Neuroimaging in Cockayne syndrome.
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ABSTRACT:
SUBMITTER: Koob M
PROVIDER: S-EPMC7964976 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Cockayne syndrome (CS) is an inherited neurodevelopmental disorder with progeroid features. Although the genes responsible for CS have been implicated in a variety of DNA repair- and transcription-related pathways, the nature of the molecular defect in CS remains mysterious. We sought to define this defect by expression analysis of cells lacking functional CSB, a SWI/SNF-like ATPase that is responsible for most CS cases. Keywords: primary disease rescue
2006-07-14 | GSE3407 | GEO
Project description: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.
| S-EPMC5379700 | biostudies-literature
Project description:UV-sensitive syndrome (UVsS) is a rare autosomal recessive disorder characterized by photosensitivity and mild freckling but without neurological abnormalities or skin tumors. UVsS cells show UV hypersensitivity and defective transcription-coupled DNA repair of UV damage. It was suggested that UVsS does not belong to any complementation groups of known photosensitive disorders such as xeroderma pigmentosum and Cockayne syndrome (CS). To identify the gene responsible for UVsS, we performed a microcell-mediated chromosome transfer based on the functional complementation of UV hypersensitivity. We found that one of the UVsS cell lines, UVs1KO, acquired UV resistance when human chromosome 10 was transferred. Because the gene responsible for CS group B (CSB), which involves neurological abnormalities and photosensitivity as well as a defect in transcription-coupled DNA repair of UV damage, is located on chromosome 10, we sequenced the CSB gene from UVs1KO and detected a homozygous null mutation. Our results indicate that previous complementation analysis of UVs1KO was erroneous. This finding was surprising because a null mutation of the CSB gene would be expected to result in CS features such as severe developmental and neurological abnormalities. On the other hand, no mutation in the CSB cDNA and a normal amount of CSB protein was detected in Kps3, a UVsS cell line obtained from an unrelated patient, indicating genetic heterogeneity in UVsS. Possible explanations for the discrepancy in the genotype-phenotype relationship in UVs1KO are presented.
| S-EPMC524447 | biostudies-literature
Project description:A 7-yr-old patient was referred to pediatric orthopedic clinic of Imam hospital (2016) with the diagnosis of cerebral palsy (CP). His parents were concerned about some inconsistency of his disease progression. After initial evaluations, the diagnosis of CP was incorrect. The true diagnosis was suspected and confirmed with molecular genetic analysis. A rare autosomal recessive disorder -Cockayne syndrome- was diagnosed. Although untreatable, it can be prevented by appropriate prenatal diagnostic tests for their future children.
| S-EPMC6160622 | biostudies-other
Project description:We report on a male patient born to healthy, first cousin, Moroccan parents. During the pregnancy growth retardation was observed. Birth weight, length, and OFC were all well below the 3rd centile. Facial anomalies, microphthalmia, cleft palate, small penis, and flexion contractures of large joints were noted. Cerebral MRI showed dysmyelination. The clinical course was characterised by feeding difficulties, growth failure, lack of development, photosensitivity, and death at 7 months. The main differential diagnoses were COFS syndrome and early onset Cockayne syndrome (CS). UV exposure of cultured fibroblasts showed inhibition of nucleic acids synthesis. Further DNA repair studies showed extreme cellular sensitivity to UV and xeroderma pigmentosum (XP)-like defective nucleotide excision repair (NER), which in combination with the clinical symptoms indicated the very rare XP-CS complex. Complementation analysis showed that the XPG gene is affected in this patient. In cases suspected of having COFS syndrome and early onset CS, extensive DNA repair studies are needed to reach the definitive diagnosis, thereby allowing reliable genetic counselling and prenatal diagnosis.
| S-EPMC1050673 | biostudies-other
Project description:The devastating genetic disorder Cockayne syndrome (CS) arises from mutations in the CSA and CSB genes. CS is characterized by progressive multisystem degeneration and is classified as a segmental premature-aging syndrome. The CS complementation group B (CSB) protein is at the interface of transcription and DNA repair and is involved in transcription-coupled and global genome-DNA repair, as well as in general transcription. Recent structure-function studies indicate a process-dependent variation in the molecular mechanism employed by CSB and provide a starting ground for a description of the mechanisms and their interplay.
| S-EPMC1180389 | biostudies-literature
Project description:BACKGROUND: Cockayne Syndrome CS (Type A - CSA; or CS Type I OMIM #216400) (Type B - CSB; or CS Type II OMIM #133540) is a rare autosomal recessive neurological disease caused by defects in DNA repair characterized by progressive cachectic dwarfism, progressive intellectual disability with cerebral leukodystrophy, microcephaly, progressive pigmentary retinopathy, sensorineural deafness photosensitivity and possibly orofacial and dental anomalies. METHODS: We studied the cranio-oro-facial status of a group of 17 CS patients from 15 families participating in the National Hospital Program for Clinical Research (PHRC) 2005 « Clinical and molecular study of Cockayne syndrome ». All patients were examined by two investigators using the Diagnosing Dental Defects Database (D[4]/phenodent) record form. RESULTS: Various oro-facial and dental anomalies were found: retrognathia; micrognathia; high- arched narrow palate; tooth crowding; hypodontia (missing permanent lateral incisor, second premolars or molars), screwdriver shaped incisors, microdontia, radiculomegaly, and enamel hypoplasia. Eruption was usually normal. Dental caries was associated with enamel defects, a high sugar/carbohydrate soft food diet, poor oral hygiene and dry mouth. Cephalometric analysis revealed mid-face hypoplasia, a small retroposed mandible and hypo-development of the skull. CONCLUSION: CS patients may have associated oro-dental features, some of which may be more frequent in CS children - some of them being described for the first time in this paper (agenesis of second permanent molars and radiculomegaly). The high susceptibility to rampant caries is related to a combination of factors as well as enamel developmental defects. Specific attention to these anomalies may contribute to diagnosis and help plan management.
| S-EPMC3599377 | biostudies-literature
Project description:Cockayne syndrome (CS) and UV-sensitive syndrome (UVSS) are rare genetic disorders caused by mutation of the DNA repair and multifunctional CSA or CSB protein, but only CS patients display a progeroid and neurodegenerative phenotype, providing a unique conceptual and experimental paradigm. As DNA methylation (DNAm) remodelling is a major ageing marker, we performed genome-wide analysis of DNAm of fibroblasts from healthy, UVSS and CS individuals. Differential analysis highlighted a CS-specific epigenomic signature (progeroid-related; not present in UVSS) enriched in three categories: developmental transcription factors, ion/neurotransmitter membrane transporters and synaptic neuro-developmental genes. A large fraction of CS-specific DNAm changes were associated with expression changes in CS samples, including in previously reported post-mortem cerebella. The progeroid phenotype of CS was further supported by epigenomic hallmarks of ageing: the prediction of DNAm of repetitive elements suggested an hypomethylation of Alu sequences in CS, and the epigenetic clock returned a marked increase in CS biological age respect to healthy and UVSS cells. The epigenomic remodelling of accelerated ageing in CS displayed both commonalities and differences with other progeroid diseases and regular ageing. CS shared DNAm changes with normal ageing more than other progeroid diseases do, and included genes functionally validated for regular ageing. Collectively, our results support the existence of an epigenomic basis of accelerated ageing in CS and unveil new genes and pathways that are potentially associated with the progeroid/degenerative phenotype.
| S-EPMC10577576 | biostudies-literature
Project description:Cockayne syndrome (CS) is a congenital syndrome characterized by growth and mental retardation, and premature ageing. The complexity of CS and mammalian models warrants simpler metazoan models that display CS-like phenotypes that could be studied in the context of a live organism. Here, we provide a characterization of neuronal and mitochondrial aberrations caused by a mutation in the csb-1 gene in Caenorhabditis elegans. We report a progressive neurodegeneration in adult animals that is enhanced upon UV-induced DNA damage. The csb-1 mutants show dysfunctional hyperfused mitochondria that degrade upon DNA damage, resulting in diminished respiratory activity. Our data support the role of endogenous DNA damage as a driving factor of CS-related neuropathology and underline the role of mitochondrial dysfunction in the disease.
| S-EPMC7641758 | biostudies-literature
Project description:Cockayne syndrome (CS) is an inherited disorder that involves photosensitivity, developmental defects, progressive degeneration and characteristics of premature aging. Evidence indicates primarily nuclear roles for the major CS proteins, CSA and CSB, specifically in DNA repair and RNA transcription. We reveal herein a complex regulation of CSB targeting that involves three major consensus signals: NLS1 (aa467-481), which directs nuclear and nucleolar localization in cooperation with NoLS1 (aa302-341), and NLS2 (aa1038-1055), which seemingly optimizes nuclear enrichment. CSB localization to the nucleolus was also found to be important for full UVC resistance. CSA, which does not contain any obvious targeting sequences, was adversely affected (i.e. presumably destabilized) by any form of truncation. No inter-coordination between the subnuclear localization of CSA and CSB was observed, implying that this aspect does not underlie the clinical features of CS. The E3 ubiquitin ligase binding partner of CSA, DDB1, played an important role in CSA stability (as well as DDB2), and facilitated CSA association with chromatin following UV irradiation; yet did not affect CSB chromatin binding. We also observed that initial recruitment of CSB to DNA interstrand crosslinks is similar in the nucleoplasm and nucleolus, although final accumulation is greater in the former. Whereas assembly of CSB at sites of DNA damage in the nucleolus was not affected by RNA polymerase I inhibition, stable retention at these sites of presumed repair was abrogated. Our studies reveal a multi-faceted regulation of the intranuclear dynamics of CSA and CSB that plays a role in mediating their cellular functions.
| S-EPMC6269539 | biostudies-literature