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1. Identification and Characterization of a Novel Recurrent ERCC6 Variant in Patients with a Severe Form of Cockayne Syndrome B

Author

Khouloud Zayoud, Najoua Miladi, Ilhem Turki, Clément Crochemore, Nadège Calmels, Cathy Obringer, Vincent Laugel, Ichraf Kraoua, Sami Bouchoucha, Miria Ricchetti, Asma Chikhaoui, Houda Yacoub-Youssef, Sinda Zarrouk, Dorra Najjar, Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory (LR11IPT05), Université de Tunis El Manar (UTM)-Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Faculté des Sciences de Bizerte [Université de Carthage], Université de Carthage - University of Carthage, Institut national de neurologie Mongi-Ben Hamida [Tunis], Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Béchir Hamza Children's Hospital, Cellules Souches et Développement / Stem Cells and Development, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP), Université de Tunis El Manar (UTM), This work was supported by the Ministry of Higher Education and Scientific Research (LR20IPT/05), the 'Programmes Transversaux de Recherche' project (PTR_Rejuvenage 2017–2019), the 'Projet Collaboratif Interne (PCI_Ageing 2019_2021), the 'MOBIDOC-753 (2017–2020) fellowship for PhD students, and the Agence Nationale de la Recherche (ANR) CS_AGE., ANR-19-CE14-0042,CS_AGE,Défauts des mitochondries et des protéases dans les cellules du syndrome progéroïde de Cockayne et pendant des processus associés au vieillissement(2019), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génétique Médicale, Inserm, UMR1112, Institut de Génétique Médicale D’Alsace, Université de Strasbourg, 67000, Strasbourg, France, Université de Strasbourg (UNISTRA), Crochemore, Clément, and Défauts des mitochondries et des protéases dans les cellules du syndrome progéroïde de Cockayne et pendant des processus associés au vieillissement - - CS_AGE2019 - ANR-19-CE14-0042 - AAPG2019 - VALID

Subjects
Cockayne syndrome, ERCC6, accelerated aging, neurodegeneration, DNA repair disorder, Genetic counseling, [SDV]Life Sciences [q-bio], Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, QH426-470, 03 medical and health sciences, Exon, symbols.namesake, 0302 clinical medicine, medicine, Genetics, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Genetics (clinical), 030304 developmental biology, Sanger sequencing, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.disease, 3. Good health, ERCC8, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation (genetic algorithm), symbols, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Nucleotide excision repair
Abstract

Cockayne syndrome (CS) is a rare disease caused by mutations in ERCC6/CSB or ERCC8/CSA. We report here the clinical, genetic, and functional analyses of three unrelated patients mutated in ERCC6/CSB with a severe phenotype. After clinical examination, two patients were investigated via next generation sequencing, targeting seventeen Nucleotide Excision Repair (NER) genes. All three patients harbored a novel, c.3156dup, homozygous mutation located in exon 18 of ERCC6/CSB that affects the C-terminal region of the protein. Sanger sequencing confirmed the mutation and the parental segregation in the three families, and Western blots showed a lack of the full-length protein. NER functional impairment was shown by reduced recovery of RNA synthesis with proficient unscheduled DNA synthesis after UV-C radiations in patient-derived fibroblasts. Despite sharing the same mutation, the clinical spectrum was heterogeneous among the three patients, and only two patients displayed clinical photosensitivity. This novel ERCC6 variant in Tunisian patients suggests a founder effect and has implications for setting-up prenatal diagnosis/genetic counselling in North Africa, where this disease is largely undiagnosed. This study reveals one of the rare cases of CS clinical heterogeneity despite the same mutation. Moreover, the occurrence of an identical homozygous mutation, which either results in clinical photosensitivity or does not, strongly suggests that this classic CS symptom relies on multiple factors.

Published
2021
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2. In vivo phenotypic and molecular characterization of retinal degeneration in mouse models of three ciliopathies

Author

Vincent Marion, Cathy Obringer, Hélène Dollfus, Nadia Messaddeq, Michel Roux, Agnès Brun, Xiangxiang Yu, Corinne Stoetzel, Daniel Ajoy, Elodie Haser, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Retinal degeneration, Rhodopsin, [SDV]Life Sciences [q-bio], Leber Congenital Amaurosis, Biology, Ciliopathies, Retina, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Mice, 0302 clinical medicine, Bardet–Biedl syndrome, Retinitis pigmentosa, medicine, Electroretinography, Animals, Bardet-Biedl Syndrome, medicine.diagnostic_test, Cilium, Retinal Degeneration, Retinal, medicine.disease, Sensory Systems, Cell biology, Ophthalmology, Disease Models, Animal, 030104 developmental biology, chemistry, 030221 ophthalmology & optometry, Alström syndrome
Abstract

International audience; Cilia are highly conserved and ubiquitously expressed organelles. Ciliary defects of genetic origins lead to ci-liopathies, in which retinal degeneration (RD) is one cardinal clinical feature. In order to efficiently find and design new therapeutic strategies the underlying mechanism of retinal degeneration of three murine model was compared. The rodent models correspond to three emblematic ciliopathies, namely: Bardet-Biedl Syndrome (BBS), Alström Syndrome (ALMS) and CEP290-mediated Leber Congenital Amaurosis (LCA). Scotopic rodent electroretinography (ERG) was used to test the retinal function of mice, Transmitted Electron microscopy (T.E.M) was performed to assess retinal structural defects and real-time PCR for targeted genes was used to monitor the expression levels of the major apoptotic Caspase-related pathways in retinal extracts to identify pathological pathways driving the RD in order to identify potential therapeutic targets. We found that BBS and CEP290-mediated LCA mouse models exhibit perinatal retinal degeneration associated with rhodopsin mis-localization in the photoreceptor and the induction of an Endoplasmic Reticulum (ER) stress. On the other hand, the tested ALMS mouse model, displayed a slower degeneration phenotype, with no Rhodopsin mislocalization nor ER-stress activity. Our data points out that behind the general phenotype of vision loss associated with these ciliopathies, the mechanisms and kinetics of disease progression are different.

Published
2019
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3. Uncommon nucleotide excision repair phenotypes revealed by targeted high-throughput sequencing

Author

Massimiliano Rossi, Boris Keren, François Feillet, Julien Tarabeux, Isabel Llano-Rivas, Florence Renaldo-Robin, Vincent Laugel, Patricia Bretones, Bérénice Doray, Marguerite Miguet, Géraldine Greff, Caroline Michot, Béatrice Digeon, Nadine Kempf, Nadège Calmels, Anne Cavau, Martine Doco-Fenzy, Claire Gasnier, Cathy Obringer, Jean-Louis Mandel, Pascal Sabouraud, Jesus Gardeazabal, Didier Bessis, Christel Depienne, Blanca Gener, Artur Mazur, Jean Muller, Sophie Julia, Geneviève Baujat, Laboratoire de Diagnostic Génétique, CHU Strasbourg-Hopital Civil, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'endocrinologie pédiatrique, Hôpital mère enfant, Bron, CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Universitaire de Reims (CHU Reims), Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), BioCruces Research Institute, University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU)-Hospital Universitario Cruces = Cruces University Hospital, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Rzeszow University, Unité de Neurologie, Hôpital Robert Debré, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [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)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génétique Humaine, Collège de France (CdF (institution)), CHU Strasbourg, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Saint-Eloi, University of the Basque Country [Bizkaia] (UPV/EHU)-Hospital Universitario Cruces = Cruces University Hospital, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [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), Chaire Génétique Humaine, CHU Strasbourg - Hopital Civil, Laboratoire de Génétique Médicale, Université de Strasbourg - Institut National de la Santé et de la Recherche Médicale (INSERM) - Faculté de Médecine, Centre de référence maladies osseuses constitutionnelles CHU Necker, Hôpital Necker - Enfants malades, Assistance publique - Hôpitaux de Paris (AP-HP) - Université Paris Descartes - Paris 5 (UPD5), CHU Reims, CHU Félix Guyon, Université de Lorraine (UL) - Institut National de la Santé et de la Recherche Médicale (INSERM), University of the Basque Country [Bizkaia] (UPV/EHU) - Cruces University Hospital, Hôpital Purpan, Hospices Civils de Lyon / Centre hospitalier Lyon Sud (HCL), Hospices Civils de Lyon, Centre de recherche en neurosciences de Lyon, Centre National de la Recherche Scientifique (CNRS) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Claude Bernard Lyon 1 (UCBL) - Université Jean Monnet - Saint-Etienne - PRES Université de Lyon, Université Pierre et Marie Curie - Paris 6 (UPMC) - Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Pitié-Salpêtrière [APHP], Institut du Cerveau et de la Moëlle Epinière (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC) - Institut National de la Santé et de la Recherche Médicale (INSERM) - CHU Pitié-Salpêtrière [APHP] - Centre National de la Recherche Scientifique (CNRS), Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and HAL UPMC, Gestionnaire

Subjects
0301 basic medicine, ERCC6, ERCC8, DNA Repair, DNA-Directed DNA Polymerase, Cockayne syndrome, Genetics(clinical), Pharmacology (medical), Poly-ADP-Ribose Binding Proteins, Genetics (clinical), Medicine(all), Genetics, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, High-Throughput Nucleotide Sequencing, Nuclear Proteins, General Medicine, 3. Good health, DNA-Binding Proteins, Phenotype, POLH, NGS, Xeroderma pigmentosum, Population, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, medicine, Humans, education, Xeroderma Pigmentosum Group D Protein, Research, DNA Helicases, xeroderma pigmentosum, medicine.disease, Endonucleases, 030104 developmental biology, DNA Repair Enzymes, Mutation, NER, ERCC2, ERCC3, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Nucleotide excision repair, Transcription Factors, ERCC5
Abstract

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. We then used the same technique to analyse samples from a prospective cohort of 40 patients. Multiplex amplification and sequencing were performed using AmpliSeq protocol on the Ion Torrent PGM (Life Technologies). Results We identified causative mutations in 17 out of the 40 patients (43 %). Four patients showed biallelic mutations in the ERCC6(CSB) gene, five in the ERCC8(CSA) gene: most of them had classical CS features but some had very mild and incomplete phenotypes. A small cohort of 4 unrelated classic XP patients from the Basque country (Northern Spain) revealed a common splicing mutation in POLH (XP-variant), demonstrating a new founder effect in this population. Interestingly, our results also found ERCC2(XPD), ERCC3(XPB) or ERCC5(XPG) mutations in two cases of UV-sensitive syndrome and in two cases with mixed XP/CS phenotypes. Conclusions Our study confirms that NGS is an efficient technique for the analysis of NER-related disorders on a molecular level. It is particularly useful for phenotypes with combined features or unusually mild symptoms. Targeted NGS used in conjunction with DNA repair functional tests and precise clinical evaluation permits rapid and cost-effective diagnosis in patients with NER-defects. Electronic supplementary material The online version of this article (doi:10.1186/s13023-016-0408-0) contains supplementary material, which is available to authorized users.

Published
2016
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