コケイン症候群

Two subpathways of Nucleotide Excision Repair (NER), global genomic (GG-NER) and transcription-coupled NER (TC-NER), remove bulky DNA lesions such as cyclobutane pyrimidine dimers (CPDs). Xeroderma pigmentosum protein D (XPD) is a DNA helicase subunit within the transcription factor IIH (TFIIH) complex that is important for DNA unwinding and damage verification during NER. Germline mutations in XPD can not only cause the cancer-prone disease Xeroderma Pigmentosum (XP), but also a combination of XP with Cockayne Syndrome (CS), a syndrome characterized by neurodegeneration and premature aging. While XP and XP/CS mutations in XPD disrupt NER, their specific effects on the NER subpathways are less well understood. In this study, we introduced two pairs of XP and XP/CS mutations into the yeast RAD3 gene, a homolog of human XPD. Our data indicates that yeast XP/CS mutants are more sensitive to UV radiation and have reduced NER capacity relative to the XP mutants. Using a damage mapping method named CPD sequencing (CPD-seq 2.0), we found that the XP/CS mutations abrogated repair by both GG-NER and TC-NER, while XP mutations impaired GG-NER but retained significant TC-NER activity. Consistent with these results, XPD mutant human cell lines established from individuals with XP/CS were sensitivity to Illudin S, an agent that induces damage repaired by TC-NER. Thus, we conclude that XP/CS mutations not only cause a more severe overall NER defect than XP mutations, but specifically disrupt the TC-NER subpathway, with this defect likely underlying the Cockayne Syndrome symptoms.

Cockayne syndrome (CS) is a rare autosomal recessive transcription-coupled nucleotide excision repair disorder (ERCC6/ERCC8) causing progressive neuromuscular deterioration and limb contractures. We report a 10-year-old boy with CS type B (ERCC6) who presented with rigid bilateral equinovarus, rendering him non-ambulatory, and elevated transaminases (ALT 682 U/L, AST 183 U/L). Bilateral fractional elongation of the Achilles tendon was performed successfully; hepatotoxic agents were avoided, and opioid/sedative dosages were meticulously titrated. Recovery was uneventful; the patient regained supported standing and resumed active physiotherapy. Functional orthopedic surgery is achievable in CS via rigorous multidisciplinary coordination, providing a valuable template for perioperative risk management.

OBJECTIVE: To carry out a comprehensive analysis of dental manifestations and identify the features of the dental system in children with premature aging syndromes. MATERIAL AND METHODS: The study included 7 patients with premature aging syndromes: a boy and a girl with Hutchinson-Gilford syndrome, 2 girls with Cockayne syndrome type A and B, one girl each with neonatal progeroid syndrome, Penttinen syndrome and mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL syndrome). During a clinical examination by a dentist, the condition of the hard tissues of the teeth, periodontal and oral mucosa was assessed. According to orthopantomography data, the condition of occlusion and dentition was assessed. RESULTS: According to the results of the observations, a common pattern was revealed for all the examined patients: jaw hypoplasia and multiple caries. UNLABELLED: In patients with Hutchinson-Guilford and MDPL-syndrome, crowding and multiple carious lesions of the teeth were the most characteristic; for a patient with Penttinen syndrome, mandibular macrognathia, mesial occlusion and thickening of the mucous membrane of the frontal, sphenoid sinuses, a decrease in the cells of the latticed labyrinth;a feature of neonatal progeroid syndrome is the presence of neonatal incisors at birth, followed by hypo-/oligodontia or adentia. CONCLUSION: Knowledge of dento-mandibular anomalies in premature aging syndromes will allow dentists to timely detect pathologic changes in the dento-mandibular system and correct the dental status of patients with progeroid syndromes, which will significantly improve their quality of life.

PURPOSE: The goal of this long-term collaboration between Vilhelm A. Bohr and Miral Dizdaroglu was to investigate oxidative DNA damage and DNA repair mechanisms and their links to aging, neurodegeneration, and disease. Using GC/MS assays, the collaboration aimed to identify other endogenous DNA lesions like FapyGua and FapyAde beyond the standard 8-oxo-Gua marker to determine their biological significance and distribution in nuclear and mitochondrial DNA. RESULTS: DNA Repair Pathways: Identified OGG1 and NTH1 as the primary glycosylases for formamidopyrimidines and demonstrated that CSB protein stimulates NEIL1 activity.Disease & Aging: Found that Cockayne syndrome group B (CSB) and Xeroderma pigmentosum group A (XPA) patients are deficient in repairing specific oxidative lesions, linking these defects to premature aging. In lung cancer, reduced hOGG1 expression correlated with elevated 8-oxo-Gua.Genomic Insights: Initial DNA damage induction was found to be similar in nuclear and mitochondrial DNA, challenging the assumption that mitochondria accumulate significantly more DNA damage. CONCLUSION: The research established that oxidative damage extends far beyond 8-oxo-Gua and that Base Excision Repair (BER) defects are central to the pathology of cancer and neurodegeneration. The findings emphasize that a multi-lesion approach is essential for understanding the link between oxidative stress and disease.