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    1172 results match your criteria Cockayne Syndrome

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    Trichothiodystrophy, complementation group A complicated with squamous cell carcinoma.
    J Eur Acad Dermatol Venereol 2017 Aug 22. Epub 2017 Aug 22.
    Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
    There are three related, clinically defined disorders of DNA repair: xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS).(1) Photosensitivity, neurological/developmental abnormalities, and skin cancer are important pathological features that can be used to distinguish between these three archetypes.(1,2) TTD is a rare, autosomal recessive disease characterized by brittle, sulfur-deficient hair and multisystem abnormalities. Read More

    Increased oxidative phosphorylation in response to acute and chronic DNA damage.
    NPJ Aging Mech Dis 2016 13;2:16022. Epub 2016 Oct 13.
    Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
    Accumulation of DNA damage is intricately linked to aging, aging-related diseases and progeroid syndromes such as Cockayne syndrome (CS). Free radicals from endogenous oxidative energy metabolism can damage DNA, however the potential of acute or chronic DNA damage to modulate cellular and/or organismal energy metabolism remains largely unexplored. We modeled chronic endogenous genotoxic stress using a DNA repair-deficient Csa(-/-)|Xpa(-/-) mouse model of CS. Read More

    Cellular sensitivity to UV-irradiation is mediated by RNA polymerase I transcription.
    PLoS One 2017 21;12(6):e0179843. Epub 2017 Jun 21.
    Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
    The nucleolus has long been considered to be a pure ribosome factory. However, over the last two decades it became clear that the nucleolus is involved in numerous other functions besides ribosome biogenesis. Our experiments indicate that the activity of RNA polymerase I (Pol I) transcription monitors the integrity of the DNA and influences the response to nucleolar stress as well as the rate of survival. Read More

    Renal Involvement in 2 Siblings With Cockayne Syndrome.
    Iran J Kidney Dis 2017 May;11(3):253-255
    Department of Pediatrics, La Rabta Hospital; Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia.
    Renal involvement in Cockayne syndrome is rare and its pathogenesis is yet unknown. We report herein 2 cases (siblings) with Cockayne syndrome type A confirmed by biochemical and molecular assays. The first case was a 13-year-old girl who presented with nephritic syndrome and a rapidly progressive kidney failure. Read More

    Two novel mutations in ERCC6 cause Cockayne syndrome B in a Chinese family.
    Mol Med Rep 2017 Jun 20;15(6):3957-3962. Epub 2017 Apr 20.
    Department of Biochemistry and Molecular Biology, Center for DNA Typing, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
    Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized principally by progressive growth failure, neurologic abnormality and premature aging. Mutations of excision repair cross‑complementation group 6 (ERCC6) and ERCC8 are predominantly responsible for CS, of which mutation of ERCC6 accounts for approximately two thirds of cases. The current report describes two siblings with severe neurologic abnormality and premature aging. Read More

    Xeroderma pigmentosum-Cockayne syndrome complex.
    Orphanet J Rare Dis 2017 Apr 4;12(1):65. Epub 2017 Apr 4.
    Forgotten Diseases Research Foundation, Santa Clara, CA, 95050, USA.
    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. Read More

    NAP1L1 accelerates activation and decreases pausing to enhance nucleosome remodeling by CSB.
    Nucleic Acids Res 2017 May;45(8):4696-4707
    Department of Physics and Astronomy, Seoul National University, Seoul 08826, Republic of Korea.
    Cockayne syndrome protein B (CSB) belongs to the SWI2/SNF2 ATP-dependent chromatin remodeler family, and CSB is the only ATP-dependent chromatin remodeler essential for transcription-coupled nucleotide excision DNA repair. CSB alone remodels nucleosomes ∼10-fold slower than the ACF remodeling complex. Strikingly, NAP1-like histone chaperones interact with CSB and greatly enhance CSB-mediated chromatin remodeling. Read More

    A complex intragenic rearrangement of ERCC8 in Chinese siblings with Cockayne syndrome.
    Sci Rep 2017 Mar 23;7:44271. Epub 2017 Mar 23.
    Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.
    Cockayne syndrome is an autosomal recessive disorder principally characterized by postnatal growth failure and progressive neurological dysfunction, due primarily to mutations in ERCC6 and ERCC8. Here, we report our diagnostic experience for two patients in a Chinese family suspected on clinical grounds to have Cockayne syndrome. Using multiple molecular techniques, including whole exome sequencing, array comparative genomic hybridization and quantitative polymerase chain reaction, we identified compound heterozygosity for a maternal splicing variant (chr5:60195556, NM_000082:c. Read More

    Cockayne syndrome B protein regulates recruitment of the Elongin A ubiquitin ligase to sites of DNA damage.
    J Biol Chem 2017 Apr 14;292(16):6431-6437. Epub 2017 Mar 14.
    From the Stowers Institute for Medical Research, Kansas City, Missouri 64110,
    Elongin A performs dual functions as the transcriptionally active subunit of RNA polymerase II (Pol II) elongation factor Elongin and as the substrate recognition subunit of a Cullin-RING E3 ubiquitin ligase that ubiquitylates Pol II in response to DNA damage. Assembly of the Elongin A ubiquitin ligase and its recruitment to sites of DNA damage is a tightly regulated process induced by DNA-damaging agents and α-amanitin, a drug that induces Pol II stalling. In this study, we demonstrate (i) that Elongin A and the ubiquitin ligase subunit CUL5 associate in cells with the Cockayne syndrome B (CSB) protein and (ii) that this interaction is also induced by DNA-damaging agents and α-amanitin. Read More

    [The place of neuropathy in the early diagnosis of Cockayne syndrome: Report on two siblings].
    Arch Pediatr 2017 Apr 28;24(4):353-359. Epub 2017 Feb 28.
    Service de neurologie et réanimation pédiatriques, hôpital Raymond-Poincaré, hôpitaux universitaires Paris-Île-de-France Ouest, AP-HP, 104, boulevard Raymond-Poincaré, 92380 Garches, France; Centre de référence de maladies neuromusculaires Garches-Necker-Mondor-Hendaye (GNMH), France; U1179 UVSQ - Inserm, université de Versailles-Saint-Quentin, 78180 Montigny, France; FILNEMUS, Réseau national français de la filière neuromusculaire, France.
    Two siblings affected with Cockayne syndrome (CS) are described: this diagnosis was suggested by the finding of a demyelinating neuropathy on electromyography in both children and consistent clinical features. CS is a rare genetic disorder with severe prognosis and a highly varied phenotype, making early diagnosis difficult. Taking into account these two cases and the literature, the current diagnosis criteria are insufficiently specific and appear late: the diagnosis may be delayed because multi-organ involvement and sensorial impairment suggests more frequent neurometabolic disorders. Read More

    Xeroderma Pigmentosum with Severe Neurological Manifestations/De Sanctis-Cacchione Syndrome and a Novel XPC Mutation.
    Case Rep Med 2017 1;2017:7162737. Epub 2017 Feb 1.
    Unidad de Genetica Médica, Facultad de Medicina, Universidad de Antioquia, Carrera 51D 62-29, Medellín, Colombia.
    Several genetic disorders caused by defective nucleotide excision repair that affect the skin and the nervous system have been described, including Xeroderma Pigmentosum (XP), De Sanctis-Cacchione syndrome (DSC), Cockayne syndrome, and Trichothiodystrophy. Cutaneous photosensitivity with an increased risk of skin malignancy is a common feature of these disorders, but clinical manifestations commonly overlap these syndromes. Several genes have been found to be altered in these pathologies, but we lack more genotype-phenotype correlations in order to make an accurate diagnosis. Read More

    CSB ablation induced apoptosis is mediated by increased endoplasmic reticulum stress response.
    PLoS One 2017 2;12(3):e0172399. Epub 2017 Mar 2.
    Unit of Molecular Genetics of Aging-Department of Ecology and Biology-University of Tuscia, Viterbo, Italy.
    The DNA repair protein Cockayne syndrome group B (CSB) has been recently identified as a promising anticancer target. Suppression, by antisense technology, of this protein causes devastating effects on tumor cells viability, through a massive induction of apoptosis, while being non-toxic to non-transformed cells. To gain insights into the mechanisms underlying the pro-apoptotic effects observed after CSB ablation, global gene expression patterns were determined, to identify genes that were significantly differentially regulated as a function of CSB expression. Read More

    A novel role for transcription-coupled nucleotide excision repair for the in vivo repair of 3,N4-ethenocytosine.
    Nucleic Acids Res 2017 Apr;45(6):3242-3252
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
    Etheno (ε) DNA base adducts are highly mutagenic lesions produced endogenously via reactions with lipid peroxidation (LPO) products. Cancer-promoting conditions, such as inflammation, can induce persistent oxidative stress and increased LPO, resulting in the accumulation of ε-adducts in different tissues. Using a recently described fluorescence multiplexed host cell reactivation assay, we show that a plasmid reporter bearing a site-specific 3,N4-ethenocytosine (εC) causes transcriptional blockage. Read More

    UV-induced proteolysis of RNA polymerase II is mediated by VCP/p97 segregase and timely orchestration by Cockayne syndrome B protein.
    Oncotarget 2017 Feb;8(7):11004-11019
    Department of Radiology, The Ohio State University, Columbus, OH 43210, USA.
    RNA polymerase II (RNAPII) acts as a damage sensor for transcription-coupled nucleotide excision repair (TC-NER) and undergoes proteolytic clearance from damaged chromatin by the ubiquitin-proteasome system (UPS). Here, we report that Valosin-containing protein (VCP)/p97, a druggable oncotarget, is essential for RNAPII's proteolytic clearance in mammalian cells. We show that inhibition of VCP/p97, or siRNA-mediated ablation of VCP/p97 and its cofactors UFD1 and UBXD7 severely impairs ultraviolet radiation (UVR)-induced RNAPII degradation. Read More

    Discrepancy between electroencephalography and hemodynamics in a patient with Cockayne syndrome during general anesthesia.
    J Clin Anesth 2016 Dec 14;35:424-426. Epub 2016 Oct 14.
    Department of Dental Anesthesiology, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address:
    Cockayne syndrome is a kind of progeria with autosomal chromosome recessiveness described first by Cockayne in 1936. Patients with this syndrome were characterized by retarded growth, cerebral atrophy, and mental retardation. We experienced an anesthetic management of a patient with Cockayne syndrome, who underwent dental treatment twice. Read More

    Neurodegeneration in accelerated aging.
    Dan Med J 2016 Nov;63(11)
    The growing proportion of elderly people represents an increasing economic burden, not least because of age-associated diseases that pose a significant cost to the health service. Finding possible interventions to age-associated disorders therefore have wide ranging implications. A number of genetically defined accelerated aging diseases have been characterized that can aid in our understanding of aging. Read More

    Analysis of Drosophila p8 and p52 mutants reveals distinct roles for the maintenance of TFIIH stability and male germ cell differentiation.
    Open Biol 2016 Oct;6(10)
    Departamento de Genética del Desarrollo, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Av Universidad 2001, Cuernavaca Morelos 62250, Mexico
    Eukaryotic gene expression is activated by factors that interact within complex machinery to initiate transcription. An important component of this machinery is the DNA repair/transcription factor TFIIH. Mutations in TFIIH result in three human syndromes: xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Read More

    Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA.
    Proc Natl Acad Sci U S A 2016 Nov 18;113(44):12502-12507. Epub 2016 Oct 18.
    Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224;
    Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work implicates mitochondrial dysfunction in the disease progression. Here, we present evidence that loss of CSA or CSB in a neuroblastoma cell line converges on mitochondrial dysfunction caused by defects in ribosomal DNA transcription and activation of the DNA damage sensor poly-ADP ribose polymerase 1 (PARP1). Read More

    Nucleotide excision repair of oxidised genomic DNA is not a source of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine.
    Free Radic Biol Med 2016 Oct 30;99:385-391. Epub 2016 Aug 30.
    Oxidative Stress Group, University of Leicester, Leicester, United Kingdom; Department of Genetics, University of Leicester, United Kingdom. Electronic address:
    Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) is a widely measured biomarker of oxidative stress. It has been commonly assumed to be a product of DNA repair, and therefore reflective of DNA oxidation. However, the source of urinary 8-oxodGuo is not understood, although potential confounding contributions from cell turnover and diet have been ruled out. Read More

    Cockayne syndrome: Clinical features, model systems and pathways.
    Ageing Res Rev 2017 Jan 6;33:3-17. Epub 2016 Aug 6.
    Laboratory of Molecular Gerontology, National Institute on Aging, Baltimore, MD, USA. Electronic address:
    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. Read More

    Understanding photodermatoses associated with defective DNA repair: Photosensitive syndromes without associated cancer predisposition.
    J Am Acad Dermatol 2016 Nov;75(5):873-882
    Department of Dermatology, Henry Ford Hospital, Detroit, Michigan. Electronic address:
    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. Read More

    Cockayne syndrome: a diffusion tensor imaging and volumetric study.
    Br J Radiol 2016 Nov 19;89(1067):20151033. Epub 2016 Sep 19.
    2 Laboratoire ICube, UMR 7357/FMTS/Université de Strasbourg-CNRS, Strasbourg, France.
    Objective: Cockayne syndrome (CS) is a rare disorder characterized by severe brain atrophy, white matter (WM) hypomyelination and basal ganglia calcifications. This study aimed to quantify atrophy and WM abnormalities using diffusion tensor imaging (DTI) and volumetric analysis, to evaluate possible differences between CS subtypes and to determine whether DTI findings may correspond to a hypomyelinating disorder.

    Methods: 14 patients with CS and 14 controls underwent brain MRI including DTI and a volumetric three-dimensional T1 weighted sequence. Read More

    PARP10 deficiency manifests by severe developmental delay and DNA repair defect.
    Neurogenetics 2016 Oct 13;17(4):227-232. Epub 2016 Sep 13.
    Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
    DNA repair mechanisms such as nucleotide excision repair (NER) and translesion synthesis (TLS) are dependent on proliferating cell nuclear antigen (PCNA), a DNA polymerase accessory protein. Recently, homozygosity for p.Ser228Ile mutation in the PCNA gene was reported in patients with neurodegeneration and impaired NER. Read More

    [Advance in research on causative genes of xeroderma pigmentosum and related diseases].
    Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2016 Oct;33(5):708-12
    Department of Dermatology, Fengxian Institute of Dermotosis Prevention, Shanghai 201408, China; Department of Dermatology, Xinhua Hospital Affiliated to Shanghai Jiaotong University Medical School, Shanghai 200092, China. Email:
    Ultraviolet light(UV)-sensitive disorders refer to a group of diseases due to damages to the nucleotide excision repair mechanism which cannot effectively repair DNA damage caused by ultraviolet radiation. The inheritance pattern of such diseases, mainly including xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy, is autosomal recessive and known to involve 13 genes. As proteins encoded by such genes are involved in DNA repair and transcription pathways. Read More

    Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice.
    Nature 2016 09 24;537(7620):427-431. Epub 2016 Aug 24.
    Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
    Mice deficient in the DNA excision-repair gene Ercc1 (Ercc1(∆/-)) show numerous accelerated ageing features that limit their lifespan to 4-6 months. They also exhibit a 'survival response', which suppresses growth and enhances cellular maintenance. Such a response resembles the anti-ageing response induced by dietary restriction (also known as caloric restriction). Read More

    Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency.
    Proc Natl Acad Sci U S A 2016 Sep 19;113(36):10151-6. Epub 2016 Aug 19.
    Department of Dermatology, University of California, San Francisco, CA 94143;
    Cockayne syndrome (CS) and xeroderma pigmentosum (XP) are human photosensitive diseases with mutations in the nucleotide excision repair (NER) pathway, which repairs DNA damage from UV exposure. CS is mutated in the transcription-coupled repair (TCR) branch of the NER pathway and exhibits developmental and neurological pathologies. The XP-C group of XP patients have mutations in the global genome repair (GGR) branch of the NER pathway and have a very high incidence of UV-induced skin cancer. Read More

    Elevated Urinary Levels of 8-Hydroxy-2'-deoxyguanosine in a Japanese Child of Xeroderma Pigmentosum/Cockayne Syndrome Complex with Infantile Onset of Nephrotic Syndrome.
    Tohoku J Exp Med 2016 ;239(3):231-5
    Department of Pediatrics, Akita University Graduate School of Medicine.
    Nucleotide excision repair (NER) is an essential biological pathway protecting against ultraviolet light-induced DNA damage. Deficient NER causes a group of rare genetic disorders including two autosomal recessive diseases, xeroderma pigmentosum (XP) and Cockayne syndrome (CS). In addition to the cutaneous photosensitivity shared in XP and CS, CS is featured by growth failure, neurological deterioration, microcephaly, and deep sunken eyes. Read More

    Mechanisms of interstrand DNA crosslink repair and human disorders.
    Genes Environ 2016 1;38. Epub 2016 May 1.
    Clinical Engineering Research Center, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593 Japan.
    Interstrand DNA crosslinks (ICLs) are the link between Watson-Crick strands of DNAs with the covalent bond and prevent separation of DNA strands. Since the ICL lesion affects both strands of the DNA, the ICL repair is not simple. So far, nucleotide excision repair (NER), structure-specific endonucleases, translesion DNA synthesis (TLS), homologous recombination (HR), and factors responsible for Fanconi anemia (FA) are identified to be involved in ICL repair. Read More

    Sources and consequences of oxidative damage from mitochondria and neurotransmitter signaling.
    Environ Mol Mutagen 2016 Jun 14;57(5):322-30. Epub 2016 Jan 14.
    Department of Dermatology, University of California San Francisco, 2340 Sutter Street, San Francisco, California.
    Cancer and neurodegeneration represent the extreme responses of growing and terminally differentiated cells to cellular and genomic damage. The damage recognition mechanisms of nucleotide excision repair, epitomized by xeroderma pigmentosum (XP), and Cockayne syndrome (CS), lie at these extremes. Patients with mutations in the DDB2 and XPC damage recognition steps of global genome repair exhibit almost exclusively actinic skin cancer. Read More

    Transcription-coupled homologous recombination after oxidative damage.
    DNA Repair (Amst) 2016 Aug 16;44:76-80. Epub 2016 May 16.
    University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 523 Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA. Electronic address:
    Oxidative DNA damage induces genomic instability and may lead to mutagenesis and carcinogenesis. As severe blockades to RNA polymerase II (RNA POLII) during transcription, oxidative DNA damage and the associated DNA strand breaks have a profoundly deleterious impact on cell survival. To protect the integrity of coding regions, high fidelity DNA repair at a transcriptionally active site in non-dividing somatic cells, (i. Read More

    Ultraviolet-B induces ERCC6 repression in lens epithelium cells of age-related nuclear cataract through coordinated DNA hypermethylation and histone deacetylation.
    Clin Epigenetics 2016 26;8:62. Epub 2016 May 26.
    Eye Institute, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu China.
    Background: Ultraviolet-B (UVB) exposure attributes to the formation of age-related nuclear cataract (ARNC), which is mediated with DNA damage. DNA damage, an important factor for pathogenesis of ARNC, is induced by UVB, and is generally resolved by the nucleotide excision repair (NER) repair mechanism. Cockayne syndrome complementation group B (CSB) protein coded by ERCC6 is a vital component for NER. Read More

    Ocular findings in a patient with Cockayne syndrome with two mutations in the ERCC6 gene.
    Ophthalmic Genet 2017 Mar-Apr;38(2):175-177. Epub 2016 May 17.
    a Department of Ophthalmology , Peking University First Hospital Key Laboratory of Vision Loss and Restoration, Ministry of Education , Beijing , China.
    Background: Cockayne syndrome is a rare, autosomal recessive, multisystem disorder that causes a senile appearance. Ophthalmic abnormalities are frequently present. Here, we report a wide range of ocular findings in a child with Cockayne syndrome. Read More

    Stabilization of Ultraviolet (UV)-stimulated Scaffold Protein A by Interaction with Ubiquitin-specific Peptidase 7 Is Essential for Transcription-coupled Nucleotide Excision Repair.
    J Biol Chem 2016 Jun 28;291(26):13771-9. Epub 2016 Apr 28.
    From the Graduate School of Frontier Biosciences, Osaka University, Yamadaoka 1-3, Suita, Osaka 565-0871, Japan
    UV-sensitive syndrome is an autosomal recessive disorder characterized by hypersensitivity to UV light and deficiency in transcription-coupled nucleotide excision repair (TC-NER), a subpathway of nucleotide excision repair that rapidly removes transcription-blocking DNA damage. UV-sensitive syndrome consists of three genetic complementation groups caused by mutations in the CSA, CSB, and UVSSA genes. UV-stimulated scaffold protein A (UVSSA), the product of UVSSA, which is required for stabilization of Cockayne syndrome group B (CSB) protein and reappearance of the hypophosphorylated form of RNA polymerase II after UV irradiation, forms a complex with ubiquitin-specific peptidase 7 (USP7). Read More

    Retin Cases Brief Rep 2017 Summer;11(3):232-235
    *Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan; and †Department of Ophthalmology, Shiley Eye Center and Jacobs Retina Center, University of California, San Diego, La Jolla, California.
    Purpose: To present peripheral retinal vasculopathy and foveal ellipsoid zone abnormalities as novel fundus manifestations of Cockayne syndrome (CS), a rare autosomal recessive condition with well-described ophthalmic associations.

    Methods: Clinical examination, wide-field fundus photography, wide-field fundus autofluorescence, wide-field fluorescein angiography, and spectral domain optical coherence tomography (SD-OCT) were used to diagnose and document the patient's clinical presentation.

    Results: Our patient presented with postnatal growth delay, neurologic dysfunction, premature aging, dental anomalies, sensory neural hearing loss, and pigmentary retinopathy. Read More

    Mutations in Cockayne Syndrome-Associated Genes (Csa and Csb) Predispose to Cisplatin-Induced Hearing Loss in Mice.
    J Neurosci 2016 Apr;36(17):4758-70
    Department of Stem Cell Biology and Regenerative Medicine, and Caruso Department of Otolaryngology, University of Southern California, Eli and Edythe Broad Center, Los Angeles, California 90033, and
    Unlabelled: Cisplatin is a common and effective chemotherapeutic agent, yet it often causes permanent hearing loss as a result of sensory hair cell death. The causes of sensitivity to DNA-damaging agents in nondividing cell populations, such as cochlear hair and supporting cells, are poorly understood, as are the specific DNA repair pathways that protect these cells. Nucleotide excision repair (NER) is a conserved and versatile DNA repair pathway for many DNA-distorting lesions, including cisplatin-DNA adducts. Read More

    A ubiquitylation site in Cockayne syndrome B required for repair of oxidative DNA damage, but not for transcription-coupled nucleotide excision repair.
    Nucleic Acids Res 2016 Jun 7;44(11):5246-55. Epub 2016 Apr 7.
    Mechanisms of Transcription Laboratory, The Francis Crick Institute, Clare Hall Laboratories, South Mimms EN6 3LD, UK
    Cockayne syndrome B (CSB), best known for its role in transcription-coupled nucleotide excision repair (TC-NER), contains a ubiquitin-binding domain (UBD), but the functional connection between protein ubiquitylation and this UBD remains unclear. Here, we show that CSB is regulated via site-specific ubiquitylation. Mass spectrometry analysis of CSB identified lysine (K) 991 as a ubiquitylation site. Read More

    A C. elegans homolog for the UV-hypersensitivity syndrome disease gene UVSSA.
    DNA Repair (Amst) 2016 May 25;41:8-15. Epub 2016 Mar 25.
    Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD), Research Center and Centre for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany. Electronic address:
    The transcription-coupled repair pathway (TC-NER) plays a vital role in removing transcription-blocking DNA lesions, particularly UV-induced damage. Clinical symptoms of the two TC-NER-deficiency syndromes, Cockayne syndrome (CS) and UV-hypersensitivity syndrome (UVSS) are dissimilar and the underlying molecular mechanism causing this difference in disease pathology is not yet clearly understood. UV-stimulated scaffold protein A (UVSSA) has been identified recently as a new causal gene for UVSS. Read More

    Uncommon nucleotide excision repair phenotypes revealed by targeted high-throughput sequencing.
    Orphanet J Rare Dis 2016 Mar 22;11:26. Epub 2016 Mar 22.
    Laboratoire de Génétique Médicale - INSERM U1112, Institut de Génétique Médicale d'Alsace (IGMA), Faculté de médecine de Strasbourg, 11 rue Humann, Strasbourg, France.
    Background: Deficient nucleotide excision repair (NER) activity causes a variety of autosomal recessive diseases including xeroderma pigmentosum (XP) a disorder which pre-disposes to skin cancer, and the severe multisystem condition known as Cockayne syndrome (CS). In view of the clinical overlap between NER-related disorders, as well as the existence of multiple phenotypes and the numerous genes involved, we developed a new diagnostic approach based on the enrichment of 16 NER-related genes by multiplex amplification coupled with next-generation sequencing (NGS).

    Methods: Our test cohort consisted of 11 DNA samples, all with known mutations and/or non pathogenic SNPs in two of the tested genes. Read More

    Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation.
    Cell Rep 2016 Mar 10;14(11):2554-61. Epub 2016 Mar 10.
    Mechanisms of Transcription Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms, Hertfordshire EN6 3LD, UK. Electronic address:
    Cockayne syndrome (CS) is a severe neurodevelopmental disorder characterized by growth abnormalities, premature aging, and photosensitivity. Mutation of Cockayne syndrome B (CSB) affects neuronal gene expression and differentiation, so we attempted to bypass its function by expressing downstream target genes. Intriguingly, ectopic expression of Synaptotagmin 9 (SYT9), a key component of the machinery controlling neurotrophin release, bypasses the need for CSB in neuritogenesis. Read More

    Ocular manifestations of genetic skin disorders.
    Clin Dermatol 2016 Mar-Apr;34(2):242-75. Epub 2015 Dec 2.
    The Vision Center, Children's Hospital Los Angeles; Department of Ophthalmology, Keck School of Medicine, University of Southern California, 4650 Sunset Blvd, MS #88, Los Angeles, CA, 90027.
    Genetic skin diseases, or genodermatoses, often have extracutaneous manifestations. Ocular manifestations in particular can have significant clinical implications, like blindness. Other manifestations, such as the corneal opacities that occur in X-linked ichthyosis, are asymptomatic but characteristic of a particular genodermatosis. Read More

    Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability.
    Mol Cell 2016 Feb 28;61(4):535-46. Epub 2016 Jan 28.
    Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Electronic address:
    XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective XPG mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known about how XPG loss results in this devastating disease. We identify XPG as a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR). Read More

    Valosin-containing Protein (VCP)/p97 Segregase Mediates Proteolytic Processing of Cockayne Syndrome Group B (CSB) in Damaged Chromatin.
    J Biol Chem 2016 Apr 29;291(14):7396-408. Epub 2016 Jan 29.
    From the Departments of Radiology and Molecular and Cellular Biochemistry and James Cancer Hospital and Solove Research Institute, Ohio State University, Columbus, Ohio 43210
    Cockayne syndrome group A and B (CSB) proteins act in transcription-coupled repair, a subpathway of nucleotide excision repair. Here we demonstrate that valosin-containing protein (VCP)/p97 segregase functions in ultraviolet radiation (UVR)-induced ubiquitin-mediated CSB degradation. We show that VCP/p97 inhibition and siRNA-mediated ablation of VCP/p97 and its cofactors UFD1 and UBXD7 impair CSB degradation. Read More

    Structural and Calorimetric Studies Demonstrate that Xeroderma Pigmentosum Type G (XPG) Can Be Imported to the Nucleus by a Classical Nuclear Import Pathway via a Monopartite NLS Sequence.
    J Mol Biol 2016 May 23;428(10 Pt A):2120-31. Epub 2016 Jan 23.
    Departamento de Física e Biofísica, Instituto de Biociências, Universidade Estadual Paulista, Botucatu, SP, 18618-970 Brazil. Electronic address:
    Xeroderma pigmentosum type G (XPG) proteins are involved in DNA lesion recognition and promotion of nucleotide excision repair. Specific mutations in these proteins may lead to Cockayne syndrome, in which the patients may display severe developmental retardation and neurological abnormalities. No structural information is available for their spacer region or the C-terminal domain, which are important, respectively, for specific nucleotide excision repair activity and substrate specificity, as well as nuclear translocation. Read More

    XPC deficiency is related to APE1 and OGG1 expression and function.
    Mutat Res 2016 Feb-Mar;784-785:25-33. Epub 2016 Jan 16.
    Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil. Electronic address:
    Oxidative DNA damage is considered to be a major cause of neurodegeneration and internal tumors observed in syndromes that result from nucleotide excision repair (NER) deficiencies, such as Xeroderma Pigmentosum (XP) and Cockayne Syndrome (CS). Recent evidence has shown that NER aids in removing oxidized DNA damage and may interact with base excision repair (BER) enzymes. Here, we investigated APE1 and OGG1 expression, localization and activity after oxidative stress in XPC-deficient cells. Read More

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