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Journal of Surgical Case Reports May 2024This retrospective case series evaluates treatment outcomes post-cochlear implantation in pediatric patients diagnosed with Cockayne syndrome (CS) and bilateral...
This retrospective case series evaluates treatment outcomes post-cochlear implantation in pediatric patients diagnosed with Cockayne syndrome (CS) and bilateral sensorineural hearing loss. Two female pediatric patients with CS type I underwent either bilateral or unilateral cochlear implantation. Visual reinforcement audiometry (VRA) and postoperative cochlear implant tolerance were the main outcome measures. Patient 1 demonstrated notable improvements in VRA results and school performance following bilateral implantation. Patient 2 experienced enhanced quality of life and environmental awareness post-unilateral implantation, despite a lack of objective VRA results due to developmental delay. The study underscores the benefits of cochlear implantation in CS patients, especially in patients who are post-lingual or with better cognitive function.
PubMed: 38803843
DOI: 10.1093/jscr/rjae346 -
Genes Apr 2024(1) Background: Cockayne syndrome (CS) is an ultra-rare multisystem disorder, classically subdivided into three forms and characterized by a clinical spectrum without a...
(1) Background: Cockayne syndrome (CS) is an ultra-rare multisystem disorder, classically subdivided into three forms and characterized by a clinical spectrum without a clear genotype-phenotype correlation for both the two causative genes (CS type B) and (CS type A). We assessed this, presenting a series of patients with genetically confirmed CSB. (2) Materials and Methods: We retrospectively collected demographic, clinical, genetic, neuroimaging, and serum neurofilament light-chain (sNFL) data about CSB patients; diagnostic and severity scores were also determined. (3) Results: Data of eight CSB patients are presented. Four patients had CS I, three patients CS II, and one patient CS III. Various degrees of ataxia and spasticity were cardinal neurologic features, with variably combined systemic characteristics. Mean age at diagnosis was lower in the type II form, in which classic CS signs were more evident. Interestingly, sNFL determination appeared to reflect clinical classification. Two novel premature stop codon and one novel missense variants were identified. All CS I subjects harbored the p.Arg735Ter variant; the milder CS III subject carried the p.Leu764Ser missense change. (4) Conclusion: Our work confirms clinical variability also in the /CSB type, where manifestations may range from severe involvement with prenatal or neonatal onset to normal psychomotor development followed by progressive ataxia. We propose, for the first time in CS, sNFL as a useful peripheral biomarker, with increased levels compared to currently available reference values and with the potential ability to reflect disease severity.
Topics: Humans; Cockayne Syndrome; Poly-ADP-Ribose Binding Proteins; DNA Repair Enzymes; Female; Male; DNA Helicases; Child; Child, Preschool; Adolescent; Retrospective Studies; Adult; Infant; Genetic Association Studies; Young Adult; Transcription Factors
PubMed: 38674442
DOI: 10.3390/genes15040508 -
DNA Repair Jun 2024Neurodegenerative diseases are the second most prevalent cause of death in industrialized countries. Alzheimer's Disease is the most widespread and also most... (Review)
Review
Neurodegenerative diseases are the second most prevalent cause of death in industrialized countries. Alzheimer's Disease is the most widespread and also most acknowledged form of dementia today. Together with Parkinson's Disease they account for over 90 % cases of neurodegenerative disorders caused by proteopathies. Far less known are the neurodegenerative pathologies in DNA repair deficiency syndromes. Such diseases like Cockayne - or Werner Syndrome are described as progeroid syndromes - diseases that cause the premature ageing of the affected persons, and there are clear implications of such diseases in neurologic dysfunction and degeneration. In this review, we aim to draw the attention on commonalities between proteopathy-associated neurodegeneration and neurodegeneration caused by DNA repair defects and discuss how mitochondria are implicated in the development of both disorder classes. Furthermore, we highlight how nematodes are a valuable and indispensable model organism to study conserved neurodegenerative processes in a fast-forward manner.
Topics: Humans; Animals; Neurodegenerative Diseases; DNA Repair; Mitochondria; Caenorhabditis elegans; DNA Repair-Deficiency Disorders; Cockayne Syndrome
PubMed: 38640601
DOI: 10.1016/j.dnarep.2024.103679 -
Cells Mar 2024Cockayne syndrome (CS) is a rare hereditary autosomal recessive disorder primarily caused by mutations in Cockayne syndrome protein A (CSA) or B (CSB). While many of the...
Cockayne Syndrome Patient iPSC-Derived Brain Organoids and Neurospheres Show Early Transcriptional Dysregulation of Biological Processes Associated with Brain Development and Metabolism.
Cockayne syndrome (CS) is a rare hereditary autosomal recessive disorder primarily caused by mutations in Cockayne syndrome protein A (CSA) or B (CSB). While many of the functions of CSB have been at least partially elucidated, little is known about the actual developmental dysregulation in this devasting disorder. Of particular interest is the regulation of cerebral development as the most debilitating symptoms are of neurological nature. We generated neurospheres and cerebral organoids utilizing Cockayne syndrome B protein (CSB)-deficient induced pluripotent stem cells derived from two patients with distinct severity levels of CS and healthy controls. The transcriptome of both developmental timepoints was explored using RNA-Seq and bioinformatic analysis to identify dysregulated biological processes common to both patients with CS in comparison to the control. CSB-deficient neurospheres displayed upregulation of the VEGFA-VEGFR2 signalling pathway, vesicle-mediated transport and head development. CSB-deficient cerebral organoids exhibited downregulation of brain development, neuron projection development and synaptic signalling. We further identified the upregulation of steroid biosynthesis as common to both timepoints, in particular the upregulation of the cholesterol biosynthesis branch. Our results provide insights into the neurodevelopmental dysregulation in patients with CS and strengthen the theory that CS is not only a neurodegenerative but also a neurodevelopmental disorder.
Topics: Humans; Induced Pluripotent Stem Cells; DNA Helicases; DNA Repair Enzymes; Cockayne Syndrome; Poly-ADP-Ribose Binding Proteins; Brain; Organoids
PubMed: 38607030
DOI: 10.3390/cells13070591 -
Nature Cell Biology May 2024Covalent DNA-protein cross-links (DPCs) are toxic DNA lesions that block replication and require repair by multiple pathways. Whether transcription blockage contributes...
Covalent DNA-protein cross-links (DPCs) are toxic DNA lesions that block replication and require repair by multiple pathways. Whether transcription blockage contributes to the toxicity of DPCs and how cells respond when RNA polymerases stall at DPCs is unknown. Here we find that DPC formation arrests transcription and induces ubiquitylation and degradation of RNA polymerase II. Using genetic screens and a method for the genome-wide mapping of DNA-protein adducts, DPC sequencing, we discover that Cockayne syndrome (CS) proteins CSB and CSA provide resistance to DPC-inducing agents by promoting DPC repair in actively transcribed genes. Consequently, CSB- or CSA-deficient cells fail to efficiently restart transcription after induction of DPCs. In contrast, nucleotide excision repair factors that act downstream of CSB and CSA at ultraviolet light-induced DNA lesions are dispensable. Our study describes a transcription-coupled DPC repair pathway and suggests that defects in this pathway may contribute to the unique neurological features of CS.
Topics: Poly-ADP-Ribose Binding Proteins; DNA Repair Enzymes; Humans; Transcription, Genetic; DNA Repair; DNA Helicases; RNA Polymerase II; Ubiquitination; Cockayne Syndrome; DNA Damage; Ultraviolet Rays; DNA; DNA Adducts; Excision Repair; Transcription Factors; Receptors, Interleukin-17
PubMed: 38600235
DOI: 10.1038/s41556-024-01391-1 -
Nature Cell Biology May 2024DNA-protein crosslinks (DPCs) induced by aldehydes interfere with replication and transcription. Hereditary deficiencies in DPC repair and aldehyde clearance processes...
DNA-protein crosslinks (DPCs) induced by aldehydes interfere with replication and transcription. Hereditary deficiencies in DPC repair and aldehyde clearance processes cause progeria, including Ruijs-Aalfs syndrome (RJALS) and AMeD syndrome (AMeDS) in humans. Although the elimination of DPC during replication has been well established, how cells overcome DPC lesions in transcription remains elusive. Here we show that endogenous aldehyde-induced DPC roadblocks are efficiently resolved by transcription-coupled repair (TCR). We develop a high-throughput sequencing technique to measure the genome-wide distribution of DPCs (DPC-seq). Using proteomics and DPC-seq, we demonstrate that the conventional TCR complex as well as VCP/p97 and the proteasome are required for the removal of formaldehyde-induced DPCs. TFIIS-dependent cleavage of RNAPII transcripts protects against transcription obstacles. Finally, a mouse model lacking both aldehyde clearance and TCR confirms endogenous DPC accumulation in actively transcribed regions. Collectively, our data provide evidence that transcription-coupled DPC repair (TC-DPCR) as well as aldehyde clearance are crucial for protecting against metabolic genotoxin, thus explaining the molecular pathogenesis of AMeDS and other disorders associated with defects in TCR, such as Cockayne syndrome.
Topics: Animals; DNA Repair; Transcription, Genetic; Humans; Aldehydes; Proteasome Endopeptidase Complex; Mice; DNA; DNA Damage; Mice, Knockout; Valosin Containing Protein; RNA Polymerase II; Mice, Inbred C57BL; Formaldehyde; Excision Repair
PubMed: 38600234
DOI: 10.1038/s41556-024-01401-2 -
Frontiers in Aging 2023According to current views the major hallmarks of physiological aging may be subdivided into three categories, primary causes of cellular damage (genomic instability,... (Review)
Review
According to current views the major hallmarks of physiological aging may be subdivided into three categories, primary causes of cellular damage (genomic instability, telomere attrition, loss of proteostasis, epigenetic alterations and compromised macroautophagy), antagonistic hallmarks that represent response to damage (deregulated nutrient sensing, cellular senescence, mitochondrial dysfunction) and integrative hallmarks that represent culprits of the phenotype (stem cell exhaustion, altered intercellular communication, chronic inflammation, dysbiosis). In contrast to physiological aging, premature aging diseases are driven by one or two distinct primary causes of aging, such as genomic instability in the case of Werner syndrome (WS), each displaying other hallmarks of aging to a variable extent. In this review we will focus on primary causes of well-investigated premature aging diseases Hutchinson-Gilford progeria syndrome (HGPS), WS, and Cockayne syndrome (CS) and for each provide an overview of reported aging hallmarks to elucidate resemblance to physiological aging on the mechanistic level and in the context of characteristic age-related diseases. Ubiquitous and tissue specific animal models of premature aging diseases will be discussed as useful tools to decipher fundamental aging-related mechanisms and develop intervention strategies to combat premature aging and age-related diseases.
PubMed: 38481648
DOI: 10.3389/fragi.2023.1327833 -
Cells Feb 2024Cockayne syndrome (CS) is a rare autosomal recessive disorder that affects the DNA repair process. It is a progeroid syndrome predisposing patients to accelerated aging...
Cockayne syndrome (CS) is a rare autosomal recessive disorder that affects the DNA repair process. It is a progeroid syndrome predisposing patients to accelerated aging and to increased susceptibility to respiratory infections. Here, we studied the immune status of CS patients to determine potential biomarkers associated with pathological aging. CS patients, as well as elderly and young, healthy donors, were enrolled in this study. Complete blood counts for patients and donors were assessed, immune cell subsets were analyzed using flow cytometry, and candidate cytokines were analyzed via multi-analyte ELISArray kits. In CS patients, we noticed a high percentage of lymphocytes, an increased rate of intermediate and non-classical monocytes, and a high level of pro-inflammatory cytokine IL-8. In addition, we identified an increased rate of particular subtypes of T Lymphocyte CD8+ CD28- CD27-, which are senescent T cells. Thus, an inflammatory state was found in CS patients that is similar to that observed in the elderly donors and is associated with an immunosenescence status in both groups. This could explain the CS patients' increased susceptibility to infections, which is partly due to an aging-associated inflammation process.
Topics: Humans; Aged; CD8-Positive T-Lymphocytes; Cockayne Syndrome; Aging; Immunosenescence; Cytokines; Biomarkers
PubMed: 38474366
DOI: 10.3390/cells13050402 -
Nucleic Acids Research May 2024CSB (Cockayne syndrome group B) and SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent, regulator of chromatin, subfamily A-like 1) are DNA translocases that...
CSB (Cockayne syndrome group B) and SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent, regulator of chromatin, subfamily A-like 1) are DNA translocases that belong to the SNF2 helicase family. They both are enriched at stalled replication forks. While SMARCAL1 is recruited by RPA32 to stalled forks, little is known about whether RPA32 also regulates CSB's association with stalled forks. Here, we report that CSB directly interacts with RPA, at least in part via a RPA32C-interacting motif within the N-terminal region of CSB. Modeling of the CSB-RPA32C interaction suggests that CSB binds the RPA32C surface previously shown to be important for binding of UNG2 and SMARCAL1. We show that this interaction is necessary for promoting fork slowing and fork degradation in BRCA2-deficient cells but dispensable for mediating restart of stalled forks. CSB competes with SMARCAL1 for RPA32 at stalled forks and acts non-redundantly with SMARCAL1 to restrain fork progression in response to mild replication stress. In contrast to CSB stimulated restart of stalled forks, SMARCAL1 inhibits restart of stalled forks in BRCA2-deficient cells, likely by suppressing BIR-mediated repair of collapsed forks. Loss of CSB leads to re-sensitization of SMARCAL1-depleted BRCA2-deficient cells to chemodrugs, underscoring a role of CSB in targeted cancer therapy.
Topics: DNA Helicases; Humans; Poly-ADP-Ribose Binding Proteins; BRCA2 Protein; DNA Replication; DNA Repair Enzymes; Replication Protein A; Protein Binding; Cell Line, Tumor; DNA Repair
PubMed: 38416570
DOI: 10.1093/nar/gkae154 -
Stem Cell Reports Mar 2024Quality control of human induced pluripotent stem cells (iPSCs) is critical to ensure reproducibility of research. Recently, KOLF2.1J was characterized and published as...
Quality control of human induced pluripotent stem cells (iPSCs) is critical to ensure reproducibility of research. Recently, KOLF2.1J was characterized and published as a male iPSC reference line to study neurological disorders. Emerging evidence suggests potential negative effects of mtDNA mutations, but its integrity was not analyzed in the original publication. To assess mtDNA integrity, we conducted a targeted mtDNA analysis followed by untargeted metabolomics analysis. We found that KOLF2.1J mtDNA integrity was intact at the time of publication and is still preserved in the commercially distributed cell line. In addition, the basal KOLF2.1J metabolome profile was similar to that of the two commercially available iPSC lines IMR90 and iPSC12, but clearly distinct from an in-house-generated ERCC6 iPSC line modeling Cockayne syndrome. Conclusively, we validate KOLF2.1J as a reference iPSC line, and encourage scientists to conduct mtDNA analysis and unbiased metabolomics whenever feasible.
Topics: Humans; Male; DNA, Mitochondrial; Induced Pluripotent Stem Cells; Reproducibility of Results; Mitochondria; Metabolome
PubMed: 38402620
DOI: 10.1016/j.stemcr.2024.01.009