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1. Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome

Author

Hélène Dollfus, Victoria Murday, Pierre Sarda, E. Raffo, Patrick Edery, Alain Sarasin, Jacqueline Vigneron, D. Gubser-Mercati, Andrew R. Gennery, Karen Fieggen, Vincent Laugel, Valérie Drouin-Garraud, F. Sauvanaud, Dominique Martin-Coignard, Hubert Journel, Louise Brueton, John Tolmie, Marie-Claire Vincent, Alan R. Lehmann, Delphine Héron, Benoît Funalot, Stanislas Lyonnet, D. Pham, Jean-Marc Egly, Mustafa A. Salih, Sylvie Odent, U. Kristensen, E. Muñoz, Agnès Bloch-Zupan, Heather Fawcett, Edward S. Tobias, J. Sanchez del Pozo, Blanca Gener, Brigitte Chabrol, Lina M. Ramos, M. Durand, Cecile Dalloz, Zornitza Stark, K. Prescott, Laurent Pasquier, Mehrdad Noruzinia, Valérie Cormier-Daire, Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de diagnostic génétique, CHU Strasbourg, Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], CHU Pontchaillou [Rennes], Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Medical Genetics, Hospital de Cruces, Division of Developmental Medicine, Royal Hospital for Sick Children, Service de génétique, Centre Hospitalier Le Mans (CH Le Mans), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique Médicale, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA)-Hôpital Chubert, Service de Pédiatrie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Consultation de Génétique, Neurologie Pédiatrique, Hôpital neuchâtelois, Service de Neurologie [CHU Limoges], CHU Limoges, Biomolécules Thérapies anti-tumorales (EA4021), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Department of Clinical Genetics, Birmingham Women's Hospital, Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Department Neurology, Hospital Clinic, Department of Pediatrics, Newcastle General Hospital, Division of Pediatric Neurology, King Saud University [Riyadh] (KSU), Department of Hematology, Tarbiat Modares University [Tehran], St James's University Hospital, Pediatric Hospital, Genetic Health Services Victoria, Groote Schuur and Red Cross Children's Hospital, Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Unité de Génétique Médicale et Foetopathologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de Génétique, Hospices Civils de Lyon (HCL), Reference Centre for Oral Manifestations of Rare Diseases, Hôpitaux Universitaires de Strasbourg, Centre for Genome Damage and Stability, University of Sussex, Génomes et cancer (GC (FRE2939)), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire ( IGBMC ), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Génétique Moléculaire et Hormonologie, Hôpital Pontchaillou, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CH Le Mans, CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique-Hôpital Chubert, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Biomolécules Thérapies anti-tumorales ( EA4021 ), Université de Limoges ( UNILIM ) -Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ), Centro de Biología Molecular Severo Ochoa ( CBMSO ), Universidad Autonoma de Madrid ( UAM ) -Consejo Superior de Investigaciones Científicas [Spain] ( CSIC ), King Saud University [Riyadh] ( KSU ), Tarbiat Modares University, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Hospices Civils de Lyon ( HCL ), Génomes et cancer ( GC (FRE2939) ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), and De Villemeur, Hervé

Subjects
Molecular Sequence Data, Prenatal diagnosis, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, Bioinformatics, Cockayne syndrome, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Databases, Genetic, Genetics, medicine, Missense mutation, Coding region, Humans, Amino Acid Sequence, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, Cockayne Syndrome, Poly-ADP-Ribose Binding Proteins, Gene, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Genetic Association Studies, 030304 developmental biology, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polymorphism, Genetic, DNA Helicases, medicine.disease, 3. Good health, ERCC8, DNA Repair Enzymes, ERCC6, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Sequence Alignment, 030217 neurology & neurosurgery, Transcription Factors
Abstract

MMNP; International audience; Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/CSA/ and www.umd.be/CSB/).

Published
2010
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2. Clinical and cellular ionizing radiation sensitivity in a patient with xeroderma pigmentosum

Author

C Bush, P B Rogers, N Foray, Michael H.L. Green, Piers N. Plowman, Alan R. Lehmann, Colin F. Arlett, T J McMillan, Christopher N. Parris, F Abbaszadeh, Centre for Genome Damage and Stability, University of Sussex, Radiotherapy/Clinical Oncology, St Bartholomew's Hospital, Division of Biosciences, Brunel University, Kingston Lane, School of Pharmacy and Biomolecular Sciences, University of Brighton, Institute of Environmental and Natural Sciences, The Institute of Cancer Research, Royal Cancer Hospital, Rayonnement Synchrotron et Recherche Medicale (RSRM), Université Joseph Fourier - Grenoble 1 (UJF)-European Synchrotron Radiation Facility (ESRF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Serduc, Raphael, and European Synchrotron Radiation Facility (ESRF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Cell Death, Skin Neoplasms, DNA Repair, medicine.medical_treatment, Photodermatosis, MESH: Osteonecrosis, Radiation Tolerance, Ionizing radiation, 0302 clinical medicine, MESH: DNA Repair, 0303 health sciences, MESH: Radiation Tolerance, Cell Death, Osteonecrosis, General Medicine, Transfection, 3. Good health, DNA-Binding Proteins, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, MESH: Hemangiosarcoma, medicine.medical_specialty, Xeroderma pigmentosum, MESH: Cell Line, Tumor, Ultraviolet Rays, Hemangiosarcoma, MESH: Radiation Injuries, MESH: Scalp, Gene product, Parietal Bone, 03 medical and health sciences, Cell Line, Tumor, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, Radiology, Nuclear Medicine and imaging, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Radiosensitivity, Radiation Injuries, 030304 developmental biology, MESH: Xeroderma Pigmentosum, MESH: DNA Damage, Xeroderma Pigmentosum, Scalp, MESH: Humans, MESH: Parietal Bone, business.industry, MESH: Skin Neoplasms, MESH: Transfection, MESH: Gamma Rays, medicine.disease, Surgery, Radiation therapy, MESH: Head and Neck Neoplasms, Cell culture, Gamma Rays, Cancer research, MESH: Ultraviolet Rays, business, MESH: DNA-Binding Proteins, DNA Damage
Abstract

International audience; XP14BR is a cell line derived from a xeroderma pigmentosum (XP) patient from complementation group C. The patient was unusual in presenting with an angiosarcoma of the scalp, treated by surgical excision and radiotherapy. Following 38 Gy in 19 fractions with 6 MEV electrons, a severe desquamation and necrosis of the underlying bone ensued, and death followed 4 years later. The cell line was correspondingly hypersensitive to the lethal effects of gamma irradiation. We had previously shown that this sensitivity could be discriminated from that seen in ataxia-telangiectasia (A-T). The cellular response to ultraviolet radiation below 280 nm (UVC) was characteristic of XP cells, indicating the second instance, in our experience, of dual cellular UVC and ionizing radiation hypersensitivity in XP. We then set out to evaluate any defects in repair of ionizing radiation damage and to verify any direct contribution of the XPC gene. The cells were defective in repair of a fraction of double strand breaks, with a pattern reminiscent of A-T. The cell line was immortalized with the vector pSV3neo and the XPC cDNA transfected in to correct the defect. The progeny derived from this transfection showed the presence of the XPC gene product, as measured by immunoblotting. A considerable restoration of normal UVC, but not ionizing radiation, sensitivity was observed amongst the clones. This differential correction of cellular sensitivity is strong evidence for the presence of a defective radiosensitivity gene, distinct from XPC, which is responsible for the clinical hypersensitivity to ionizing radiation. It is important to resolve how widespread ionizing radiation sensitivity is amongst XP patients.

Published
2006
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3. Co-localization in replication foci and interaction of human Y-family members, DNA polymerase pol eta and REVl protein

Author

Marie-Pierre Reck, Agnès Tissier, Alan R. Lehmann, Robert P. P. Fuchs, Agnès Cordonnier, Patricia Kannouche, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, and Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS)

Subjects
DNA Replication, MESH: Cell Nucleus, DNA Repair, Ultraviolet Rays, DNA polymerase, DNA polymerase II, Eukaryotic DNA replication, MESH: DNA Replication, DNA-Directed DNA Polymerase, In Vitro Techniques, MESH: Base Sequence, MESH: Two-Hybrid System Techniques, Biochemistry, S Phase, MESH: Recombinant Proteins, 03 medical and health sciences, Control of chromosome duplication, Two-Hybrid System Techniques, MESH: DNA-Directed DNA Polymerase, Humans, MESH: Nucleotidyltransferases, MESH: Cell Line, Transformed, Molecular Biology, Cell Line, Transformed, 030304 developmental biology, Cell Nucleus, Genetics, MESH: DNA Damage, MESH: DNA Repair, 0303 health sciences, DNA clamp, MESH: Humans, Base Sequence, biology, 030302 biochemistry & molecular biology, DNA replication, MESH: S Phase, MESH: DNA, Nuclear Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, DNA, Cell Biology, Nucleotidyltransferases, Recombinant Proteins, biology.protein, REV1, MESH: Ultraviolet Rays, Primase, DNA Damage
Abstract

The progress of replicative DNA polymerases along the replication fork may be impeded by the presence of lesions in the genome. One way to circumvent such hurdles involves the recruitment of specialized DNA polymerases that perform limited incorporation of nucleotides in the vicinity of the damaged site. This process entails DNA polymerase switch between replicative and specialized DNA polymerases. Five eukaryotic proteins can carry out translesion synthesis (TLS) of damaged DNA in vitro, DNA polymerases zeta, eta, iota, and kappa, and REV1. To identify novel proteins that interact with hpol eta, we performed a yeast two-hybrid screen. In this paper, we show that hREV1 interacts with hpol eta as well as with hpol kappa and poorly with hpol iota. Furthermore, cellular localization analysis demonstrates that hREV1 is present, with hpol eta in replication factories at stalled replication forks and is tightly associated with nuclear structures. This hREV1 nuclear localization occurs independently of the presence of hpol eta. Taken together, our data suggest a central role for hREV1 as a scaffold that recruits DNA polymerases involved in TLS.

Published
2004
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4. Identical mutations in the CSB gene associated with either Cockayne syndrome or the DeSanctis-cacchione variant of xeroderma pigmentosum

Author

Stefano Colella, Alan R. Lehmann, Elena Botta, Miria Stefanini, Tiziana Nardo, and Consiglio Nazionale delle Ricerche (CNR)

Subjects
Xeroderma pigmentosum, [SDV]Life Sciences [q-bio], Nonsense mutation, Mutation, Missense, Biology, medicine.disease_cause, Cockayne syndrome, Nuclear Family, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Point Mutation, Allele, Cockayne Syndrome, Poly-ADP-Ribose Binding Proteins, Molecular Biology, Genetics (clinical), Cells, Cultured, In Situ Hybridization, Fluorescence, 030304 developmental biology, 0303 health sciences, Mutation, Xeroderma Pigmentosum, Genetic disorder, DNA Helicases, Genetic Variation, General Medicine, medicine.disease, Phenotype, Molecular biology, Stop codon, DNA Repair Enzymes, Codon, Terminator, 030217 neurology & neurosurgery
Abstract

International audience; Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are two hereditary disorders in which photosensitivity is associated with distinct clinical and cellular phenotypes and results from genetically different defects. We have identified the primary molecular alteration in two patients in whom clinical manifestations strongly reminiscent of a severe form of XP were unexpectedly associated with the CS cellular phenotype and with a defect in the CSB gene. Sequencing of the CSB -coding region in both cDNA and genomic DNA showed that these patients had identical alterations to those in a patient with the clinical features of the classical form of CS. These data, together with fluorescence in situ hybridization analysis, demonstrated that the two siblings with XP as well as the CS patient were homozygous for the same CSB mutated allele, containing a silent C2830T change and a nonsense mutation C2282T converting Arg735 to a stop codon. The finding that the same inactivating mutation underlies different pathological phenotypes indicates that there is no simple correlation between the molecular defect and the clinical features. Therefore, alterations in the CSB gene give rise to the same repair defect at the cellular level but other genetic and/or environmental factors determine the pathological phenotype.

Published
2000
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5. Alterations in the CSB gene in three Italian patients with the severe form of Cockayne syndrome (CS) but without clinical photosensitivity

Author

Stefano Colella, Donna L. Mallery, Ruffa G, Tiziana Nardo, Roberta Ricci, Alan R. Lehmann, Miria Stefanini, Carla Borrone, and Consiglio Nazionale delle Ricerche (CNR)

Subjects
Heterozygote, DNA Repair, DNA repair, Ultraviolet Rays, [SDV]Life Sciences [q-bio], Biology, Compound heterozygosity, Cockayne syndrome, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Transcription (biology), Reference Values, Genetics, medicine, Humans, Photosensitivity Disorders, Cockayne Syndrome, Poly-ADP-Ribose Binding Proteins, Molecular Biology, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Genetic Complementation Test, DNA Helicases, Infant, Heterozygote advantage, General Medicine, Sequence Analysis, DNA, Fibroblasts, medicine.disease, Molecular biology, Phenotype, 3. Good health, DNA Repair Enzymes, chemistry, Italy, Child, Preschool, Mutation, RNA, 030217 neurology & neurosurgery, DNA
Abstract

International audience; Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by postnatal growth failure, mental retardation and otherwise clinically heterogeneous features which commonly include cutaneous photosensitivity. Cultured cells from sun-sensitive CS patients are hypersensitive to ultraviolet (UV) light and, following UV irradiation, are unable to restore RNA synthesis rates to normal levels. This has been attributed to a specific deficiency in CS cells in the ability to carry out preferential repair of damage in actively transcribed regions of DNA. We report here a cellular and molecular analysis of three Italian CS patients who were of particular interest because none of them was sun-sensitive, despite showing most of the features of the severe form of CS, including the characteristic cellular sensitivity to UV irradiation. They all were altered in the CSB gene. The genetically related patients CS1PV and CS3PV were homozygous for the C1436T transition resulting in the change Arg453opal. Patient CS2PV was a compound heterozygote for two new causative mutations, insertions of an A at position 1051 and of TGTC at 2053, leading to truncated proteins of 367 and 681 amino acids. These mutations result in severely truncated proteins, as do many of those that we previously identified in several sun-sensitive CS-B patients. These observations confirm that the CSB gene is not essential for viability and cell proliferation, an important issue to be considered in any speculation on the recently proposed additional function of the CSB protein in transcription. Our investigations provide data supporting the notion that other factors, besides the site of the mutation, influence the type and severity of the CS clinical features.

Published
1999
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6. DNA joining in mammalian cells

Author

Claude Prigent, M.S. Satoh, Deborah E. Barnes, Graham Daly, Tomas Lindahl, Alan R. Lehmann, P. Robins, R.A. Nash, Edward Roberts, Prigent, Claude, Clare Hall Laboratories, Cancer Research UK - London Res Inst, MRC Cell Mutation Unit, and University of Sussex

Subjects
Binding Sites, DNA Ligases, DNA Repair, Sequence Homology, Amino Acid, Molecular Sequence Data, Chromosome Mapping, DNA, Biology, Biochemistry, Models, Biological, Cell biology, chemistry.chemical_compound, DNA Ligase ATP, chemistry, Genetics, Animals, Humans, Amino Acid Sequence, Phosphorylation, Poly(ADP-ribose) Polymerases, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS, DNA Damage
Abstract

International audience

Published
1993

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