The emerging role of Cockayne group A and B proteins in ubiquitin/proteasome-directed protein degradation.

When mutated, csa and csb genes are responsible of the complex phenotype of the premature aging Cockayne Syndrome (CS). Our working hypothesis is to reconcile the multiple cellular and molecular phenotypes associated to CS within the unifying molecular function of CSA and CSB proteins in the cascade of events leading to ubiquitin/proteasome-directed protein degradation, which occurs in processes as DNA repair, transcription and cell division. This achievement may reasonably explain the plethora of cellular UPS-regulated functions that result impaired when either CSA or CSB are mutated and suggestively explains part of their pleiotropic effect. This review is aimed to solicit the interest of the scientific community in further investigating this aspect, since we believe that the identification of the ubiquitin-proteasome machinery as a new potential therapeutic target, able to comprehensively face the different molecular aspects of CS, whether confirmed and corroborated by in vivo studies, would open a promising avenue to design effective therapeutic intervention.

Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction.

Cockayne syndrome (CS) is a rare autosomal recessive inherited disorder characterized by a variety of clinical features, including increased sensitivity to sunlight, progressive neurological abnormalities, and the appearance of premature aging. However, the pathogenesis of CS remains unclear due to the limitations of current disease models. Here, we generate integration-free induced pluripotent stem cells (iPSCs) from fibroblasts from a CS patient bearing mutations in CSB/ERCC6 gene and further derive isogenic gene-corrected CS-iPSCs (GC-iPSCs) using the CRISPR/Cas9 system. CS-associated phenotypic defects are recapitulated in CS-iPSC-derived mesenchymal stem cells (MSCs) and neural stem cells (NSCs), both of which display increased susceptibility to DNA damage stress. Premature aging defects in CS-MSCs are rescued by the targeted correction of mutant ERCC6. We next map the transcriptomic landscapes in CS-iPSCs and GC-iPSCs and their somatic stem cell derivatives (MSCs and NSCs) in the absence or presence of ultraviolet (UV) and replicative stresses, revealing that defects in DNA repair account for CS pathologies. Moreover, we generate autologous GC-MSCs free of pathogenic mutation under a cGMP (Current Good Manufacturing Practice)-compliant condition, which hold potential for use as improved biomaterials for future stem cell replacement therapy for CS. Collectively, our models demonstrate novel disease features and molecular mechanisms and lay a foundation for the development of novel therapeutic strategies to treat CS.

Xeroderma pigmentosum-Cockayne syndrome complex.

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.

Understanding photodermatoses associated with defective DNA repair: Photosensitive syndromes without associated cancer predisposition.

Photodermatoses associated with defective DNA repair are a group of photosensitive hereditary skin disorders. In this review, we focus on diseases and syndromes with defective nucleotide excision repair that are not accompanied by an increased risk of cutaneous malignancies despite having photosensitivity. Specifically, the gene mutations and transcription defects, epidemiology, and clinical features of Cockayne syndrome, cerebro-oculo-facial-skeletal syndrome, ultraviolet-sensitive syndrome, and trichothiodystrophy will be discussed. These conditions may also have other extracutaneous involvement affecting the neurologic system and growth and development. Rigorous photoprotection remains an important component of the management of these inherited DNA repair-deficiency photodermatoses.

[Cockayne syndrome].

Cockayne syndrome is a rare autosomal recessive disease. This paper reports a case of Cockayne syndrome confirmed by gene analysis. The baby (male, 7 years old) was referred to Peking University Third Hospital with recurrent desquamation, pigmentation and growth and development failure for 6 years, and recurrent dental caries and tooth loss for 2 years. Physical examination showed very low body weight, body length and head circumference, yellow hair, a lot of fawn spots on the face, skin dry and less elastic, and subcutaneous lipopenia. He had an unusual appearance with sunken eyes, sharp nose, sharp mandible, big auricle and dental caries and tooth loss. Crura spasticity and ataxia with excessive tendon reflexion, and ankle movement limitation while bending back were observed. He had slured speech. The level of serum insulin like growth factor I was low, and the results of blood and urinary amino acid analysis suggested malnutrition. The results of blood growth hormone, thyroxin, parathyroxin, liver function, renal function, lipoprotein profile and blood glucose and electrolytes were all within normal limit. An electronic hearing examination showed moderate neural hearing loss. The sonogram of eyes revealed small eye axis and vitreous body opacity of right side. MRI of brain revealed bilateral calcification of basal ganglia and generalized cerebral and cerebellar atrophy, and brainstem and callus were also atrophic. Genetic analysis confirmed with CSA gene mutation. So the boy was definitely diagnosed with Cockayne syndrome. He was discharged because of no effective treatment.

Defective repair of 5-hydroxy-2'-deoxycytidine in Cockayne syndrome cells and its complementation by Escherichia coli formamidopyrimidine DNA glycosylase and endonuclease III.

Repair of the oxidized purine 8-oxo-7,8-dihydro-2'-deoxyguanosine is inefficient in cells belonging to both complementation groups A and B of Cockayne syndrome (CS), a developmental and neurological disorder characterized by defective transcription-coupled repair. We show here that both CS-A and CS-B cells are also defective in the repair of 5-hydroxy-2'-deoxycytidine (5-OHdC), an oxidized pyrimidine with cytotoxic and mutagenic properties. The defect in the repair of oxidatively damaged DNA in CS cells thus extends to oxidized pyrimidines, indicating a general flaw in the repair of oxidized lesions in this syndrome. The defect could not be reproduced in in vitro repair experiments on oligonucleotide substrates, suggesting a role for both CS-A and CS-B proteins in chromatin remodeling during 5-OHdC repair. Expression of Escherichia coli formamidopyrimidine DNA glycosylase (FPG) or endonuclease III complemented the 5-OHdC repair deficiency. Hence, the expression of a single enzyme, FPG from E. coli, stably corrects the delayed removal of both oxidized purines and oxidized pyrimidines in CS cells.

Deep brain stimulation to treat hyperkinetic symptoms of Cockayne syndrome.

Cockayne syndrome manifests a spectrum of neurological dysfunction that includes medically intractable movement disorders. Deep brain stimulation has not been well studied in such rare neurodegenerative conditions. In this case, stimulation of the ventral intermediate nucleus of the thalamus was used to manage severe motor symptoms in a young man with Cockayne syndrome. There was a marked and progressive response to thalamic stimulation within weeks of surgery. These results suggest that patients with Cockayne syndrome should be considered for deep brain stimulation to treat refractory movement disorders.

Síndrome de De Sanctis-Cacchione / De Sanctis-Cacchione syndrome

Se presenta el caso de un paciente con fotosensibilidad desde los primeros meses de su vida y con máculas pigmentadas en áreas expuestas, algunas de ellas con atipia clínica, que fueron aumentando en número a largo del tiempo. Los estudios de biología molecular detectaron alteración en la capacidad de reparación del ADN, por lo que se diagnosticó de xeroderma pigmentoso. Al poco tiempo de nacer ya se había observado retraso psicomotor, bajo peso y microcefalia sin que se filiara la causa. Progresivamente fue manifestando alteraciones neurológicas que incluían sordera neurosensorial, hiporreflexia y arreflexia, así como movimientos coreoatetósicos. Por todo ello consideramos que el paciente puede incluirse en el síndrome de De Sanctis-Cacchione

We present a male patient with photosensitivity since the earliest months of his life, and pigmented macules in exposed areas, some showing clinical atypia, which increased in number over time. Molecular biology studies detected an alteration in DNA repair ability, so xeroderma pigmentosum was diagnosed. Shortly after birth, low weight, microcephaly and psychomotor retardation had been observed, but the cause was not established. The patient progressively showed neurological disorders that included perceptive deafness, hyporeflexia and areflexia, as well as choreoathetotic movements. Therefore, we felt that the patient's symptoms fit De Sanctis-Cacchione syndrome

Restoring DNA repair capacity of cells from three distinct diseases by XPD gene-recombinant adenovirus.

The nucleotide excision repair (NER) is one of the major human DNA repair pathways. Defects in one of the proteins that act in this system result in three distinct autosomal recessive syndromes: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). TFIIH is a nine-protein complex essential for NER activity, initiation of RNA polymerase II transcription and with a possible role in cell cycle regulation. XPD is part of the TFIIH complex and has a helicase function, unwinding the DNA in the 5' --> 3' direction. Mutations in the XPD gene are found in XP, TTD and XP/CS patients, the latter exhibiting both XP and CS symptoms. Correction of DNA repair defects of these cells by transducing the complementing wild-type gene is one potential strategy for helping these patients. Over the last years, adenovirus vectors have been largely used in gene delivering because of their efficient transduction, high titer, and stability. In this work, we present the construction of a recombinant adenovirus carrying the XPD gene, which is coexpressed with the EGFP reporter gene by an IRES sequence, making it easier to follow cell infection. Infection by this recombinant adenovirus grants full correction of SV40-transformed and primary skin fibroblasts obtained from XP-D, TTD and XP/CS patients.

[Clinical and cellular studies in a patient with Cockayne syndrome]. / Un caso di sindrome di Cockayne: caratteristiche cliniche e cellulari.

Hypersensitivity to the lethal effect of ultraviolet light (UV) and other DNA-damaging agents has been observed in cells from patients affected by Cockayne syndrome, suggesting that this syndrome is deficient in the capability to repair damage in cellular DNA. We report a case showing the main clinical features of Cockayne syndrome in which the clinical and cellular photosensitivity described as typical for Cockayne syndrome is not present. These cytological results suggest that there is considerable clinical and cellular heterogeneity in Cockayne syndrome and that cellular sensitivity to UV might not be as essential for the diagnosis of Cockayne syndrome as previously thought.

Cockayne syndrome--a case report, and a review of the premature aging syndromes in paediatrics.

The premature aging syndromes are a rare eccentric group of syndromes in which predominantly senile features develop prematurely. Cockayne Syndrome is one of several premature aging syndromes; it has been recognised, but hitherto unreported in the local literature. This is a case report of a child with the classical features of Cockayne Syndrome.