data expose regulation of global RNAPII levels as integral to the cellular DNA-damage response and open the intriguing possibility that RNAPII pool size generally affects cell-specific transcription programs in genome instability disorders and even normal cells.
Topics: DNA Damage; DNA Repair; HEK293 Cells; Humans; RNA Polymerase II; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Transcription, Genetic; Ubiquitination; Ultraviolet Rays
PubMed: 32142654
DOI: 10.1016/j.cell.2020.02.009 -
Orphanet Journal of Rare Diseases Apr 2017Xeroderma pigmentosum-Cockayne syndrome complex is a very rare multisystem degenerative disorder (Orpha: 220295; OMIM: 278730, 278760, 278780, 610651). Published... (Review)
Review
Xeroderma pigmentosum-Cockayne syndrome complex is a very rare multisystem degenerative disorder (Orpha: 220295; OMIM: 278730, 278760, 278780, 610651). Published information on XP-CS is mostly scattered throughout the literature. We compiled statistics related to symptom prevalence in XP-CS and have written a clinical description of the syndrome. We also drew on clinical practices used in XP and in Cockayne syndrome without XP to aid management of XP-CS.Extensive searches of the literature identified 43 XP-CS patients. The diagnosis had been confirmed with molecular or biochemical methods in 42 of them. Clinical features of each patient were summarized in spreadsheets and summary statistics were generated from this data. XP patients are classified into complementation groups according to the gene that is mutated. There are four groups in XP-CS, and classification was available for 42 patients. Twenty-one were in the XP-G complementation group, 13 in XP-D, 5 in XP-B, and 3 in XP-F. Overall, the clinical features of XP-CS are very similar to those of CS without XP, with the exception of skin cancers in XP-CS. However, one intriguing finding was that cancer incidence was lower in XP-CS compared to XP alone or XP-neurological disorder. The cancer rate in XP-CS was higher than in CS without XP, an unsurprising finding. There is preliminary evidence for the existence of severity groups in XP-CS, as is the case in CS.Although health problems in XP-CS vary both in severity and in when they the first occur, there was overall homogeneity between all complementation groups and putative severity groups. Severely affected patients met fewer milestones and died at younger ages compared to more mildly affected patients.
Topics: Cockayne Syndrome; Humans; Mutation; Xeroderma Pigmentosum
PubMed: 28376890
DOI: 10.1186/s13023-017-0616-2 -
Orphanet Journal of Rare Diseases Feb 2021Cockayne syndrome is a progressive multisystem genetic disorder linked to defective DNA repair and transcription. This rare condition encompasses a very wide spectrum of...
BACKGROUND
Cockayne syndrome is a progressive multisystem genetic disorder linked to defective DNA repair and transcription. This rare condition encompasses a very wide spectrum of clinical severity levels ranging from severe prenatal onset to mild adult-onset subtypes. The rarity, complexity and variability of the disease make early diagnosis and severity assessment difficult. Based on similar approaches in other neurodegenerative disorders, we propose to validate diagnostic and severity scores for Cockayne syndrome.
METHODS
Clinical, imaging and genetic data were retrospectively collected from 69 molecularly confirmed CS patients. A clinical diagnostic score and a clinical-radiological diagnostic score for CS were built using a multivariable logistic regression model with a stepwise variable selection procedure. A severity score for CS was designed on five items (head circumference, growth failure, neurosensorial signs, motor autonomy, communication skills) and validated by comparison with classical predefined severity subtypes of CS.
RESULTS
Short stature, enophtalmos, hearing loss, cataracts, cutaneous photosensitivity, frequent dental caries, enamel hypoplasia, morphological abnormalities of the teeth, areflexia and spasticity were included in the clinical diagnostic score as being the most statistically relevant criteria. Appropriate weights and thresholds were assigned to obtain optimal sensitivity and specificity (95.7% and 86.4% respectively). The severity score was shown to be able to quantitatively differentiate classical predefined subtypes of CS and confirmed the continuous distribution of the clinical presentations in CS. Longitudinal follow-up of the severity score was able to reflect the natural course of the disease.
CONCLUSION
The diagnostic and severity scores for CS will facilitate early diagnosis and longitudinal evaluation of future therapeutic interventions. Prospective studies will be needed to confirm these findings.
Topics: Adult; Cockayne Syndrome; Dental Caries; Female; Humans; Photosensitivity Disorders; Pregnancy; Prospective Studies; Retrospective Studies
PubMed: 33536051
DOI: 10.1186/s13023-021-01686-8