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123 results on '"Patrick Revy"'

1. Human RTEL1 Interacts with KPNB1 (Importin β) and NUP153 and Connects Nuclear Import to Nuclear Envelope Stability in S-Phase

Author

Michael Schertzer, Laurent Jullien, André L. Pinto, Rodrigo T. Calado, Patrick Revy, and Arturo Londoño-Vallejo

Subjects
Regulator of TElomere Length Helicase 1, protein import, nuclear envelope, nuclear pore, KPNB1 (importin β), NUP153, Cytology, QH573-671
Abstract

Regulator of TElomere Length Helicase 1 (RTEL1) is a helicase required for telomere maintenance and genome replication and repair. RTEL1 has been previously shown to participate in the nuclear export of small nuclear RNAs. Here we show that RTEL1 deficiency leads to a nuclear envelope destabilization exclusively in cells entering S-phase and in direct connection to origin firing. We discovered that inhibiting protein import also leads to similar, albeit non-cell cycle-related, nuclear envelope disruptions. Remarkably, overexpression of wild-type RTEL1, or of its C-terminal part lacking the helicase domain, protects cells against nuclear envelope anomalies mediated by protein import inhibition. We identified distinct domains in the C-terminus of RTEL1 essential for the interaction with KPNB1 (importin β) and NUP153, respectively, and we demonstrated that, on its own, the latter domain can promote the dynamic nuclear internalization of peptides that freely diffuse through the nuclear pore. Consistent with putative functions exerted in protein import, RTEL1 can be visualized on both sides of the nuclear pore using high-resolution microscopy. In all, our work points to an unanticipated, helicase-independent, role of RTEL1 in connecting both nucleocytoplasmic trafficking and nuclear envelope integrity to genome replication initiation in S-phase.

Published
2023
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2. Somatic genetic rescue of a germline ribosome assembly defect

Author

Shengjiang Tan, Laëtitia Kermasson, Christine Hilcenko, Vasileios Kargas, David Traynor, Ahmed Z. Boukerrou, Norberto Escudero-Urquijo, Alexandre Faille, Alexis Bertrand, Maxim Rossmann, Beatriz Goyenechea, Li Jin, Jonathan Moreil, Olivier Alibeu, Blandine Beaupain, Christine Bôle-Feysot, Stefano Fumagalli, Sophie Kaltenbach, Jean-Alain Martignoles, Cécile Masson, Patrick Nitschké, Mélanie Parisot, Aurore Pouliet, Isabelle Radford-Weiss, Frédéric Tores, Jean-Pierre de Villartay, Mohammed Zarhrate, Ai Ling Koh, Kong Boo Phua, Bruno Reversade, Peter J. Bond, Christine Bellanné-Chantelot, Isabelle Callebaut, François Delhommeau, Jean Donadieu, Alan J. Warren, and Patrick Revy

Subjects
Science
Abstract

Shwachman-Diamond syndrome (SDS) is a leukemia predisposition disorder that is caused by defective release of eIF6 during ribosome assembly. Here the authors show that acquired somatic EIF6 mutations are frequent in the hematopoietic cells from individuals with SDS and provide a selective advantage over non-modified cells.

Published
2021
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3. Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome

Author

Christelle Arrondel, Sophia Missoury, Rozemarijn Snoek, Julie Patat, Giulia Menara, Bruno Collinet, Dominique Liger, Dominique Durand, Olivier Gribouval, Olivia Boyer, Laurine Buscara, Gaëlle Martin, Eduardo Machuca, Fabien Nevo, Ewen Lescop, Daniela A. Braun, Anne-Claire Boschat, Sylvia Sanquer, Ida Chiara Guerrera, Patrick Revy, Mélanie Parisot, Cécile Masson, Nathalie Boddaert, Marina Charbit, Stéphane Decramer, Robert Novo, Marie-Alice Macher, Bruno Ranchin, Justine Bacchetta, Audrey Laurent, Sophie Collardeau-Frachon, Albertien M. van Eerde, Friedhelm Hildebrandt, Daniella Magen, Corinne Antignac, Herman van Tilbeurgh, and Géraldine Mollet

Subjects
Science
Abstract

The biosynthesis of N6-threonylcarbamoylated adenosine 37 in tRNA (t6A) involves the YRDC enzyme and the KEOPS complex. Here, the authors report mutations in YRDC and the KEOPS component GON7 in Galloway-Mowat syndrome and determine the crystal structure of a GON7-containg subcomplex that suggests a role in KEOPS complex stability.

Published
2019
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4. Myelodysplastic syndromes and idiopathic pulmonary fibrosis: a dangerous liaison

Author

Spyros A. Papiris, Panagiotis Tsirigotis, Caroline Kannengiesser, Lykourgos Kolilekas, Konstantinos Gkirkas, Andriana I. Papaioannou, Patrick Revy, Paschalina Giouleka, Georgia Papadaki, Konstantinos Kagouridis, Vassiliki Pappa, Raphael Borie, Catherine Boileau, Demosthenes Bouros, Bruno Crestani, and Effrosyni D. Manali

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Abstract Previous studies have shown that the co-existence of bone marrow failure and pulmonary fibrosis in a single patient or in a family is suggestive of telomere related genes (TRG) germline mutations. This study presents the genetic background, clinical characteristics, and outcome of a group of five Greek patients co-affected with IPF and MDS. Four out of five patients developed an IPF acute exacerbation that was not reversible. We failed to detect any mutation in the TERT, TERC, DKC1, TINF2, RTEL1, PARN, NAF1, ACD, NHP2 and NOP10 genes in any patient. Moreover, telomere length was normal in the two patients tested. This could suggest that although the co-occurence of IPF and MDS are suggestive of TRG mutation in patients

Published
2019
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5. Impaired telomere integrity and rRNA biogenesis in PARN‐deficient patients and knock‐out models

Author

Maname Benyelles, Harikleia Episkopou, Marie‐Françoise O'Donohue, Laëtitia Kermasson, Pierre Frange, Florian Poulain, Fatma Burcu Belen, Meltem Polat, Christine Bole‐Feysot, Francina Langa‐Vives, Pierre‐Emmanuel Gleizes, Jean‐Pierre de Villartay, Isabelle Callebaut, Anabelle Decottignies, and Patrick Revy

Subjects
Høyeraal–Hreidarsson syndrome, p53, PARN, rRNA, shelterin, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract PARN, poly(A)‐specific ribonuclease, regulates the turnover of mRNAs and the maturation and stabilization of the hTR RNA component of telomerase. Biallelic PARN mutations were associated with Høyeraal–Hreidarsson (HH) syndrome, a rare telomere biology disorder that, because of its severity, is likely not exclusively due to hTR down‐regulation. Whether PARN deficiency was affecting the expression of telomere‐related genes was still unclear. Using cells from two unrelated HH individuals carrying novel PARN mutations and a human PARN knock‐out (KO) cell line with inducible PARN complementation, we found that PARN deficiency affects both telomere length and stability and down‐regulates the expression of TRF1, TRF2, TPP1, RAP1, and POT1 shelterin transcripts. Down‐regulation of dyskerin‐encoding DKC1 mRNA was also observed and found to result from p53 activation in PARN‐deficient cells. We further showed that PARN deficiency compromises ribosomal RNA biogenesis in patients' fibroblasts and cells from heterozygous Parn KO mice. Homozygous Parn KO however resulted in early embryonic lethality that was not overcome by p53 KO. Our results refine our knowledge on the pleiotropic cellular consequences of PARN deficiency.

Published
2019
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6. Publisher Correction: Somatic genetic rescue of a germline ribosome assembly defect

Author

Shengjiang Tan, Laëtitia Kermasson, Christine Hilcenko, Vasileios Kargas, David Traynor, Ahmed Z. Boukerrou, Norberto Escudero-Urquijo, Alexandre Faille, Alexis Bertrand, Maxim Rossmann, Beatriz Goyenechea, Li Jin, Jonathan Moreil, Olivier Alibeu, Blandine Beaupain, Christine Bôle-Feysot, Stefano Fumagalli, Sophie Kaltenbach, Jean-Alain Martignoles, Cécile Masson, Patrick Nitschké, Mélanie Parisot, Aurore Pouliet, Isabelle Radford-Weiss, Frédéric Tores, Jean-Pierre de Villartay, Mohammed Zarhrate, Ai Ling Koh, Kong Boo Phua, Bruno Reversade, Peter J. Bond, Christine Bellanné-Chantelot, Isabelle Callebaut, François Delhommeau, Jean Donadieu, Alan J. Warren, and Patrick Revy

Subjects
Science
Published
2022
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7. Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

Author

Fabien Touzot, Laetitia Kermasson, Laurent Jullien, Despina Moshous, Christelle Ménard, Aydan Ikincioğullari, Figen Doğu, Sinan Sari, Vannina Giacobbi-Milet, Amos Etzioni, Jean Soulier, Arturo Londono-Vallejo, Alain Fischer, Isabelle Callebaut, Jean-Pierre de Villartay, Thierry Leblanc, Caroline Kannengiesser, and Patrick Revy

Subjects
Specialties of internal medicine, RC581-951
Abstract

Abstract: Telomeres are repetitive hexameric sequences located at the end of linear chromosomes. They adopt a lariat-like structure, the T-loop, to prevent them from being recognized as DNA breaks by the DNA repair machinery. RTEL1 is a DNA helicase required for proper telomere replication and stability. In particular, it has been postulated that RTEL1 is involved in the opening of the T-loop during telomere replication to avoid sudden telomere deletion and telomere circle (T-circle) formation. In humans, biallelic RTEL1 mutations cause Hoyeraal-Hreidarsson syndrome (HH), a rare and severe telomere biology disorder characterized by intrauterine growth retardation, bone marrow failure, microcephaly and/or cerebellar hypoplasia, and immunodeficiency. To date, 18 different RTEL1 mutations have been described in 19 cases of HH with short telomeres. The impaired T-loop resolution has been proposed to be a major cause of telomere shortening in RTEL1 deficiency. However, the biological and clinical consequences of this disorder remain incompletely documented. Here, we describe 4 new patients harboring biallelic RTEL1 mutations, including 2 novel missense mutations located in the C-terminal end of RTEL1 (p.Cys1268Arg and p.Val1294Phe). Clinical characteristics from these 4 patients were collected as those from 4 other RTEL1-deficient patients previously reported. In addition, we assessed whether T-circles, the product of improper T-loop resolution, were detected in our RTEL1-deficient patients. Overall, our study broadens and refines the clinical and biological spectrum of human RTEL1 deficiency.

Published
2016
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8. RAG2 and XLF/Cernunnos interplay reveals a novel role for the RAG complex in DNA repair

Author

Chloé Lescale, Vincent Abramowski, Marie Bedora-Faure, Valentine Murigneux, Gabriella Vera, David B. Roth, Patrick Revy, Jean-Pierre de Villartay, and Ludovic Deriano

Subjects
Science
Abstract

Antigen receptor diversity relies on careful DNA cleavage and repair. Here the authors identify a functional interplay between RAG2 and XLF during V(D)J recombination, revealing an important role for the RAG complex in repairing induced DNA double-strand breaks and maintaining genome integrity.

Published
2016
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9. First clinical description of a pedigree with complete NAF1 deletion

Author

Jean Galtier, Sophie Dimicoli-Salazar, Aurélien Trimouille, Elodie Lainey, Patrick Revy, Audrey Bidet, Yoann Vial, Edouard Forcade, Marie-Laure Negrier-Leibreich, Etienne Rivière, Julie Tinat, Nathalie Le Meur, Christelle Ménard, Arnaud Pigneux, Thibaut Leguay, Pierre-Yves Dumas, Ba Ibrahima, and Caroline Kannengiesser

Subjects
Cancer Research, Oncology, Hematology
Published
2022

10. Data from Unraveling Ewing Sarcoma Tumorigenesis Originating from Patient-Derived Mesenchymal Stem Cells

Author

Erika Brunet, Didier Surdez, Olivier Delattre, Thomas G.P. Grünewald, Maria Jasin, Mark Tomishima, Sophie Kaltenbach, Lucile Couronné, Isabelle Janoueix-Lerosey, Cécile Pierre-Eugène, Carine Giovannangeli, Anne De Cian, Benjamin Renouf, Patrick Revy, Sakina Zaïdi, Loelia Babin, Maxime Heintzé, Sandrine Grossetête, and Anna Sole

Abstract

Ewing sarcoma is characterized by pathognomonic translocations, most frequently fusing EWSR1 with FLI1. An estimated 30% of Ewing sarcoma tumors also display genetic alterations in STAG2, TP53, or CDKN2A (SPC). Numerous attempts to develop relevant Ewing sarcoma models from primary human cells have been unsuccessful in faithfully recapitulating the phenotypic, transcriptomic, and epigenetic features of Ewing sarcoma. In this study, by engineering the t(11;22)(q24;q12) translocation together with a combination of SPC mutations, we generated a wide collection of immortalized cells (EWIma cells) tolerating EWSR1-FLI1 expression from primary mesenchymal stem cells (MSC) derived from a patient with Ewing sarcoma. Within this model, SPC alterations strongly favored Ewing sarcoma oncogenicity. Xenograft experiments with independent EWIma cells induced tumors and metastases in mice, which displayed bona fide features of Ewing sarcoma. EWIma cells presented balanced but also more complex translocation profiles mimicking chromoplexy, which is frequently observed in Ewing sarcoma and other cancers. Collectively, these results demonstrate that bone marrow–derived MSCs are a source of origin for Ewing sarcoma and also provide original experimental models to investigate Ewing sarcomagenesis.Significance:These findings demonstrate that Ewing sarcoma can originate from human bone-marrow–derived mesenchymal stem cells and that recurrent mutations support EWSR1-FLI1 translocation-mediated transformation.

Published
2023

11. Supplementary Data from Unraveling Ewing Sarcoma Tumorigenesis Originating from Patient-Derived Mesenchymal Stem Cells

Author

Erika Brunet, Didier Surdez, Olivier Delattre, Thomas G.P. Grünewald, Maria Jasin, Mark Tomishima, Sophie Kaltenbach, Lucile Couronné, Isabelle Janoueix-Lerosey, Cécile Pierre-Eugène, Carine Giovannangeli, Anne De Cian, Benjamin Renouf, Patrick Revy, Sakina Zaïdi, Loelia Babin, Maxime Heintzé, Sandrine Grossetête, and Anna Sole

Abstract

SupReferences+SupMAt&Met+Suptables+SupFig

Published
2023

12. Genetics of human telomere biology disorders

Author

Patrick Revy, Caroline Kannengiesser, and Alison A. Bertuch

Subjects
Genetics, Molecular Biology, Genetics (clinical)
Abstract

Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that prevent the activation of DNA damage response and repair pathways. Numerous factors localize at telomeres to regulate their length, structure and function, to avert replicative senescence or genome instability and cell death. In humans, Mendelian defects in several of these factors can result in abnormally short or dysfunctional telomeres, causing a group of rare heterogeneous premature-ageing diseases, termed telomeropathies, short-telomere syndromes or telomere biology disorders (TBDs). Here, we review the TBD-causing genes identified so far and describe their main functions associated with telomere biology. We present molecular aspects of TBDs, including genetic anticipation, phenocopy, incomplete penetrance and somatic genetic rescue, which underlie the complexity of these diseases. We also discuss the implications of phenotypic and genetic features of TBDs on fundamental aspects related to human telomere biology, ageing and cancer, as well as on diagnostic, therapeutic and clinical approaches.

Published
2022

13. Dynamic Interactions Within the Splenic Niche and Long-Lasting Germinal Center Imprinting Define Human Anti-Vaccinia Long-Lived Memory B Cells

Author

Pascal Chappert, François Huetz, Marie-Alix Espinasse, Fabrice Chatonnet, Louise Pannetier, Lucie Da Silva, Clara Goetz, Jérôme Megret, Aurélien Sokal, Etienne Crickx, Ivan Nemazanyy, Vincent Jung, Chiara Guerrera, Sébastien Storck, Matthieu Mahévas, Antonio Cosma, Patrick Revy, Thierry Fest, Claude-Agnès Reynaud, and Jean-Claude Weill

Published
2022

14. Somatic genetic rescue of a germline ribosome assembly defect

Author

Vasileios Kargas, Mélanie Parisot, Norberto Escudero-Urquijo, Alexis Bertrand, Christine Bellanné-Chantelot, Jean Donadieu, Mohammed Zarhrate, Patrick Nitschke, Cécile Masson, Laëtitia Kermasson, Beatriz Goyenechea, Sophie Kaltenbach, Alan J. Warren, David Traynor, Stefano Fumagalli, Li Jin, Blandine Beaupain, Bruno Reversade, Ahmed Z. Boukerrou, Peter J. Bond, M. Rossmann, Olivier Alibeu, Jean-Alain Martignoles, Christine Bole-Feysot, Jonathan Moreil, Shengjiang Tan, François Delhommeau, Patrick Revy, Kong Boo Phua, Alexandre Faille, Aurore Pouliet, Christine Hilcenko, Frédéric Tores, Isabelle Radford-Weiss, Ai Ling Koh, Isabelle Callebaut, Jean-Pierre de Villartay, Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), MRC Laboratory of Molecular Biology [Cambridge, UK] (LMB), University of Cambridge [UK] (CAM)-Medical Research Council, Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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), KK Women's and Children's Hospital [Singapore], Genome Institute of Singapore (GIS), Bioinformatics Institute [Singapore], Agency for science, technology and research [Singapore] (A*STAR), National University of Singapore (NUS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Babraham Research Campus [Cambridge, Royaume-Uni], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Sorbonne Paris Cité (USPC), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ACS - Heart failure & arrhythmias, ARD - Amsterdam Reproduction and Development, Escudero-Urquijo, Norberto [0000-0002-8201-5884], Parisot, Mélanie [0000-0003-4312-2035], Reversade, Bruno [0000-0002-4070-7997], Bond, Peter J. [0000-0003-2900-098X], Bellanné-Chantelot, Christine [0000-0001-8415-6771], Warren, Alan J. [0000-0001-9277-4553], Revy, Patrick [0000-0003-0758-8022], Apollo - University of Cambridge Repository, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Hilcenko, Christine [0000-0002-9596-7833], Rossmann, Maxim [0000-0001-8811-3277], Bond, Peter J [0000-0003-2900-098X], Warren, Alan [0000-0001-9277-4553], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), HAL-SU, Gestionnaire, ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Warren, Alan J [0000-0001-9277-4553]

Subjects
Somatic cell, [SDV]Life Sciences [q-bio], General Physics and Astronomy, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Germline, 631/208/737, 692/699/1541, Ribosome assembly, 13/1, 0302 clinical medicine, hemic and lymphatic diseases, 38/22, Dictyostelium, Eukaryotic Initiation Factors, Child, Cells, Cultured, Biological Phenomena, Genetics, 0303 health sciences, Multidisciplinary, 631/208/514/2254, article, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Ribosome Subunits, Large, Eukaryotic, Ribosome, Shwachman-Diamond Syndrome, 3. Good health, [SDV] Life Sciences [q-bio], 64/24, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Child, Preschool, Drosophila, Haematological diseases, Protein Binding, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Science, 45/23, Saccharomyces cerevisiae, Biology, Molecular Dynamics Simulation, General Biochemistry, Genetics and Molecular Biology, 82/80, 03 medical and health sciences, Young Adult, Germline mutation, Animals, Humans, Gene, Ribonucleoprotein, U5 Small Nuclear, 030304 developmental biology, Sequence Homology, Amino Acid, Eukaryotic Large Ribosomal Subunit, Point mutation, Infant, Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, SBDS, 96/44, Peptide Elongation Factors, Germ Cells, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Protein Biosynthesis, Mutation, Next-generation sequencing, 631/337/574/1789, Ribosomes
Abstract

Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations in the EIF6 gene are a frequent mechanism of SGR in Shwachman-Diamond syndrome (SDS), a leukemia predisposition disorder caused by a germline defect in ribosome assembly. Biallelic mutations in the SBDS or EFL1 genes in SDS impair release of the anti-association factor eIF6 from the 60S ribosomal subunit, a key step in the translational activation of ribosomes. Here, we identify diverse mosaic somatic genetic events (point mutations, interstitial deletion, reciprocal chromosomal translocation) in SDS hematopoietic cells that reduce eIF6 expression or disrupt its interaction with the 60S subunit, thereby conferring a selective advantage over non-modified cells. SDS-related somatic EIF6 missense mutations that reduce eIF6 dosage or eIF6 binding to the 60S subunit suppress the defects in ribosome assembly and protein synthesis across multiple SBDS-deficient species including yeast, Dictyostelium and Drosophila. Our data suggest that SGR is a universal phenomenon that may influence the clinical evolution of diverse Mendelian disorders and support eIF6 suppressor mimics as a therapeutic strategy in SDS., Shwachman-Diamond syndrome (SDS) is a leukemia predisposition disorder that is caused by defective release of eIF6 during ribosome assembly. Here the authors show that acquired somatic EIF6 mutations are frequent in the hematopoietic cells from individuals with SDS and provide a selective advantage over non-modified cells.

Published
2021

15. Gain-of-Function Mutations in RPA1 Cause a Syndrome with Short Telomeres and Somatic Genetic Rescue

Author

Masayoshi Honda, Melchior Lauten, Marcus B. Valentine, Patrick Revy, Stéphane Coulon, Richa Sharma, Charnise Goodings, Caroline Kannengiesser, Fabian Beier, Melanie Boerries, Shondra M. Pruett-Miller, Sophie L Granger, Miriam Erlacher, Maria Spies, Axel Künstner, Megan A. Cooper, Jill A. Rosenfeld, Vincent Géli, Carole Saintomé, Victor B Pastor, Charlotte M. Niemeyer, Dmitri Churikov, Marcin W. Wlodarski, Sophia Polychronopoulou, Hauke Busch, Ti-Cheng Chang, Sandrine Hirschi, Louis Sanchez, Charikleia Kelaidi, Sushree S. Sahoo, Marc S. Wold, Alfonso G Fernandez, Sarah K. Nicholas, Indian Institute of Technology Delhi (IIT Delhi), Uppsala University, Freiburg Institute for Advanced Studies-LifeNet, Albert-Ludwigs-Universität Freiburg, St Jude Children's Research Hospital, University of Iowa [Iowa City], Sorbonne Université (SU), Universität zu Lübeck = University of Lübeck [Lübeck], Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), CHU Strasbourg, Université de Strasbourg (UNISTRA), German Cancer Consortium [Heidelberg] (DKTK), University Hospital Schleswig-Holstein-Campus Luebeck, 'Aghia Sophia' Children's Hospital, University of Freiburg [Freiburg], Washington University in Saint Louis (WUSTL), Baylor College of Medicine (BCM), Baylor University, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Muséum national d'Histoire naturelle (MNHN), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Washington University School of Medicine in St. Louis, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Sorbonne Université - UFR Sciences de la vie (UFR 927 ), Universität zu Lübeck [Lübeck], RWTH Aachen University, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
Adult, Male, Heterozygote, Adolescent, Somatic cell, [SDV]Life Sciences [q-bio], Immunology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, medicine.disease_cause, Biochemistry, Germline, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Replication Protein A, medicine, Missense mutation, Humans, Child, Gene, Telomere Shortening, 030304 developmental biology, Genetics, 0303 health sciences, Mutation, Infant, Newborn, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Differentiation, Cell Biology, Hematology, DNA-binding domain, Bone Marrow Failure Disorders, Middle Aged, Telomere, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Gain of Function Mutation, Myelodysplastic Syndromes, Female, Blood Commentary, Stem cell, 030215 immunology
Abstract

Human telomere biology disorders (TBD)/short telomere syndromes (STS) are heterogeneous disorders caused by inherited loss-of-function mutations in telomere-associated genes. Here, we identify 3 germline heterozygous missense variants in the RPA1 gene in 4 unrelated probands presenting with short telomeres and varying clinical features of TBD/STS, including bone marrow failure, myelodysplastic syndrome, T- and B-cell lymphopenia, pulmonary fibrosis, or skin manifestations. All variants cluster to DNA-binding domain A of RPA1 protein. RPA1 is a single-strand DNA-binding protein required for DNA replication and repair and involved in telomere maintenance. We showed that RPA1E240K and RPA1V227A proteins exhibit increased binding to single-strand and telomeric DNA, implying a gain in DNA-binding function, whereas RPA1T270A has binding properties similar to wild-type protein. To study the mutational effect in a cellular system, CRISPR/Cas9 was used to knock-in the RPA1E240K mutation into healthy inducible pluripotent stem cells. This resulted in severe telomere shortening and impaired hematopoietic differentiation. Furthermore, in patients with RPA1E240K, we discovered somatic genetic rescue in hematopoietic cells due to an acquired truncating cis RPA1 mutation or a uniparental isodisomy 17p with loss of mutant allele, coinciding with stabilized blood counts. Using single-cell sequencing, the 2 somatic genetic rescue events were proven to be independently acquired in hematopoietic stem cells. In summary, we describe the first human disease caused by germline RPA1 variants in individuals with TBD/STS.

Published
2021

16. Human anti-smallpox long-lived memory B cells are defined by dynamic interactions in the splenic niche and long-lasting germinal center imprinting

Author

Pascal Chappert, François Huetz, Marie-Alix Espinasse, Fabrice Chatonnet, Louise Pannetier, Lucie Da Silva, Clara Goetz, Jérome Mégret, Aurélien Sokal, Etienne Crickx, Ivan Nemazanyy, Vincent Jung, Chiara Guerrera, Sébastien Storck, Matthieu Mahévas, Antonio Cosma, Patrick Revy, Thierry Fest, Claude-Agnès Reynaud, Jean-Claude Weill, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Luxembourg Institute of Health (LIH), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)

Subjects
B-Lymphocytes, [SDV]Life Sciences [q-bio], splenic microenvironment, Immunology, affinity selection, [SDV.CAN]Life Sciences [q-bio]/Cancer, Germinal Center, telomeres, smallpox, Infectious Diseases, Immunoglobulin G, memory B cells, Humans, Immunology and Allergy, long-lasting immune memory, Immunologic Memory, vaccinia
Abstract

International audience; Memory B cells (MBCs) can persist for a lifetime, but the mechanisms that allow their long-term survival remain poorly understood. Here, we isolated and analyzed human splenic smallpox/vaccinia protein B5-specific MBCs in individuals who were vaccinated more than 40 years ago. Only a handful of clones persisted over such an extended period, and they displayed limited intra-clonal diversity with signs of extensive affinity-based selection. These long-lived MBCs appeared enriched in a CD21hiCD20hi IgG+ splenic B cell subset displaying a marginal-zone-like NOTCH/MYC-driven signature, but they did not harbor a unique longevity-associated transcriptional or metabolic profile. Finally, the telomeres of B5-specific, long-lived MBCs were longer than those in patient-paired naive B cells in all the samples analyzed. Overall, these results imply that separate mechanisms such as early telomere elongation, affinity selection during the contraction phase, and access to a specific niche contribute to ensuring the functional longevity of MBCs.

Published
2022

17. Unraveling Ewing Sarcoma Tumorigenesis Originating from Patient-Derived Mesenchymal Stem Cells

Author

Patrick Revy, Thomas G. P. Grunewald, Sandrine Grossetête, Mark J. Tomishima, Anna Sole, Isabelle Janoueix-Lerosey, Benjamin Renouf, Erika Brunet, Cécile Pierre-Eugène, Maxime Heintzé, Sophie Kaltenbach, Maria Jasin, Anne De Cian, Loelia Babin, Sakina Zaidi, Didier Surdez, Carine Giovannangeli, Olivier Delattre, Lucile Couronné, University of Zurich, Surdez, Didier, Brunet, Erika, Giovannangeli, Carine, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Memorial Sloane Kettering Cancer Center [New York], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Hopp Children's Cancer Center Heidelberg [Heidelber, Germany] (KITZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Heidelberg University Hospital [Heidelberg], Heidelberg University Hospital [Heidelberg], Heidelberg University, and Universität Zürich [Zürich] = University of Zurich (UZH)

Subjects
Cancer Research, [SDV]Life Sciences [q-bio], medicine.disease_cause, Translocation, Genetic, Mice, 0302 clinical medicine, CDKN2A, 1306 Cancer Research, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, In Situ Hybridization, Fluorescence, Gene Editing, Gene Rearrangement, 0303 health sciences, Chromoplexy, [SDV] Life Sciences [q-bio], Cell Transformation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, FLI1, Gene Targeting, Heterografts, 10046 Balgrist University Hospital, Swiss Spinal Cord Injury Center, 2730 Oncology, Sarcoma, Disease Susceptibility, 610 Medicine & health, Sarcoma, Ewing, Biology, Article, Immunophenotyping, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Epigenetics, 030304 developmental biology, Gene Expression Profiling, Mesenchymal stem cell, fungi, Computational Biology, Mesenchymal Stem Cells, medicine.disease, Disease Models, Animal, Mutation, Cancer research, CRISPR-Cas Systems, Carcinogenesis, Immortalised cell line, Biomarkers
Abstract

Ewing sarcoma is characterized by pathognomonic translocations, most frequently fusing EWSR1 with FLI1. An estimated 30% of Ewing sarcoma tumors also display genetic alterations in STAG2, TP53, or CDKN2A (SPC). Numerous attempts to develop relevant Ewing sarcoma models from primary human cells have been unsuccessful in faithfully recapitulating the phenotypic, transcriptomic, and epigenetic features of Ewing sarcoma. In this study, by engineering the t(11;22)(q24;q12) translocation together with a combination of SPC mutations, we generated a wide collection of immortalized cells (EWIma cells) tolerating EWSR1-FLI1 expression from primary mesenchymal stem cells (MSC) derived from a patient with Ewing sarcoma. Within this model, SPC alterations strongly favored Ewing sarcoma oncogenicity. Xenograft experiments with independent EWIma cells induced tumors and metastases in mice, which displayed bona fide features of Ewing sarcoma. EWIma cells presented balanced but also more complex translocation profiles mimicking chromoplexy, which is frequently observed in Ewing sarcoma and other cancers. Collectively, these results demonstrate that bone marrow–derived MSCs are a source of origin for Ewing sarcoma and also provide original experimental models to investigate Ewing sarcomagenesis. Significance: These findings demonstrate that Ewing sarcoma can originate from human bone-marrow–derived mesenchymal stem cells and that recurrent mutations support EWSR1-FLI1 translocation-mediated transformation.

Published
2021

18. EFL1 deficiency: a little is better than nothing

Author

Patrick Revy and Jean Donadieu

Subjects
medicine.medical_specialty, business.industry, Immunology, MEDLINE, Cell Biology, Hematology, Biochemistry, Nothing, medicine, Humans, Lipomatosis, Exocrine Pancreatic Insufficiency, Psychiatry, business
Published
2021

19. Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects

Author

Laëtitia Kermasson, Dmitri Churikov, Aya Awad, Riham Smoom, Elodie Lainey, Fabien Touzot, Séverine Audebert-Bellanger, Sophie Haro, Lauréline Roger, Emilia Costa, Maload Mouf, Adriana Bottero, Matias Oleastro, Chrystelle Abdo, Jean-Pierre de Villartay, Vincent Géli, Yehuda Tzfati, Isabelle Callebaut, Silvia Danielian, Gabriela Soares, Caroline Kannengiesser, Patrick Revy, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem (HUJ), Hôpital Robert Debré, CHU Sainte Justine [Montréal], Hôpital Morvan - CHRU de Brest (CHU - BREST ), Muséum national d'Histoire naturelle (MNHN), Centro Hospitalar Universitário do Porto, Hospital Nacional de Pediatría Prof. Dr Juan P. Garrahan [Buenos Aires], Hospital Nacional de Pediatría J.P. Garrahan, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 'Juan Pedro Garrahan' National Hospital of Pediatrics, Buenos Aires, Centro de Genética Jacinto Magalhães [Porto], Hospital de São João [Porto], AP-HP - Hôpital Bichat - Claude Bernard [Paris], and ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018)

Subjects
Fetal Growth Retardation, [SDV]Life Sciences [q-bio], Intellectual Disability, Immunology, Mutation, Microcephaly, Humans, Cell Biology, Hematology, Telomere, Biochemistry, Dyskeratosis Congenita
Abstract

Inherited bone marrow failure syndromes (IBMFSs) are a group of disorders typified by impaired production of 1 or several blood cell types. The telomere biology disorders dyskeratosis congenita (DC) and its severe variant, Høyeraal-Hreidarsson (HH) syndrome, are rare IBMFSs characterized by bone marrow failure, developmental defects, and various premature aging complications associated with critically short telomeres. We identified biallelic variants in the gene encoding the 5′-to-3′ DNA exonuclease Apollo/SNM1B in 3 unrelated patients presenting with a DC/HH phenotype consisting of early-onset hypocellular bone marrow failure, B and NK lymphopenia, developmental anomalies, microcephaly, and/or intrauterine growth retardation. All 3 patients carry a homozygous or compound heterozygous (in combination with a null allele) missense variant affecting the same residue L142 (L142F or L142S) located in the catalytic domain of Apollo. Apollo-deficient cells from patients exhibited spontaneous chromosome instability and impaired DNA repair that was complemented by CRISPR/Cas9-mediated gene correction. Furthermore, patients’ cells showed signs of telomere fragility that were not associated with global reduction of telomere length. Unlike patients’ cells, human Apollo KO HT1080 cell lines showed strong telomere dysfunction accompanied by excessive telomere shortening, suggesting that the L142S and L142F Apollo variants are hypomorphic. Collectively, these findings define human Apollo as a genome caretaker and identify biallelic Apollo variants as a genetic cause of a hitherto unrecognized severe IBMFS that combines clinical hallmarks of DC/HH with normal telomere length.

Published
2021

20. A Disease-Causing Single Amino Acid Deletion in the Coiled-Coil Domain of RAD50 Impairs MRE11 Complex Functions in Yeast and Humans

Author

Laëtitia Kermasson, Laurence Maggiorella, Marcel Hohl, Mauro Modesti, John H.J. Petrini, Talia Ileri, Jean-Pierre de Villartay, Marie Chansel-Da Cruz, Petr Cejka, Ilaria Ceppi, Patrick Revy, Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, DNA Repair, Developmental Disabilities, [SDV]Life Sciences [q-bio], medicine.disease_cause, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Sequence Analysis, Protein, law, DNA Breaks, Double-Stranded, Child, ComputingMilieux_MISCELLANEOUS, Sequence Deletion, Coiled coil, MRE11 Homologue Protein, Mutation, Chemistry, MRE11, Acid Anhydride Hydrolases, 3. Good health, Cell biology, DNA-Binding Proteins, Child, Preschool, Recombinant DNA, biological phenomena, cell phenomena, and immunity, Protein Binding, Signal Transduction, DNA Replication, replication, Saccharomyces cerevisiae Proteins, MRN, DNA repair, DNA damage, Saccharomyces cerevisiae, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Protein Domains, coiled-coil, medicine, Humans, Endodeoxyribonucleases, DNA replication, Bone Marrow Failure Disorders, enzymes and coenzymes (carbohydrates), Exodeoxyribonucleases, 030104 developmental biology, Rad50, RAD50, nuclease activity, immunodeficiency, 030217 neurology & neurosurgery, DNA
Abstract

Summary The MRE11-RAD50-NBS1 complex plays a central role in response to DNA double-strand breaks. Here, we identify a patient with bone marrow failure and developmental defects caused by biallelic RAD50 mutations. One of the mutations creates a null allele, whereas the other (RAD50E1035Δ) leads to the loss of a single residue in the heptad repeats within the RAD50 coiled-coil domain. This mutation represents a human RAD50 separation-of-function mutation that impairs DNA repair, DNA replication, and DNA end resection without affecting ATM-dependent DNA damage response. Purified recombinant proteins indicate that RAD50E1035Δ impairs MRE11 nuclease activity. The corresponding mutation in Saccharomyces cerevisiae causes severe thermosensitive defects in both DNA repair and Tel1ATM-dependent signaling. These findings demonstrate that a minor heptad break in the RAD50 coiled coil suffices to impede MRE11 complex functions in human and yeast. Furthermore, these results emphasize the importance of the RAD50 coiled coil to regulate MRE11-dependent DNA end resection in humans., Graphical Abstract, Highlights • A human RAD50 mutant impairs DNA repair but not ATM-dependent DDR • A single amino acid deletion disrupts the coiled-coil structure of RAD50 • A Rad50 mutant yeast strain exhibits an extremely severe thermosensitive phenotype, Chansel-Da Cruz et al. provide evidence that a mutation in the human RAD50 coiled coil located away from the MRE11 interaction interface uncouples the signaling function of the MRN complex from its broken DNA end processing activities. This demonstrates the crucial role of the RAD50 coiled coil in the MRE11 complex regulation.

Published
2020

21. Telomere-Related Gene mutations in a Greek cohort of suspected monogenic pulmonary fibrosis patients

Author

Aikaterini Markopoulou, Athina Trachalaki, Effrosyni D. Manali, Evangelos Bouros, Spyros Papiris, Nadia Nathan, Paschalis Steiropoulos, Chrysa Bazaka, Athanasios Konstantinidis, Nikolaos Malamadakis, Anna Karakatsani, Khedidja Rebah, Caroline Kannengiesser, Raphael Borie, Lykourgos Kolilekas, Theodoros P. Vassilakopoulos, Demosthenes Bouros, Evangelos Markozannes, Zoe Daniil, Ilias Papanikolaou, Aggeliki Haritou, Ioanna Korbila, Vasilios Tzilas, Panagiotis Lyberopoulos, Sofia Spyropoulou, Andriana I. Papaioannou, Ioannis Tomos, Areti Xyfteri, Konstantinos Kagouridis, Catherine Boileau, Evangelia Fouka, Despoina Papakosta, Philippe Dieudé, Elodie Lainey, Bruno Crestani, Maria Maniati, Patrick Revy, Katerina M. Antoniou, Athina Gogali, Marie Legendre, Ibrahima Ba, Claire Oudin, Argyrios Tzouvelekis, Stylianos Loukides, and Christelle Ménard

Subjects
medicine.medical_specialty, business.industry, Interstitial lung disease, Context (language use), Disease, medicine.disease, Gastroenterology, FEV1/FVC ratio, DLCO, Internal medicine, Pulmonary fibrosis, Cohort, medicine, Genetic predisposition, business
Abstract

Background: Telomere-related genes (TRG) mutations are detected in 30% of familial pulmonary fibrosis (FPF) and are also associated with personal/familial extra-pulmonary disease suggestive of short telomere syndrome (STS). Aim: to evaluate the prevalence of TRG mutations in a national cohort of interstitial lung disease (ILD) with suspected genetic predisposition in Greece and to define patients’ characteristics and impact on outcome.Methods: Genetic diagnoses made between December 2014-September 2019 in patients with FPF, pulmonary fibrosis at young age or personal and/or family extra-pulmonary disease suggestive of STS were analyzed. Results: 150 ILD patients, 73% male, age-at-diagnosis 67 years old, 33% non-smokers, 75% with definite/probable UIP or CPFE, 93% with dyspnea/cough, FVC% pred 75%, DLCO% pred 49% were tested; FPF was 65%, 19% young age, 21% personal and 17% family extra-pulmonary disease suggestive of STS; 21% were tested for more than 1 indication. TRG pathogenic variations were detected in 19 (13%): 13 in a familial, 3 in young age and 3 in extra-pulmonary disease suggestive of STS context as follows: TERT, TERC, RTEL1, PARN, NOP10, NHP2 in 8,5,2,2,1 and 1 respectively. No difference was detected in epidemiological-clinical-radiologic-functional characteristics between patients without and with mutations apart from age-at-diagnosis [69 vs 62 years, p

Published
2020

22. First heterozygous NOP10 mutation in familial pulmonary fibrosis

Author

Spyros Papiris, Effrosyni D. Manali, Ibrahima Ba, Lykourgos Kolilekas, Caroline Kannengiesser, Catherine Boileau, Claire Oudin, Isabelle Callebaut, Raphael Borie, Patrick Revy, Adrien Borgel, Elodie Lainey, Katerina Malagari, Aggeliki Haritou, Bruno Crestani, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
Pulmonary and Respiratory Medicine, 0303 health sciences, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine.disease, Bioinformatics, 3. Good health, Telomere, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Pulmonary fibrosis, Mutation (genetic algorithm), medicine, business, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

We provide first evidence that a heterozygous NOP10 mutation (c.17A>G,p.Tyr6Cys) identified in a large family co-segregates with adult-onset familial PF and predisposes to short telomere syndrome (familial PF, liver, haematological diseases)http://bit.ly/2wvXsUd

Published
2020

23. Full length RTEL1 is required for the elongation of the single-stranded telomeric overhang by telomerase

Author

Yehuda Tzfati, Noa Lamm, Noa Hourvitz, Aya Awad, Patrick Revy, Riham Smoom, Galina Glousker, Shadi Tawil, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
Genome instability, Telomerase, AcademicSubjects/SCI00010, Somatic cell, DNA damage, MESH: Fetal Growth Retardation, MESH: DNA Helicases, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Genome Integrity, Repair and Replication, Biology, Dyskeratosis Congenita, MESH: Microcephaly, MESH: Telomere Homeostasis, MESH: Intellectual Disability, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Telomere Homeostasis, Protein Domains, Intellectual Disability, MESH: Telomere Shortening, Genetics, Humans, Cells, Cultured, Telomere Shortening, 030304 developmental biology, 0303 health sciences, Fetal Growth Retardation, MESH: Humans, DNA Helicases, MESH: Telomerase, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Fibroblasts, Telomere, Cell biology, MESH: Dyskeratosis Congenita, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, MESH: Fibroblasts, Microcephaly, MESH: Protein Domains, Ectopic expression, 030217 neurology & neurosurgery, MESH: Cells, Cultured
Abstract

Telomeres cap the ends of eukaryotic chromosomes and distinguish them from broken DNA ends to suppress DNA damage response, cell cycle arrest and genomic instability. Telomeres are elongated by telomerase to compensate for incomplete replication and nuclease degradation and to extend the proliferation potential of germ and stem cells and most cancers. However, telomeres in somatic cells gradually shorten with age, ultimately leading to cellular senescence. Hoyeraal-Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and diverse symptoms including bone marrow failure, immunodeficiency, and neurodevelopmental defects. HHS is caused by germline mutations in telomerase subunits, factors essential for its biogenesis and recruitment to telomeres, and in the helicase RTEL1. While diverse phenotypes were associated with RTEL1 deficiency, the telomeric role of RTEL1 affected in HHS is yet unknown. Inducible ectopic expression of wild-type RTEL1 in patient fibroblasts rescued the cells, enabled telomerase-dependent telomere elongation and suppressed the abnormal cellular phenotypes, while silencing its expression resulted in gradual telomere shortening. Our observations reveal an essential role of the RTEL1 C-terminus in facilitating telomerase action at the telomeric 3′ overhang. Thus, the common etiology for HHS is the compromised telomerase action, resulting in telomere shortening and reduced lifespan of telomerase positive cells.

Published
2020

24. First heterozygous

Author

Caroline, Kannengiesser, Effrosyni D, Manali, Patrick, Revy, Isabelle, Callebaut, Ibrahima, Ba, Adrien, Borgel, Claire, Oudin, Aggeliki, Haritou, Lykourgos, Kolilekas, Katerina, Malagari, Raphael, Borie, Elodie, Lainey, Catherine, Boileau, Bruno, Crestani, and Spyros A, Papiris

Subjects
Heterozygote, Ribonucleoproteins, Small Nucleolar, Pulmonary Fibrosis, Mutation, Humans
Published
2019

25. Impact and Dynamics of TP53 Mutated Clones in Shwachman Diamond Syndrome in a Series of 80 Patients

Author

Eric Jeziorski, Yves Bertrand, Flore Sicre de Fontbrune, Virginie Gandemer, Blandine Beaupain, Frédéric Millot, Jean Donadieu, François Delhommeau, Jean-Alain Martignoles, Marie-Laure Couec, Claude Preudhomme, Laetitia Largeaud, Cecile Renard, Nathalie Aladjidi, Pierre-Simon Rohrlich, Wadih Abou Chahla, Claire Fieschi, Sophie Kaltenbach, Stéphane Blanche, Despina Moushous, Pierre Hirsch, Isabelle Meyts, Guy Leverger, Thomas Longval, Jean Louis Stephan, Vincent Barlogis, Aline Moignet Autrel, Fanny Fouyssac, Dalila Adjaoud, Marlène Pasquet, Olivier Tournilhac, Vahid Asnafi, Patrick Revy, Pascale Flandrin-Gresta, Christine Bellanné-Chantelot, Liana Carausu, Nawa Hachem, Thierry Leblanc, Hélène Lapillonne, Jean Soulier, and Mira El-Khoury

Subjects
Shwachman–Diamond syndrome, medicine.medical_specialty, Acute leukemia, business.industry, Immunology, Cell Biology, Hematology, SBDS, medicine.disease, Biochemistry, Transplantation, Germline mutation, Internal medicine, Cohort, medicine, Aplastic anemia, Prospective cohort study, business
Abstract

Introduction : Hematological complications (HC) as Aplastic anemia (AA) and myelodysplasia and acute leukemia (MDS/AL) are frequent and life threatening in patients with Shwachman Diamond Syndrome (SDS) with SBDS mutations. The therapy of such events is based on Hematopoetic stem cell transplantation (HSCT), which results remain quite poor, especially in case of malignancy. So far, it is difficult to anticipate to such HC and a lot is expected from the study of clonal evolution prior HC. Methods: A Targeted panel of 43 genes involved in MDS/AL (sensibility 1%) has been evaluated in 80 patients with SBDS mutation, representative of a nation based cohort of 154 patients. This cross sectional study has been completed by a prospective study for 40 patients evaluated at several time points. Results: The evaluation was performed in various situations: steady state i.e. no haematological complication, in MDS/AL and AA and lastly after HSCT. At the first evaluation, somatic mutation was found in 21 patients (30%) among the 70 in steady state and in 7 of the 8 cases with HC (6/6 cases with MDS/AL, in 1 among the 2 cases with AA) while the 1 of the 2 patients long term survivors after HSCT have no mutation and the other one kept a TP53 clone with a normal blood count and a low (1.5%) variant allele frequency (VAF). Among the 40 patients with several time points, 17 have a mutation at the first time points, but 10 others had additional mutation later. Globally, the most frequent gene involved was TP53 (82%) while mutations in other genes have been observed rarely. VAF in patients with vs without HC is lower (median VAF 0% vs 22.8% respectively p < 0.001) . Complex caryotype, monosomy 7, Iso7q were associated with P53 clone while in Del20q, 8 patients out 14 have a P53 mutations. The comparison between blood and bone marrow results allow the possibility to monitor such mutations in blood. Clonal evolution in one patient who presents a MDS in the course of the follow up had shown a competition between clones. Conclusion: Acquired TP53 is extremely frequent in patients with SBDS mutations, even in the absence of HC, but the prevalence as well as the VAF increased in case of HC. When sequential evaluation could be performed, competition between clones is frequent and a clinical decision remains therefore difficult, just on the evaluation of a time point. Acknowledgments: The French SCN registry is supported by grants from Amgen, Chugai, Prolong Pharma, X4 Pharma, Inserm, the Association 111 les Arts, the Association RMHE, the Association Sportive de Saint Quentin Fallavier. The authors thank the association IRIS and Mrs Grosjean and Mr Gonnot(ASSQF), the association Barth France for their support. Disclosures Sicre de Fontbrune: Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Renard:Jazz Pharmaceuticals: Research Funding. Tournilhac:ABBVIE: Consultancy, Honoraria, Other: Travle grant; INNATE Pharma: Consultancy, Honoraria; GILEAD: Consultancy, Honoraria, Other: Travel Grant; Takeda: Consultancy, Honoraria, Other: Travel grant; Janssen: Consultancy, Honoraria, Other: Travel grant.

Published
2020

26. Somatic genetic rescue in Mendelian haematopoietic diseases

Author

Alain Fischer, Patrick Revy, Caroline Kannengiesser, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Chaire Médecine expérimentale (A. Fischer), and Collège de France (CdF (institution))

Subjects
MESH: Mutation, Somatic cell, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, MESH: Phenotype, MESH: Microcephaly, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Germline mutation, Neoplasms, Genetics, Animals, Humans, MESH: Animals, MESH: Neoplasms, Molecular Biology, Genetics (clinical), Genetic mosaicism, 030304 developmental biology, MESH: Symptom Flare Up, 0303 health sciences, MESH: Humans, Mosaicism, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, MESH: Multiprotein Complexes, MESH: Hematologic Diseases, MESH: RNA, Transfer, Hematologic Diseases, Phenotype, 3. Good health, Haematopoiesis, On cells, MESH: RNA-Binding Proteins, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Mutation, MESH: Nephrosis, Mendelian inheritance, symbols, MESH: Mosaicism, Cancer development, MESH: Nuclear Proteins, 030217 neurology & neurosurgery
Abstract

International audience; Somatic mutations occur spontaneously in normal individuals and accumulate throughout life. These genetic modifications contribute to progressive ageing phenotypes and are directly involved in cancer development. However, a growing number of studies of Mendelian haematopoietic disorders indicate that somatic genetic events can offset the pathogenic effect of germline mutations at the cellular level, leading to genetic mosaicism and, in some cases, resulting in a milder disease phenotype. Notably, spontaneous genetic events that confer a positive effect on cells do not always benefit the individual, for whom the effects can be neutral or even clinically detrimental. These somatic genetic rescue events have important diagnostic, therapeutic and clinical consequences and constitute valuable models for studying the differentiation and/or homeostasis of haematopoietic lineages.

Published
2019

27. Myelodysplastic syndromes and idiopathic pulmonary fibrosis: a dangerous liaison

Author

Panagiotis Tsirigotis, Catherine Boileau, Konstantinos Kagouridis, Demosthenes Bouros, Lykourgos Kolilekas, Patrick Revy, Paschalina Giouleka, Raphael Borie, Effrosyni D. Manali, Caroline Kannengiesser, Spyros Papiris, Vassiliki Pappa, Georgia Papadaki, Andriana I. Papaioannou, Bruno Crestani, Konstantinos Gkirkas, National and Kapodistrian University of Athens (NKUA), Attikon University Hospital, 2nd Propedeutic Clinic of Internal Medicine, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Second Department of Internal Medicine, Propaedeutic, University of Athens Medical School [Athens], Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Medical School, Democritus University of Thrace (DUTH), Physiopathologie et Epidemiologie de l'Insuffisance Respiratoire, National and Kapodistrian University of Athens = University of Athens (NKUA | UoA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), University of Athens, Medical School, University General Hospital Attikon, and Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Exacerbation, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], TINF2, medicine.disease_cause, 03 medical and health sciences, Idiopathic pulmonary fibrosis, 0302 clinical medicine, Germline mutation, Internal medicine, Pulmonary fibrosis, medicine, Humans, Letter to the Editor, Aged, lcsh:RC705-779, Aged, 80 and over, Mutation, business.industry, Myelodysplastic syndromes, Bone marrow failure, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, lcsh:Diseases of the respiratory system, Symptom Flare Up, medicine.disease, Idiopathic Pulmonary Fibrosis, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030228 respiratory system, Myelodysplastic Syndromes, Female, business
Abstract

International audience; Previous studies have shown that the co-existence of bone marrow failure and pulmonary fibrosis in a single patient or in a family is suggestive of telomere related genes (TRG) germline mutations. This study presents the genetic background, clinical characteristics, and outcome of a group of five Greek patients co-affected with IPF and MDS. Four out of five patients developed an IPF acute exacerbation that was not reversible. We failed to detect any mutation in the TERT, TERC, DKC1, TINF2, RTEL1, PARN, NAF1, ACD, NHP2 and NOP10 genes in any patient. Moreover, telomere length was normal in the two patients tested. This could suggest that although the co-occurence of IPF and MDS are suggestive of TRG mutation in patients

Published
2019

28. EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome

Author

Dana Ranta, Jean Donadieu, Pekka Jaako, Alan J. Warren, Etienne Lengliné, Laetitia Kermasson, Christine Bellanné-Chantelot, Angela Hoslin, Alexandre Faille, Hubert Ducou Le Pointe, Patrick Revy, Abraham Acevedo-Arozena, Christine Bole-Feysot, Caroline Kannengiesser, Blandine Beaupain, Shengjiang Tan, Patrick Nitschke, Odile Fenneteau, Jean-Pierre de Villartay, Stefano Fumagalli, Maryline Poirée, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, CIC - Biotherapie - GHU Ouest APHP (CIC-BT 502), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hematologie et Médecine Interne, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Pédiatrie, Unité d'Oncologie et Hématologie Pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Radiologie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], 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 de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National History Museum of London, Acevedo-Arozena, Abraham [0000-0001-6127-7116], Bellanné-Chantelot, Christine [0000-0001-8415-6771], Warren, Alan J [0000-0001-9277-4553], Revy, Patrick [0000-0003-0758-8022], Apollo - University of Cambridge Repository, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Service d'Hémato-oncologie Pédiatrique, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Saint-Antoine [APHP], Service d’oncologie hématologie pédiatrique [CHU Trousseau], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)

Subjects
Male, Models, Molecular, Ribosomopathy, Protein Conformation, DNA Mutational Analysis, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine.disease_cause, Biochemistry, Ribosome, Mice, 0302 clinical medicine, Peptide Initiation Factors, Large ribosomal subunit, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, Genetics, 0303 health sciences, Shwachman–Diamond syndrome, Mutation, Translation (biology), [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Shwachman-Diamond Syndrome, 3. Good health, Pedigree, Phenotype, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, EIF6, 030220 oncology & carcinogenesis, Female, Disease Susceptibility, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Immunology, Mice, Transgenic, Biology, 03 medical and health sciences, Structure-Activity Relationship, Red Cells, Iron, and Erythropoiesis, medicine, Animals, Humans, Ribonucleoprotein, U5 Small Nuclear, 030304 developmental biology, Whole Genome Sequencing, Infant, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, medicine.disease, Peptide Elongation Factors, Disease Models, Animal, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Ribosome Subunits, Genome-Wide Association Study
Abstract

Shwachman-Diamond syndrome (SDS) is a recessive disorder typified by bone marrow failure and predisposition to hematological malignancies. SDS is predominantly caused by deficiency of the allosteric regulator Shwachman-Bodian-Diamond syndrome that cooperates with elongation factor-like GTPase 1 (EFL1) to catalyze release of the ribosome antiassociation factor eIF6 and activate translation. Here, we report biallelic mutations in EFL1 in 3 unrelated individuals with clinical features of SDS. Cellular defects in these individuals include impaired ribosomal subunit joining and attenuated global protein translation as a consequence of defective eIF6 eviction. In mice, Efl1 deficiency recapitulates key aspects of the SDS phenotype. By identifying biallelic EFL1 mutations in SDS, we define this leukemia predisposition disorder as a ribosomopathy that is caused by corruption of a fundamental, conserved mechanism, which licenses entry of the large ribosomal subunit into translation.

Published
2019

29. NHP2 deficiency impairs rRNA biogenesis and causes pulmonary fibrosis and Høyeraal-Hreidarsson syndrome

Author

Nicolas Pottier, Ibrahima Ba, Maname Benyelles, Emmanuelle Ollivier, Patrick Revy, Laetitia Kermasson, Elodie Lainey, Cécile Fourrage, Alicia Fernandes, Raphael Borie, Marie-Françoise O'Donohue, Caroline Kannengiesser, Chantal Lagresle-Peyrou, Hilario Nunes, Anne-Sophie Gamez, Bruno Crestani, Denis Caillaud, Fanny Morice-Picard, Jean-Pierre de Villartay, Isabelle Callebaut, Christelle Ménard, Clarisse Cazelles, Ambroise Marçais, Pierre-Emmanuel Gleizes, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinical Investigation Center in Biotherapy, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pneumologie [Avicenne], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Clinical Bioinformatics laboratory (Equipe Inserm U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de Pneumologie et Allergologie, CHU Clermont-Ferrand, Impact de l'environnement chimique sur la santé humaine - ULR 4483 (IMPECS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Physiopathologie et Epidemiologie de l'Insuffisance Respiratoire, Laboratoire de biologie moléculaire eucaryote (LBME), Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Hôpital Bichat - Claude Bernard, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), ANR-16-CE11-0029,RIBOMAN,Une approche intégrative de la biogenèse des ribosomes(2016), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Hôpital Avicenne, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Impact de l'environnement chimique sur la santé humaine (IMPECS)

Subjects
0301 basic medicine, Premature aging, Male, Telomerase, Transcription, Genetic, Pulmonary Fibrosis, Sequence Homology, Hoyeraal-Hreidarsson syndrome, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, medicine.disease_cause, Dyskerin, Dyskeratosis Congenita, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Intellectual Disability, Genetics, medicine, Humans, Amino Acid Sequence, Promoter Regions, Genetic, Molecular Biology, Genetics (clinical), Aged, Mutation, Fetal Growth Retardation, Infant, Newborn, Nuclear Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, Middle Aged, medicine.disease, Ribonucleoproteins, Small Nuclear, 3. Good health, Telomere, Pedigree, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, RNA, Ribosomal, 030220 oncology & carcinogenesis, Cancer research, Microcephaly, Female, Dyskeratosis congenita
Abstract

Telomeres are nucleoprotein structures at the end of chromosomes. The telomerase complex, constituted of the catalytic subunit TERT, the RNA matrix hTR and several cofactors, including the H/ACA box ribonucleoproteins Dyskerin, NOP10, GAR1, NAF1 and NHP2, regulates telomere length. In humans, inherited defects in telomere length maintenance are responsible for a wide spectrum of clinical premature aging manifestations including pulmonary fibrosis (PF), dyskeratosis congenita (DC), bone marrow failure and predisposition to cancer. NHP2 mutations have been so far reported only in two patients with DC. Here, we report the first case of Høyeraal–Hreidarsson syndrome, the severe form of DC, caused by biallelic missense mutations in NHP2. Additionally, we identified three unrelated patients with PF carrying NHP2 heterozygous mutations. Strikingly, one of these patients acquired a somatic mutation in the promoter of TERT that likely conferred a selective advantage in a subset of blood cells. Finally, we demonstrate that a functional deficit of human NHP2 affects ribosomal RNA biogenesis. Together, our results broaden the functional consequences and clinical spectrum of NHP2 deficiency.

Published
2019

30. Regulator of telomere length 1 ( RTEL1 ) mutations are associated with heterogeneous pulmonary and extra-pulmonary phenotypes

Author

Arturo Londoño-Vallejo, Clément Gauvain, Julie Traclet, Tristan Dégot, Vincent Cottin, Marie Wislez, Raphael Borie, Bruno Crestani, Stéphane Dominique, Lidwine Wemeau-Stervinou, Patrick Revy, Aurélie Cazes, Caroline Kannengiesser, Pierre-Antoine Juge, Hilario Nunes, Christelle Ménard, Diane Bouvry, Catherine Boileau, Jacques Cadranel, Marie-Pierre Debray, Sébastien Quétant, Anne Sophie Gamez, Hervé Mal, Grégoire Prévot, Philippe Dieudé, Madeleine Jaillet, Arnaud Mailleux, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), Rétrovirus et Pathologie Comparée (RPC), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Département de Radiologie [Bichat] (DR- Bichat), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Centre National de la Recherche Scientifique (CNRS), Service de pneumologie et réanimation [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Service de Rhumatologie, AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-AP-HP, CHU Rouen, Normandie Université (NU), Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Telomeres and Cancer Laboratory, Institut Curie, Service de pneumologie B, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Service de cardiologie, Service de Pneumologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Hypoxie et Poumon : pneumopathologies fibrosantes, modulations ventilatoires et circulatoires (H&P), Université Paris 13 (UP13)-UFR SMBH, Service de pneumologie [Toulouse], CHU Toulouse [Toulouse]-Hôpital Larrey, Centre Hospitalier Universitaire [Grenoble] (CHU), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Infections Virales et Pathologie Comparée - UMR 754 (IVPC), Université de Lyon-Université de Lyon, Service de pneumologie. Centre de compétence des maladies pulmonaires rares, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Theranoscan, Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et Epidemiologie de l'Insuffisance Respiratoire, Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Centre de Recherche Saint-Antoine (UMRS893), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Toulouse [Toulouse]-Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), UFR SMBH-Université Paris 13 (UP13), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Gene mutation, 03 medical and health sciences, Idiopathic pulmonary fibrosis, 0302 clinical medicine, Fibrosis, Pulmonary fibrosis, Medicine, Telomerase reverse transcriptase, Exome, Exome sequencing, business.industry, Interstitial lung disease, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, respiratory system, medicine.disease, 3. Good health, respiratory tract diseases, 030104 developmental biology, 030228 respiratory system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, business
Abstract

Regulator of telomere length 1 (RTEL1) mutations have been evidenced in 5–9% of familial pulmonary fibrosis; however, the phenotype of patients with interstitial lung disease (ILD) and RTEL1 mutations is poorly understood.Whole exome sequencing was performed in 252 probands with ILD and we included all patients with ILD and RTEL1 mutation. RTEL1 expression was evaluated by immunochemistry in the lungs of controls, as well as in RTEL1 and telomerase reverse transcriptase (TERT) mutation carriers.We identified 35 subjects from 17 families. Median age at diagnosis of ILD was 53.1 years (range 28.0–80.6). The most frequent pulmonary diagnoses were idiopathic pulmonary fibrosis (n=20, 57%), secondary ILD (n=7, 20%) and unclassifiable fibrosis or interstitial pneumonia with autoimmune features (n=7, 20%). The median transplant-free and overall survival periods were 39.2 months and 45.3 months, respectively. Forced vital capacity at diagnosis was the only factor associated with decreased transplant-free survival. Extra-pulmonary manifestations were less frequent as compared to other telomere-related gene mutation carriers. A systematic analysis of the literature identified 110 patients with ILD and RTEL1 mutations (including this series) and confirmed the heterogeneity of the pulmonary phenotype, the prevalence of non-idiopathic diseases and the low prevalence of extra-pulmonary manifestations.Immunohistochemistry showed that RTEL1 was expressed by bronchial and alveolar epithelial cells, as well as by alveolar macrophages and lymphocytes, but not by fibroblasts.

Published
2019

31. Mutations of the RTEL1 Helicase in a Hoyeraal-Hreidarsson Syndrome Patient Highlight the Importance of the ARCH Domain

Author

Patrick Revy, Laurent Jullien, Laetitia Kermasson, Isabelle Callebaut, Arturo Londoño-Vallejo, Caroline Kannengiesser, Thierry Leblanc, Valérie Cormier-Daire, Jean Soulier, and Jean-Pierre de Villartay

Subjects
0301 basic medicine, Genetics, Mutation, biology, Protein domain, Helicase, Hoyeraal-Hreidarsson syndrome, Compound heterozygosity, medicine.disease, medicine.disease_cause, Molecular biology, Exon skipping, Telomere, 03 medical and health sciences, 030104 developmental biology, biology.protein, medicine, Genetics (clinical), Dyskeratosis congenita
Abstract

The DNA helicase RTEL1 participates in telomere maintenance and genome stability. Biallelic mutations in the RTEL1 gene account for the severe telomere biology disorder characteristic of the Hoyeraal-Hreidarsson syndrome (HH). Here, we report a HH patient (P4) carrying two novel compound heterozygous mutations in RTEL1: a premature stop codon (c.949A>T, p.Lys317*) and an intronic deletion leading to an exon skipping and an in-frame deletion of 25 amino-acids (p.Ile398_Lys422). P4's cells exhibit short and dysfunctional telomeres similarly to other RTEL1-deficient patients. 3D structure predictions indicated that the p.Ile398_Lys422 deletion affects a part of the helicase ARCH domain, which lines the pore formed with the core HD and the iron-sulfur cluster domains and is highly specific of sequences from the eukaryotic XPD family members.

Published
2016

32. TERT/TERC mutations in a Greek cohort of suspected genetic pulmonary fibrosis patients

Author

Katerina Vlami, Philippe Dieudé, Demosthenes Bouros, Chrysa Bazaka, Aikaterini Markopoulou, Lykourgos Kolilekas, Paschalina Giouleka, Konstantinos Kagouridis, Thomas Raptakis, Athina Gogali, Athanasios Konstantinidis, Nadia Nathan, Stylianos Loukides, Maria Maniati, Evangelos Bouros, Vasileios Tzilas, Aggeliki Charitou, Mina Gaga, Zoe Daniil, Ilias Papanikolaou, Paschalis Steiropoulos, Bruno Crestani, Athina Trachalaki, Maria Kallieri, Effrosyni D. Manali, Andriana I. Papaioannou, Spyros Papiris, Despoina Papakosta, Areti Xyfteri, Georgia Papadaki, Catherine Boileau, Argyrios Tzouvelekis, Evangelia Fouka, Anna Karakatsani, Caroline Kannengiesser, Patrick Revy, Eleni Stagaki, Katerina M. Antoniou, Anastasia Papaporfyriou, Ioanna Korbila, Ioannis Tomos, Raphael Borie, and Panagiotis Lyberopoulos

Subjects
medicine.medical_specialty, business.industry, Internal medicine, Pulmonary fibrosis, Cohort, medicine, medicine.disease, business
Published
2018

33. Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS

Author

Gillian I. Rice, Patrick Revy, Yanick J. Crow, Russell C. Dale, Mathieu P Rodero, Nicolas Manel, Darragh Duffy, Mathieu Maurin, Florence Petit, Cécile Conrad, Elias Bou Samra, Matthieu Gratia, Mounira Amor-Guéret, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Stress génotoxiques et cancer, Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Manchester [Manchester], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), The University of Sydney, University of Edinburgh, This work was supported by Laboratoire d'Excellence Vaccine Research Institute (ANR-10-LABX-77), Laboratoire d'Excellence Biologie des Cellules Dendritiques (ANR-10-IDEX-0001-02 PSL* and ANR-11-LABX-0043), ACTERIA Foundation, Fondation Schlumberger pour l'Education et la Recherche, Agence Nationale de Recherche sur le Sida et les hépatites virales (ECTZ25472 and ECTZ36691), Sidaction (VIH2016126002), Bristol-Myers Squibb Foundation, European Research Council (grant 309848 HIVINNATE and INSERM) to N. Manel, National Research Agency (ANR-14-CE14-0004) and Institut Curie to N. Manel and M. Amor-Gueret, Institut National du Cancer (2016-1-PLBIO-03-ICR-1), Ligue Nationale Contre le Cancer (Comité de l’Essonne), and Centre National de la Recherche Scientifique to M. Amor-Gueret. Y.J. Crow acknowledges the European Research Council (GA 309449 and 786142 - E-T1IFNs), ERA-NET Neuron (MR/M501803/1), and a state subsidy managed by the National Research Agency (France) under the 'Investments for the Future' program bearing the reference ANR-10-IAHU-01. Y.J. Crow and D. Duffy acknowledge the National Research Agency (grant CE17001002), We thank Philippe Benaroch for critical reading of the manuscript, Vincent Bondet for the Simoa analysis, Santy Marques-Ladeira for bioinformatics analysis, Xavier Lahaye for molecular biology, Géraldine Buhagiar-Labarchède and Rosine Onclercq-Delic for technical assistance, Aude Vieillefon, Audrey Rapinat, and David Gentien from the Genomics Platform of the translational research department of Institut Curie, and Prof. Dominique Stoppa-Lyonnet, Head of the Department of Genetics at Institut Curie and Professor of Medical Genetics at University Paris Descartes, for stimulating discussions. Y.J. Crow and D. Duffy thank ImmunoQure AG for sharing of antibodies used to assess interferon alpha protein levels in the Simoa assay., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-14-CE14-0004,INNATENUCLEOTIDES,Un nouveau modèle de régulation de la réponse immunitaire innée par le métabolisme des nucléotides(2014), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016), European Project: 309848,EC:FP7:ERC,ERC-2012-StG_20111109,HIVINNATE(2013), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Vougny, Marie-Christine, Laboratoires d'excellence - Initiative for the creation of a Vaccine Research Institute - - VRI2010 - ANR-10-LABX-0077 - LABX - VALID, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Appel à projets générique - Un nouveau modèle de régulation de la réponse immunitaire innée par le métabolisme des nucléotides - - INNATENUCLEOTIDES2014 - ANR-14-CE14-0004 - Appel à projets générique - VALID, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Investigation des interferonopathies type I humaine - - IFNX2016 - ANR-16-CE17-0010 - AAPG2016 - VALID, Innate sensing of HIV and immune responses - HIVINNATE - - EC:FP7:ERC2013-01-01 - 2017-12-31 - 309848 - VALID, Definition and characterization of type I interferonopathies - T1-IFN - - EC:FP7:ERC2013-03-01 - 2018-02-28 - 309449 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Université Paris Descartes - Paris 5 (UPD5), Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes - Paris 5 (UPD5), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Paris-Sud - Paris 11 (UP11), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de dynamique des systèmes neuroendocriniens, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris-Sud - Paris 11 (UP11)-Institut Curie-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Genome instability, Male, Human Disease, [SDV]Life Sciences [q-bio], 0302 clinical medicine, Cytosol, Transduction, Genetic, 2',5'-Oligoadenylate Synthetase, Immunology and Allergy, Bloom syndrome, Child, ComputingMilieux_MISCELLANEOUS, Research Articles, RecQ Helicases, Genome Stability, RNA-Binding Proteins, Nucleotidyltransferases, 3. Good health, Cell biology, Bloom syndrome protein, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, Bloom Syndrome, congenital, hereditary, and neonatal diseases and abnormalities, [SDV.IMM] Life Sciences [q-bio]/Immunology, DNA damage, Immunology, Innate Immunity and Inflammation, Inflammation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Article, 03 medical and health sciences, Immune system, medicine, Genetics, Humans, Gene, Adaptor Proteins, Signal Transducing, Innate immune system, Tumor Suppressor Proteins, nutritional and metabolic diseases, Membrane Proteins, Fibroblasts, medicine.disease, Phosphoproteins, Immunity, Innate, 030104 developmental biology, Exodeoxyribonucleases, HEK293 Cells, Interferon Regulatory Factor-3, Apoptosis Regulatory Proteins, Transcriptome, DNA Damage, HeLa Cells
Abstract

How self-DNA avoids unchecked activation of innate DNA sensors is poorly understood. Gratia et al. show that BLM protein, mutated in Bloom syndrome (BS), restrains interferon-stimulated gene induction and micronuclei recognition by cGAS. Consistently, BS patients exhibit an interferon signature., Cellular innate immune sensors of DNA are essential for host defense against invading pathogens. However, the presence of self-DNA inside cells poses a risk of triggering unchecked immune responses. The mechanisms limiting induction of inflammation by self-DNA are poorly understood. BLM RecQ–like helicase is essential for genome integrity and is deficient in Bloom syndrome (BS), a rare genetic disease characterized by genome instability, accumulation of micronuclei, susceptibility to cancer, and immunodeficiency. Here, we show that BLM-deficient fibroblasts show constitutive up-regulation of inflammatory interferon-stimulated gene (ISG) expression, which is mediated by the cGAS–STING–IRF3 cytosolic DNA–sensing pathway. Increased DNA damage or down-regulation of the cytoplasmic exonuclease TREX1 enhances ISG expression in BLM-deficient fibroblasts. cGAS-containing cytoplasmic micronuclei are increased in BS cells. Finally, BS patients demonstrate elevated ISG expression in peripheral blood. These results reveal that BLM limits ISG induction, thus connecting DNA damage to cellular innate immune response, which may contribute to human pathogenesis.

Published
2018

34. Regulator of telomere length 1 (

Author

Raphael, Borie, Diane, Bouvry, Vincent, Cottin, Clement, Gauvain, Aurélie, Cazes, Marie-Pierre, Debray, Jacques, Cadranel, Philippe, Dieude, Tristan, Degot, Stephane, Dominique, Anne Sophie, Gamez, Madeleine, Jaillet, Pierre-Antoine, Juge, Arturo, Londono-Vallejo, Arnaud, Mailleux, Hervé, Mal, Catherine, Boileau, Christelle, Menard, Hilario, Nunes, Gregoire, Prevot, Sebastien, Quetant, Patrick, Revy, Julie, Traclet, Lidwine, Wemeau-Stervinou, Marie, Wislez, Caroline, Kannengiesser, and Bruno, Crestani

Subjects
Adult, Aged, 80 and over, Lung Diseases, Male, Heterozygote, Vital Capacity, DNA Helicases, Sequence Analysis, DNA, Middle Aged, Pedigree, Phenotype, Gene Expression Regulation, Mutation, Humans, Exome, Female, Lung Diseases, Interstitial, Telomerase, Aged, Follow-Up Studies
Abstract

Regulator of telomere length 1 (

Published
2018

35. Reduced recruitment of 53BP1 during interstrand crosslink repair is associated with genetically inherited attenuation of mitomycin C sensitivity in a family with Fanconi anemia

Author

Francina Langa Vives, Jean Soulier, Armand Biver, Jean-Pierre de Villartay, Patrick Revy, Nada Jabado, Benoit Roch, Emilie Lesport, Nadia Vasquez, Alina Ferster, LANGA VIVES, FRANCINA, Programme de Recherche Translationnelle en Santé - Conséquences des défauts de réparation de l'ADN et du maintien des télomères sur le fonctionnement du Système Immunitaire: application aux DICV et aux déficits immunitaires avec syndromes dysmorphiques - - Immune-Rep2013 - ANR-13-PRTS-0004 - PRTS - VALID, Primary immunodeficiency diseases as models for the study of the immune system - PIDIMMUN - - EC:FP7:ERC2010-07-01 - 2015-06-30 - 249816 - VALID, Genome dynamics in the immune system (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique] (HUDERF), Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), McGill University = Université McGill [Montréal, Canada], Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris] (IP), This work was supported by institutional grants from INSERM, the Institut National du Cancer (PLBIO11-151) and Agence Nationale de la Recherche (ANR-13-PRTS-0004), by grants from La Ligue Nationale contre le Cancer (Equipe Labellisée LA LIGUE), and ERC PID-IMMUN (no. 249816). EL was supported by a grant from ARC Fondation., ANR-13-PRTS-0004,Immune-Rep,Conséquences des défauts de réparation de l'ADN et du maintien des télomères sur le fonctionnement du Système Immunitaire: application aux DICV et aux déficits immunitaires avec syndromes dysmorphiques(2013), European Project: 249816,EC:FP7:ERC,ERC-2009-AdG,PIDIMMUN(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Institut Pasteur [Paris]

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Interstrand crosslink, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, chemistry.chemical_compound, FANCG, Fanconi anemia, medicine, Mitomycin C, DNA interstrand crosslinks, medicine.disease, Phenotype, 53BP1, Double Strand Break Repair, [SDV] Life Sciences [q-bio], 030104 developmental biology, Oncology, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, DNA double strand break repair, ATM, Cancer research, Homologous recombination, DNA, Research Paper, Psychiatrie
Abstract

The Fanconi anemia (FA) pathway is implicated in the repair of DNA interstrand crosslinks (ICL). In this process, it has been shown that FA factors regulate the choice for DNA double strand break repair towards homologous recombination (HR). As this mechanism is impaired in FA deficient cells exposed to crosslinking agents, an inappropriate usage of non-homologous end joining (NHEJ) leads to the accumulation of toxic chromosomal abnormalities. We studied a family with two FANCG patients and found a genetically inherited attenuation of mitomycin C sensitivity resulting in-vitro in an attenuated phenotype for one patient or in increased resistance for two healthy relatives. A heterozygous mutation in ATM was identified in these 3 subjects but was not directly linked to the observed phenotype. However, the attenuation of ICL sensitivity was associated with a reduced recruitment of 53BP1 during the course of ICL repair, and increased HR levels. These results further demonstrate the importance of favoring HR over NHEJ for the survival of cells challenged with ICLs., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2018

37. Unraveling the pathogenesis of Hoyeraal-Hreidarsson syndrome, a complex telomere biology disorder

Author

Galina Glousker, Sharon A. Savage, Fabien Touzot, Patrick Revy, and Yehuda Tzfati

Subjects
Genetics, Mutation, Fetal Growth Retardation, Genetic disorder, Telomere Homeostasis, Hoyeraal-Hreidarsson syndrome, Hematology, Disease, Telomere, Biology, medicine.disease, medicine.disease_cause, Article, Dyskeratosis Congenita, Germline mutation, Intellectual Disability, Microcephaly, medicine, Humans, Dyskeratosis congenita
Abstract

Summary Hoyeraal–Hreidarsson (HH) syndrome is a multisystem genetic disorder characterized by very short telomeres and considered a clinically severe variant of dyskeratosis congenita. The main cause of mortality, usually in early childhood, is bone marrow failure. Mutations in several telomere biology genes have been reported to cause HH in about 60% of the HH patients, but the genetic defects in the rest of the patients are still unknown. Understanding the aetiology of HH and its diverse manifestations is challenging because of the complexity of telomere biology and the multiple telomeric and non-telomeric functions played by telomere-associated proteins in processes such as telomere replication, telomere protection, DNA damage response and ribosome and spliceosome assembly. Here we review the known clinical complications, molecular defects and germline mutations associated with HH, and elucidate possible mechanistic explanations and remaining questions in our understanding of the disease.

Published
2015

38. PROMIDISα: A T-cell receptor α signature associated with immunodeficiencies caused by V(D)J recombination defects

Author

Felipe Suarez, Vincent Allain, Figen Dogu, Catherine Dubois d'Enghien, Patrick Revy, Funda Erol Cipe, Andrea Finocchi, Jean-Pierre de Villartay, Alain Fischer, Claire Fieschi, Marion Malphettes, David Boutboul, Alexandre Belot, Nizar Mahlaoui, Nathalie Auger, Despina Moshous, Jérémie Rosain, Marie Ouachée-Chardin, Sophie Kaltenbach, Dominique Stoppa-Lyonnet, Aurélie Berland, Lionel Galicier, Laurence Perrin, Stéphane Blanche, Capucine Picard, Isabelle Melki, Alice Fiévet, Thierry Leblanc, Eric Oksenhendler, Genome dynamics in the immune system (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for the Study of Primary Immunodeficiencies [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pediatric Immuno-Haematology and Rheumatology Unit, CHU Necker - Enfants Malades [AP-HP], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Service de Génétique Oncologique, Institut Curie [Paris], Service d'hématologie et immunologie pédiatrique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique clinique [Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Institut Gustave Roussy (IGR), Département de biologie et pathologie médicales [Gustave Roussy], Kanuni Sultan Suleyman Research and Training Hospital [Istanbul], Children's Hospital Bambino Gesù IRCCS [Rome], University of Rome TorVergata, Ankara University School of Medicine [Turkey], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Hopital Saint-Louis [AP-HP] (AP-HP), CCSD, Accord Elsevier, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France - Chaire Médecine expérimentale (A. Fischer), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)

Subjects
0301 basic medicine, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, DCLRE1C, Receptors, Antigen, T-Cell, alpha-beta, DNA repair, Primary immunodeficiency, T-cell receptor α repertoire, V(D)J recombination, ataxia telangiectasia, next-generation sequencing, Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Middle Aged, Prospective Studies, Retrospective Studies, V(D)J Recombination, Immunologic Deficiency Syndromes, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 0302 clinical medicine, Receptors, Immunology and Allergy, Immunodeficiency, alpha-beta, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Settore MED/38, 3. Good health, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Antigen, Immunology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Recombination-activating gene, 03 medical and health sciences, medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Preschool, Severe combined immunodeficiency, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Newborn, T-Cell, Nibrin, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, business, Nijmegen breakage syndrome, 030215 immunology
Abstract

International audience; BACKGROUND:V(D)J recombination ensures the diversity of the adaptive immune system. Although its complete defect causes severe combined immunodeficiency (ie, T-B- severe combined immunodeficiency), its suboptimal activity is associated with a broad spectrum of immune manifestations, such as late-onset combined immunodeficiency and autoimmunity. The earliest molecular diagnosis of these patients is required to adopt the best therapy strategy, particularly when it involves a myeloablative conditioning regimen for hematopoietic stem cell transplantation.OBJECTIVE:We aimed at developing biomarkers based on analysis of the T-cell receptor (TCR) α repertoire to assist in the diagnosis of patients with primary immunodeficiencies with V(D)J recombination and DNA repair deficiencies.METHODS:We used flow cytometric (fluorescence-activated cell sorting) analysis to quantify TCR-Vα7.2-expressing T lymphocytes in peripheral blood and developed PROMIDISα, a multiplex RT-PCR/next-generation sequencing assay, to evaluate a subset of the TCRα repertoire in T lymphocytes.RESULTS:The combined fluorescence-activated cell sorting and PROMIDISα analyses revealed specific signatures in patients with V(D)J recombination-defective primary immunodeficiencies or ataxia telangiectasia/Nijmegen breakage syndromes.CONCLUSION:Analysis of the TCRα repertoire is particularly appropriate in a prospective way to identify patients with partial immune defects caused by suboptimal V(D)J recombination activity, a DNA repair defect, or both. It also constitutes a valuable tool for the retrospective in vivo functional validation of variants identified through exome or panel sequencing. Its broader implementation might be of interest to assist early diagnosis of patients presenting with hypomorphic DNA repair defects inclined to experience acute toxicity during prehematopoietic stem cell transplantation conditioning.

Published
2017

39. PAXX and Xlf interplay revealed by impaired CNS development and immunodeficiency of double KO mice

Author

Ana Cumano, Benoit Roch, Laetitia Kermasson, Ramy Elsaid, Vincent Abramowski, Jean-Paul Moussu, Olivier Etienne, Aurélie Berland, Jean-Pierre de Villartay, Stefania Musilli, Patrick Revy, Junjie Yang, François D. Boussin, Karelia Lipson-Ruffert, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Radiopathologie (LRP), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Transgenèse et archivage d'animaux modèles (TAAM), Centre National de la Recherche Scientifique (CNRS), This work was supported by institutional grants from INSERM, the Institut National du Cancer (PLBIO16-280), the Agence Nationale de la Recherche ('Investissement d’Avenir' program ANR-10-IAHU-01), and by grants from La Ligue Nationale contre le Cancer (Equipe Labellisée LA LIGUE), Pasteur Institute, ANR (Program REVIVE and grant Twothyme) to AC., We thank Catherine Cailleau (SEAT) for exceptional care of our mouse lines, Sophie Berissi for help in immunohistochemistry and Olivier Alibeu, Aurore Pouliet, and Christine Bole-Feyssot (Genomic facility, Imagine Institute) for their assistance in NGS, ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-14-CE11-0022,Twothyme,Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T.(2014), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), Vougny, Marie-Christine, Laboratoires d'excellence - Stem Cells in Regenerative Biology and Medicine - - REVIVE2010 - ANR-10-LABX-0073 - LABX - VALID, Appel à projets générique - Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T. - - Twothyme2014 - ANR-14-CE11-0022 - Appel à projets générique - VALID, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Central Nervous System, DNA End-Joining Repair, [SDV.IMM] Life Sciences [q-bio]/Immunology, Biology, medicine.disease_cause, 03 medical and health sciences, Mice, Immune system, medicine, Animals, Lymphocytes, Molecular Biology, Immunodeficiency, Loss function, chemistry.chemical_classification, Mice, Knockout, DNA ligase, Mutation, Original Paper, Genetic interaction, Immunologic Deficiency Syndromes, Cell Biology, DNA repair protein XRCC4, medicine.disease, Acquired immune system, Phenotype, Cell biology, Resin Cements, DNA-Binding Proteins, Mice, Inbred C57BL, 030104 developmental biology, chemistry, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract

International audience; The repair of DNA double-stranded breaks (DNAdsb) through non-homologous end joining (NHEJ) is a prerequisite for the proper development of the central nervous system and the adaptive immune system. Yet, mice with Xlf or PAXX loss of function are viable and present with very mild immune phenotypes, although their lymphoid cells are sensitive to ionizing radiation attesting for the role of these factors in NHEJ. In contrast, we show here that mice defective for both Xlf and PAXX are embryonically lethal owing to a massive apoptosis of post-mitotic neurons, a situation reminiscent to XRCC4 or DNA Ligase IV KO conditions. The development of the adaptive immune system in Xlf(-/-)PAXX(-/-) E18.5 embryos is severely affected with the block of B- and T-cell maturation at the stage of IgH and TCRβ gene rearrangements, respectively. This damaging phenotype highlights the functional nexus between Xlf and PAXX, which is critical for the completion of NHEJ-dependent mechanisms during mouse development.Cell Death and Differentiation advance online publication, 27 October 2017; doi:10.1038/cdd.2017.184.

Published
2017

40. AB0007 Shared genetic predisposition in rheumatoid arthritis–interstitial lung disease and familial pulmonary fibrosis

Author

Serge Amselem, Marie-Christophe Boissier, Catherine Boileau, Benoit Wallaert, Aurélien Justet, Gabriel Thabut, Baptiste Coustet, A Clément, Bruno Crestani, Martin Soubrier, Yannick Allanore, Vincent Cottin, S. Ottaviani, Nadia Nathan, Christelle Ménard, Olivier Sand, Steven Gazal, Hilario Nunes, Lidwine Wemeau-Stervinou, H. Lioté, Isabelle Callebaut, Philippe Dieudé, Pierre-Antoine Juge, Marie-Pierre Debray, P. Richette, R.M. Flipo, Patrick Revy, Dominique Valeyre, Dlm Florence, S. Marchand-Adam, J. Sibilia, T. Schaeverbeke, Aline Frazier, Christophe Richez, Caroline Kannengiesser, Raphael Borie, Claire Dromer, and N. Saidenberg

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Pathology, Mutation, business.industry, Interstitial lung disease, Odds ratio, respiratory system, medicine.disease, medicine.disease_cause, respiratory tract diseases, Pathogenesis, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Usual interstitial pneumonia, 030220 oncology & carcinogenesis, Rheumatoid arthritis, Internal medicine, Pulmonary fibrosis, medicine, Genetic predisposition, business
Abstract

Background Despite its high prevalence and mortality, little is known about the pathogenesis of RA–associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA–ILD frequently share the usual interstitial pneumonia pattern and common environmental risk factors, we hypothesized that the two diseases may share additional risk factors including FPF-linked genes. Objectives Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD. Methods We used whole-exome sequencing (WES) followed by restricted analysis of a discrete number of FPF-linked genes and performed a Burden test to assess the excess number of mutations in RA–ILD patients compared to controls. Results Among the 101 RA–ILD patients included, 12 (11.9%) had 13 WESidentified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA–ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations for RA–ILD patients (p=9.45’10-4, odds ratio [OR] 3.17 95% CI 1.53 – 6.12). Telomeres were shorter for RA-ILD patients with a TERT, RTEL1 or PARN mutation than controls (p=2.87x10-2). Conclusions Our results support the contribution of FPF-linked genes to RA–ILD susceptibility. Disclosure of Interest None declared

Published
2017

41. Corrigendum: Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts

Author

Rosaline Caumes, Andrea Berger, John Stone, Roberta Battini, Charles Marques Lourenço, Gerardine Quaghebeur, Nicholas A. Fletcher, Elliott H. Sherr, Marjo S. van der Knaap, Sanjeev S. Bhaskar, Marco Henneke, Kanaga R. Sinnathuray, Pierre Landrieu, James O'Sullivan, Calvin Soh, Himanshu Goel, Patrick Ferreira, Katrin Õunap, Cheryl Hemingway, Laurence C. Goosey, Graham D. Pavitt, Hilde Van Esch, Prab Prabhakar, Yoann Rose, Jill E. Urquhart, Yanick J. Crow, Gabriela M. Baerlocher, Simon G. Williams, Mathieu P Rodero, Ram L. Kumar, Emma M. Jenkinson, Gillian I. Rice, Sarju G. Mehta, Adeline Vanderver, Timothy J. Malpas, Christopher J. Kershaw, Imke Metz, Edward Blair, Paul R. Kasher, Imelda Hughes, Patrick Revy, David Cassiman, Duccio Maria Cordelli, Angela Barnicoat, Andrea Whitney, Janice E. Brunstrom-Hernandez, Axel Panzer, Kristin W. Barañano, Liesbeth De Waele, Geraldine Aubert, Raphael Schiffmann, H. Stewart, Monika Haubitz, Rosalind J. Jefferson, Alan Fryer, Anthony Oojageer, Carolina Uggenti, John H. Livingston, Sam Griffiths-Jones, Christine E. G. van Mol, Johannes A. Buckard, Raymond T. O'Keefe, Lieven Lagae, Emma Wakeling, Sakkubai Naidu, Alex J. Fay, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Department of Medical Genetics, and HMNC Brain Health

Subjects
0303 health sciences, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Biology, medicine.disease, Article, 3. Good health, Leukoencephalopathy, 03 medical and health sciences, 0302 clinical medicine, Cerebral microangiopathy, Genetics, medicine, 610 Medicine & health, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

Although ribosomes are ubiquitously expressed and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein encoding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.

Published
2017

42. Mutations in KEOPS-complex genes cause nephritic syndrome with primary microcephaly

Author

Sebastian A. Leidel, Sarah Vergult, Olivier Gribouval, Olivia Boyer, Annapurna Poduri, Fatih Ozaltin, Heon Yung Gee, Oraly Sanchez-Ferras, Ankana Daga, David A. Sweetser, Chyong Hsin Hsu, Carolin E. Sadowski, Nithiwat Vatanavicharn, Shirlee Shril, Bruno Collinet, Verena Matejas, Jeremy F.P. Ullmann, Jennifer A. Lawson, Weizhen Tan, David Chitayat, Peter Kannu, Emmanuelle Lemyre, Megan T. Cho, Gaëlle H. Martin, Amber Begtrup, Jui Hsing Chang, Matthias T.F. Wolf, Agnieszka Prytuła, Jennifer Hu, Peter C. Dedon, Sik Nin Wong, Gessica Truglio, Maxime Bouchard, Sandra D. Kienast, Tobias Hermle, Merlin Airik, Manish D. Sinha, Rebecca O. Littlejohn, Takashi Shiihara, Daniella Magen, Yu Yuan Ke, Kenza Soulami, Denny Schanze, Chitra Prasad, Dominique Liger, Svjetlana Lovric, Kazuyuki Nakamura, Jameela A. Kari, Wai Ming Lai, Wen Hui Tsai, Jeng Daw Tsai, Eugen Widmeier, Neveen A. Soliman, Tilman Jobst-Schwan, Shazia Ashraf, Amira Masri, Jia Rao, Jillian K. Warejko, Tamara Basta, Martin Zenker, Brendan Beeson, Corinne Antignac, Malcolm Bruce, Patrick E. Gipson, Mónica Furlano, Géraldine Mollet, Johanna Magdalena Schmidt, Jessica L. Waxler, Daniela A. Braun, Karin Scharmann, David Schapiro, Shrikant Mane, Shuan-Pei Lin, Marleen Praet, Patrick M. Gaffney, Werner L. Pabst, Charlotte A. Hoogstraten, Björn Menten, Nina De Rocker, Richard P. Lifton, Anne Claire Boschat, Klaas J. Wierenga, Chao Huei Chen, Cathy Kiraly-Borri, Nathalie Boddaert, Marie Claire Daugeron, Bert Callewaert, Gaik Siew Ch’ng, Sylvia Sanquer, Won-Il Choi, Udo Vester, Herman van Tilbeurgh, Rezan Topaloglu, David Viskochil, Elizabeth Roeder, Friedhelm Hildebrandt, I. Chiara Guerrera, Rhonda E. Schnur, Patrick Rump, Babak Behnam, Patrick Revy, Mastaneh Moghtaderi, Université Paris Descartes - Paris 5 (UPD5), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), Laboratoire des Maladies Rénales Héréditaires, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Département Microbiologie (Dpt Microbio), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biologie Cellulaire des Archées (ARCHEE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Service de néphrologie pédiatrique [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), Division of Nephrology, Boston Children's Hospital, Institute of Human Genetics (University Hospital Magdeburg), University Hospital of the Otto von Guericke University of Magdeburg, Service de Radiologie et imagerie médicale [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), UPMC - UFR Sciences de la vie (UFR 927 ), Université Pierre et Marie Curie - Paris 6 (UPMC), Département Biochimie, Biophysique et Biologie Structurale (B3S), Fonction et Architecture des Assemblages Macromoléculaires (FAAM), Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Plateforme Protéomique Necker [SFR Necker] (PPN - 3P5), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie métabolique [CHU Necker], Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ghent University Hospital, Institut de génétique et microbiologie [Orsay] (IGM), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, GeneDx [Gaithersburg, MD, USA], Université de Montréal (UdeM), CHU Sainte Justine [Montréal], University of Amman, Cabinet de Néphrologie pédiatrique [Casablanca, Maroc], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Singapore-MIT Alliance for Research and Technology (SMART), Massachusetts Institute of Technology (MIT), Yale University [New Haven], Yale University School of Medicine, University of Toronto, Center for Medical Genetics [Ghent], Institute of Human Genetics, University Hospital Magdeburg, Service de Génétique Médicale [CHU Necker], Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University Hospital Erlangen, Université de Montréal [Montréal], Sapienza University [Rome], Singapore-MIT Alliance for Research and Technology (SMART) Centre, CREATE Tower, Singapore 138602, Singapore (SMART), Singapore-MIT Alliance for Research and Technology (SMART) Centre, Howard Hugues Medical Institute, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Yale School of Medicine [New Haven, Connecticut] (YSM), and Çocuk Sağlığı ve Hastalıkları

Subjects
Microcephaly, Nephrotic Syndrome, MICROBIO, FAAM, DNA Repair, cell migration, congenital nephrotic syndrome, Apoptosis, DNA damage response, Pediatrics, Galloway Mowat syndrome, Mice, gene silencing, Models, Cell Movement, GALLOWAY-MOWAT SYNDROME, molecular pathology, newborn, caspase 3, KEOPS complex, ARCHEE, microcephaly, Cytoskeleton, Genetics & Heredity, Mutation, Gene knockdown, clinical article, UNFOLDED PROTEIN RESPONSE, Intracellular Signaling Peptides and Proteins, Endoplasmic Reticulum Stress, transfer RNA, 3. Good health, Cell biology, TRANSFER-RNA MODIFICATION, Nephrosis, TPRKB protein, actin filament, phenotype, embryo, Article, loss of function mutation, in vivo study, 03 medical and health sciences, OSGEP protein, protein serine threonine kinase, Genetics, Humans, YEAST, human, mouse, autosomal recessive disorder, animal model, Molecular, MASS-SPECTROMETRY, DNA, zebrafish protein, medicine.disease, LAGE3 protein, Transfer, carrier protein, 030104 developmental biology, proteasome, cell proliferation, Multiprotein Complexes, Unfolded protein response, CRISPR-Cas Systems, Carrier Proteins, Models, Molecular, 0301 basic medicine, SECKEL-SYNDROME, Hernia, Protein Conformation, [SDV]Life Sciences [q-bio], Medizin, Post-Transcriptional, medicine.disease_cause, lethality, Gene Knockout Techniques, TP53RK protein, RNA, Transfer, multiprotein complex, gene mutation, RNA Processing, Post-Transcriptional, Zebrafish, Hiatal, child, biology, Podocytes, LAGE3 protein, human, apoptosis, Metalloendopeptidases, Protein-Serine-Threonine Kinases, unclassified drug, epidermal growth factor, female, O-sialoglycoprotein endopeptidase, endoplasmic reticulum stress, metalloproteinase, B3S, WDR73, RNA Processing, DNA repair, CRISPR-CAS9 system, animal experiment, Protein Serine-Threonine Kinases, GENOME MAINTENANCE, male, medicine, KINASE, Animals, signal peptide, controlled study, TPRKB protein, human, TP53RK protein, human, nonhuman, gene deletion, Telomere Homeostasis, Zebrafish Proteins, Actin cytoskeleton, biology.organism_classification, Molecular biology, actin related protein 2-3 complex, infant, Hernia, Hiatal, adolescent, RNA, homozygosity
Abstract

Galloway-Mowat syndrome (GAMOS) is a severe autosomal-recessive disease characterized by the combination of early-onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies. To date, mutations of WDR73 are the only known monogenic cause of GAMOS and in most affected individuals the molecular diagnosis remains elusive. We here identify recessive mutations of OSGEP, TP53RK, TPRKB, or LAGE3, encoding the 4 subunits of the KEOPS complex in 33 individuals of 30 families with GAMOS. CRISPR/Cas9 knockout in zebrafish and mice recapitulates the human phenotype of microcephaly and results in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibits cell proliferation, which human mutations fail to rescue, and knockdown of either gene activates DNA damage response signaling and induces apoptosis. OSGEP and TP53RK molecularly interact and co-localize with the actin-regulating ARP2/3 complex. Furthermore, knockdown of OSGEP and TP53RK induces defects of the actin cytoskeleton and reduces migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identify 4 novel monogenic causes of GAMOS, describe the first link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

Published
2017

43. Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis

Author

Steven Gazal, Hilario Nunes, Jean Sibilia, Christelle Ménard, Aurélien Justet, Philippe Dieudé, Isabelle Callebaut, Amélie Bonnefond, Martin Soubrier, Patrick Revy, Catherine Boileau, Pierre-Antoine Juge, Thierry Schaeverbeke, Aline Frazier, Nathalie Saidenberg, Sébastien Ottaviani, Nadia Nathan, Bruno Crestani, Christophe Béroud, Baptiste Coustet, Vincent Cottin, Lidwine Wemeau-Stervinou, Jean-Pierre Desvignes, Marie-Christophe Boissier, Florence Dastot-Le Moal, Serge Amselem, Philippe Froguel, Yannick Allanore, Annick Clement, Olivier Sand, Gabriel Thabut, Marie-Pierre Debray, Pascal Richette, Caroline Kannengiesser, Benoit Wallaert, Christophe Richez, Dominique Valeyre, Sylvain Marchand-Adam, Huguette Lioté, Nicolas Leulliot, René-Marc Flipo, Raphael Borie, Claire Dromer, David Salgado, Service de Rhumathologie, Hôpital Bichat - Claude Bernard, Assistance Publique - Hôpitaux de Paris (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Université Sorbonne Paris Cité (USPC), Service de Pneumologie, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), UMR 1152, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), UMR 1149, Centre de Recherches sur l'Inflammation, Ecologie et Ecophysiologie Forestières [devient SILVA en 2018] (EEF), Institut National de la Recherche Agronomique (INRA)-Université de Lorraine (UL), Plateforme de génomique constitutionnelle, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pneumologie et Immuno-Allergologie [CHU LIlle], Pole Cardio-vasculaire et pulmonaire [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Service de Radiologie, Hospices Civils de Lyon (HCL), UMR 1100, Université Francois Rabelais [Tours], Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Rhumatologie, CH Belfort-Montbéliard, UMR 5164, Immuno ConcEpT Lab, Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), Sorbonne Université (SU), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD [France-Ouest]), Muséum national d'Histoire naturelle (MNHN), Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Université de Lille, Droit et Santé, Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UMR 1132, Service de Rhumatologie, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Department of Genomics of Common Diseases, Imperial College London, Service Rhumatologie A, Hôpital Cochin [AP-HP], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Imagerie, service de Rhumatologie, Centre Hospitalier Universitaire de Lille (CHU de Lille), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service Rhumatologie, Hôpital La Rabta [Tunis], FMTS, CRHI, Laboratoire Immunologie Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA), Fédération Hospitalo-Universitaire OMICARE, Rétrovirus et Pathologie Comparée (RPC), Institut National de la Recherche Agronomique (INRA)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL), Maladie Pulmonaires Rares, Hôpital Louis Pradel [CHU - HCL], UMR U1125 Service rhumatologie, service de rhumatologie, CHU Clermont-Ferrand, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Hôpital Avicenne [AP-HP], service de génétique, Societe Francaise de Rhumatologie, Club Rhumatismes Inflammation, la Chancellerie des Universites de Paris (legs Poix), Sorbonne Paris Cite (FPI-SPC Program), Agence Nationale de la Recherche ANR-10-LABX-46 ANR-10-EQPX-07-01 ANR-14-CE10-0006 ANR-10-INBS-09, France Genomique National Infrastructure, Pfizer, Chugai, Centre de Resources Biologiques Hopital Bichat Paris France, ANR-14-CE10-0006,GENEXGERTEL,Rôles génomiques et extragénomiques de RTEL1(2014), Hôpital Bichat - Claude Bernard, Assistance Publique - Hôpitaux de Paris ( AP-HP ), Université Paris Diderot (Paris 7), Université Sorbonne Paris Cité ( USPC ), Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Saint-Etienne, UMR 1137, Fac Sci, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de Pneumologie et Immuno-Allergologie, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Hospices Civils de Lyon ( HCL ), Service de Pneumologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie (Paris 6), Centre National de la Recherche Scientifique ( CNRS ), Université de Bordeaux ( UB ), Sorbonne Universités, Institut de minéralogie, de physique des matériaux et de cosmochimie ( IMPMC ), Muséum National d'Histoire Naturelle ( MNHN ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique ( CNRS ), Institut de Recherche pour le Développement ( IRD [France-Ouest] ), Muséum National d’Histoire Naturelle ( MNHN ), Laboratoire de cristallographie et RMN biologiques ( LCRB - UMR 8015 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Droit et Santé (Lille 2) ( UDSL ), European Genomic Institute for Diabetes ( EGID ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Lariboisière, Génomique Intégrative et Modélisation des Maladies Métaboliques ( EGID ), Université de Lille-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Pasteur de Lille, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), CHU Cochin [AP-HP], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Centre Hospitalier Universitaire de Lille ( CHU de Lille ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Hôpital La Rabta [Tunis), Université de Strasbourg ( UNISTRA ), Rétrovirus et Pathologie Comparée ( RPC ), Institut National de la Recherche Agronomique ( INRA ) -École pratique des hautes études ( EPHE ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon ( ENVL ), Département Génétique, Institut de l'Elevage, Centre Reference Maladies Respiratoires Rares, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris ( AP-HP ), Centre Hospitalier Universitaire de Clermont-Ferrand, Unité de Nutrition Humaine - Clermont Auvergne ( UNH ), Université Clermont Auvergne ( UCA ) -Institut national de la recherche agronomique [Auvergne/Rhône-Alpes] ( INRA Auvergne/Rhône-Alpes ), Centre de Recherche en Nutrition Humaine d'Auvergne ( CRNH d'Auvergne ), Hôpital Avicenne, Assistance Publique - Hôpitaux de Paris ( AP-HP ), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), Institut de l'élevage (IDELE), ProdInra, Archive Ouverte, Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau], Service de Pneumologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique et embryologie médicales [CHU Trousseau], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), European Genomic Institute for Diabetes [Lille] (EGID), Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE)-Université Claude Bernard Lyon 1 (UCBL), Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris (AP-HP), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Hôpital Avicenne, Assistance Publique - Hôpitaux de Paris (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Paris Descartes - Paris 5 (UPD5), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Pathology, medicine.disease_cause, Arthritis, Rheumatoid, 0302 clinical medicine, Risk Factors, Pulmonary fibrosis, Exome, Telomerase, Exome sequencing, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Interstitial lung disease, Middle Aged, 3. Good health, Europe, Polyarthrite rhumatoïde, maladie pulmonaire, Phenotype, Rheumatoid arthritis, Female, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, Heterozygote, fibrose pulmonaire, 03 medical and health sciences, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, respiratory system diseases, Genetic Association Studies, Aged, 030203 arthritis & rheumatology, pulmonary fibrosis, business.industry, Case-control study, DNA Helicases, Sequence Analysis, DNA, medicine.disease, 030228 respiratory system, Case-Control Studies, Immunology, business, Lung Diseases, Interstitial, Software, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls.Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations in RA-ILD patients (OR 3.17, 95% CI 1.53–6.12; p=9.45×10−4). Telomeres were shorter in RA-ILD patients with a TERT, RTEL1 or PARN mutation than in controls (p=2.87×10−2).Our results support the contribution of FPF-linked genes to RA-ILD susceptibility.

Published
2017

44. Mutations in XLF/NHEJ1/Cernunnos gene results in downregulation of telomerase genes expression and telomere shortening

Author

Leandro Sastre, Javier Benitez, Julian Sevilla Navarro, Jaime Carrillo, Eduardo López Granados, Patrick Revy, Cristina Manguan-García, Elena G Arias-Salgado, Rosario Perona, Laura Pintado-Berninches, Oriol Calvete, Guillermo Guenechea, Jean-Pierre de Villartay, Instituto de Salud Carlos III, Centre National de la Recherche Scientifique (France), and European Commission

Subjects
Male, 0301 basic medicine, Premature aging, Senescence, Telomerase, Down-Regulation, Gene Expression, Biology, medicine.disease_cause, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Telomere Homeostasis, Genetics, medicine, Humans, Child, Molecular Biology, Telomere Shortening, Genetics (clinical), Mutation, General Medicine, Telomere, Shelterin, Phenotype, Molecular biology, DNA-Binding Proteins, DNA Repair Enzymes, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research
Abstract

NHEJ1-patients develop severe progressive lymphocytopenia and premature aging of hematopoietic stem cells (HSCs) at a young age. Here we show a patient with a homozygous-NHEJ1 mutation identified by whole exome-sequencing that developed severe pancytopenia and bone marrow aplasia correlating with the presence of short telomeres. The mutation resulted in a truncated protein. In an attempt to identify the mechanism behind the short telomere phenotype found in the NHEJ1-patient we downregulated NHEJ1 expression in 293T and CD34+cells. This downregulation resulted in reduced telomerase activity and decreased expression of several telomerase/shelterin genes. Interestingly, cell lines derived from two other NHEJ1-deficient patients with different mutations also showed increased p21 expression, inhibition in expression of several telomerase complex genes and shortened telomeres. Decrease in expression of telomerase/shelterin genes did not occur when we inhibited expression of other NHEJ genes mutated in SCID patients: DNA-PK, Artemis or LigaseIV. Because premature aging of HSCs is observed only in NHEJ1 patients, we propose that is the result of senescence induced by decreased expression of telomerase/shelterin genes that lead to an inhibition of telomerase activity. Previous reports failed to find this connection because of the use of patient´s cells immortalized by TERT expression or recombined telomeres by ALT pathway. In summary, defective regulation of telomere biology together with defective V(D)J recombination can negatively impact on the evolution of the disease in these patients. Identification of telomere shortening is important since it may open new therapeutic interventions for these patients by treatments aimed to recover the expression of telomerase genes., R.P. laboratory is partially funded by grant P14-01495 (Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain supported by FEDER funds) and ER15PR07ACC114/757 from CIBERER. J.B. laboratory is funded by PI12/00070 and PI16/00440 (FIS) supported by FEDER funds and ER14PROACC13G706. C.M-G granted by the CIBERER. P.R is a scientist from Centre National de la Recherche Scientifique (CNRS). P.R and J-P.V are from a laboratory “Labellise´ La Ligue”.

Published
2017

45. Prevalence and characteristics of TERT and TERC mutations in suspected genetic pulmonary fibrosis

Author

Lidwine Wemeau-Stervinou, Julie Mankikian, Patrick Revy, Martine Reynaud Gaubert, Christelle Ménard, Jacques Cadranel, Dominique Israel-Biet, Hervé Mal, Grégoire Prévot, Bruno Crestani, Caroline Kannengiesser, Hilario Nunes, Abdellatif Tazi, Dominique Valeyre, Gabriel Thabut, Vincent Cottin, Marion Reocreux, Raphael Borie, Clément Picard, Stéphane Jouneau, Bernard Grandchamp, Anne Bergeron Lafaurie, Laure Tabèze, Sylvain Marchand-Adam, Jean-François Cordier, Jean-Marc Naccache, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie A, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre de compétence des maladies pulmonaires rares, Service de pneumologie B, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service de médecine nucléaire [Bobigny], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence des Maladies Pulmonaires Rares [Hôpital Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Department of Pneumology [Lyon], Hospices Civils de Lyon (HCL), Pathologies Respiratoires : Protéolyse et Aérosolthérapie, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse], Service de pneumologie [Saint-Louis], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Theranoscan, Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'oncologie médicale (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Pneumologie, Paris, Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), CHU Marseille, Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironnement et cancer (MiCa), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Service des maladies respiratoires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Avicenne-Jean Verdier-René Muret, Hôpital Bichat - Claude Bernard, OMMIC S.A.S., OMMIC SAS, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et Epidemiologie de l'Insuffisance Respiratoire, Département Hospitalo-universtaire FIRE (Fibrosis, Inflammation and Remodeling), LabEx Inflamex, Service de pneumologie A, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Bichat, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), OMMIC, Chard-Hutchinson, Xavier, Service de Pneumologie = Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Physiopathologie et Epidémiologie des Maladies Respiratoires, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Centre de compétence des maladies pulmonaires rares, Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne-Université Paris 13 ( UP13 ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Hospices Civils de Lyon ( HCL ), Université de Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU, Hôpital Larrey, Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Service de pneumologie et réanimation [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Etablissement Français du Sang - Alpes-Méditerranée ( EFS - Alpes-Méditerranée ), Anthropologie bio-culturelle, Droit, Ethique et Santé ( ADES ), Aix Marseille Université ( AMU ) -EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique ( CNRS ), Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Centre d'Investigation Clinique [Rennes] ( CIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Microenvironnement et cancer ( MiCa ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Claude Bernard Lyon 1 ( UCBL ), Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Avicenne-Jean Verdier-René Muret, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Hôpital Bichat, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Pulmonary and Respiratory Medicine, Adult, Male, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Macrocytosis, 030204 cardiovascular system & hematology, Gene mutation, medicine.disease_cause, Gastroenterology, [ SDV.EE ] Life Sciences [q-bio]/Ecology, environment, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, Cause of Death, Pulmonary fibrosis, Telomerase rna, medicine, Humans, Interstitial pneumonia, Telomerase reverse transcriptase, Telomerase, Aged, Retrospective Studies, Aged, 80 and over, [SDV.EE]Life Sciences [q-bio]/Ecology, environment, Mutation, [ SDV ] Life Sciences [q-bio], business.industry, Middle Aged, Telomere, medicine.disease, Survival Analysis, Idiopathic Pulmonary Fibrosis, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.EE] Life Sciences [q-bio]/Ecology, environment, Logistic Models, 030228 respiratory system, Multivariate Analysis, RNA, Female, France, business
Abstract

Telomerase reverse transcriptase (TERT) or telomerase RNA (TERC) gene mutation is a major monogenic cause of pulmonary fibrosis. Sequencing of TERT/TERC genes is proposed to patients with familial pulmonary fibrosis. Little is known about the possible predictors of this mutation and its impact on prognosis.We retrospectively analysed all the genetic diagnoses made between 2007–2014 in patients with pulmonary fibrosis. We evaluated the prevalence of TERT/TERC disease-associated variant (DAV), factors associated with a DAV, and the impact of the DAV on survival.237 patients with pulmonary fibrosis (153 with familial pulmonary fibrosis, 84 with telomere syndrome features without familial pulmonary fibrosis) were tested for TERT/TERC DAV. DAV was diagnosed in 40 patients (16.8%), including five with non-idiopathic interstitial pneumonia. Prevalence of TERT/TERC DAV did not significantly differ between patients with familial pulmonary fibrosis or with only telomere syndrome features (18.2% versus 16.4%). Young age, red blood cell macrocytosis, and low platelet count were associated with the presence of DAV; the probability of DAV was increased for patients 40–60 years. Transplant-free survival was lower with than without TERT/TERC DAV (4.2 versus 7.2 years; p=0.046).TERT/TERC DAV were associated with specific clinical and biological features and reduced transplant-free survival.

Published
2016

46. RTEL1, une hélicase de l’ADN essentielle à la stabilité du génome

Author

Laetitia Kermasson, Jean-Pierre de Villartay, Patrick Revy, Mike Schertzer, Laurent Jullien, Arturo Londoño-Vallejo, Tangui Le Guen, and Axelle Lefebvre

Subjects
Genetics, Mutation, DNA repair, Regulator, Helicase, General Medicine, Biology, medicine.disease, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Telomere, medicine, biology.protein, A-DNA, Dyskeratosis congenita, Genome stability
Abstract

RTEL1 (regulator of telomere length helicase 1) is a DNA helicase that has been identified more than 10 years ago. Many works since, mainly in the nematode Caenorhabditis elegans and the mouse, have highlighted its role in chromosomal stability, maintenance of telomere length, and DNA repair. Recently, four laboratories have characterized RTEL1 mutations in patients with dyskeratosis congenita (DC) and Hoyeraal-Hreidarsson (HH) syndrome, a rare and severe variant of DC. We here summarize the current knowledge on RTEL1 and discuss the possible other functions that RTEL1 could play.

Published
2013

47. The C-terminal extension of human RTEL1, mutated in Hoyeraal-Hreidarsson syndrome, contains Harmonin-N-like domains

Author

Michael Schertzer, Isabelle Callebaut, Patrick Revy, Guilhem Faure, and Arturo Londoño-Vallejo

Subjects
Genetics, 0303 health sciences, biology, Sequence analysis, DNA repair, 030302 biochemistry & molecular biology, Helicase, Hoyeraal-Hreidarsson syndrome, medicine.disease, Biochemistry, Telomere, 03 medical and health sciences, Germline mutation, Structural Biology, biology.protein, medicine, Molecular Biology, Function (biology), Dyskeratosis congenita, 030304 developmental biology
Abstract

Several studies have recently shown that germline mutations in RTEL1, an essential DNA helicase involved in telomere regulation and DNA repair, cause Hoyeraal-Hreidarsson syndrome (HHS), a severe form of dyskeratosis congenita. Using original new softwares, facilitating the delineation of the different domains of the protein and the identification of remote relationships for orphan domains, we outline here that the C-terminal extension of RTEL1, downstream of its catalytic domain and including several HHS-associated mutations, contains a yet unidentified tandem of harmonin-N-like domains, which may serve as a hub for partner interaction. This finding highlights the potential critical role of this region for the function of RTEL1 and gives insights into the impact that the identified mutations would have on the structure and function of these domains.

Published
2013

48. Cernunnos Deficiency Reduces Thymocyte Life Span and Alters the T Cell Repertoire in Mice and Humans

Author

Vincent Abramowski, Annick Lim, Jean-Pierre de Villartay, Sylvain Latour, Christine Bole-Feysot, Laurent Malivert, Patrick Revy, Benoit Florkin, Paola Rivera-Munoz, Christelle Martin, and Gabriella Vera

Subjects
DNA Repair, Cell Survival, DNA repair, DNA damage, T-Lymphocytes, T cell, Molecular Sequence Data, Biology, Gene Knockout Techniques, Mice, Immune system, medicine, Animals, Humans, Lymphocyte Count, Molecular Biology, Cell Proliferation, Mice, Knockout, Thymocytes, Base Sequence, Cell growth, V(D)J recombination, Articles, Cell Biology, V(D)J Recombination, DNA-Binding Proteins, Thymocyte, DNA Repair Enzymes, medicine.anatomical_structure, Immunology, Tumor Suppressor Protein p53
Abstract

Cernunnos is a DNA repair factor of the nonhomologous end-joining machinery. Its deficiency in humans causes radiosensitive severe combined immune deficiency (SCID) with microcephaly, characterized in part by a profound lymphopenia. In contrast to the human condition, the immune system of Cernunnos knockout (KO) mice is not overwhelmingly affected. In particular, Cernunnos is dispensable during V(D)J recombination in lymphoid cells. Nevertheless, the viability of thymocytes is reduced in Cernunnos KO mice, owing to the chronic activation of a P53-dependent DNA damage response. This translates into a qualitative alteration of the T cell repertoire to one in which the most distal Vα and Jα segments are missing. This results in the contraction of discrete T cell populations, such as invariant natural killer T (iNKT) and mucosa-associated invariant T (MAIT) cells, in both humans and mice.

Published
2013

49. Primary Microcephaly, Impaired DNA Replication, and Genomic Instability Caused by Compound HeterozygousATRMutations

Author

Houda Mokrani-Benhelli, Fabien Touzot, Nadia Vasquez, Laetitia Gaillard, Alain Fischer, Jun Komatsu, Marina Cavazzana-Calvo, Anne Durandy, Emmanuel Conseiller, Eliane Gluckman, Jean Soulier, Christine Francannet, Tangui Le Guen, Patrick Revy, Patricia Biasutto, Jean-Pierre de Villartay, and Capucine Picard

Subjects
DNA Replication, Male, Genome instability, Heterozygote, DNA damage, RNA Splicing, Blotting, Western, Molecular Sequence Data, Mutation, Missense, DNA, Single-Stranded, Fluorescent Antibody Technique, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Protein Serine-Threonine Kinases, Biology, medicine.disease_cause, Genomic Instability, Cell Line, Mice, Genetics, medicine, Animals, Humans, DNA Breaks, Double-Stranded, Child, Alleles, In Situ Hybridization, Fluorescence, Genetics (clinical), Comparative Genomic Hybridization, Mutation, Base Sequence, Tumor Suppressor Proteins, DNA replication, Fibroblasts, medicine.disease, DNA-Binding Proteins, Seckel syndrome, Ataxia-telangiectasia, Microcephaly, Female, Ataxia telangiectasia and Rad3 related, Gene Deletion, Genome-Wide Association Study, Signal Transduction
Abstract

Ataxia telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases are two key regulators of DNA-damage responses (DDR) that are mainly activated in response to DNA double-strand breaks and single-stranded DNA damages, respectively. Seckel syndrome, a rare genetic disorder characterized by a microcephaly and a markedly reduced body size, has been associated with defective ATR-dependent DNA damage signaling. However, the only human genetic ATR defect reported so far is a hypomorphic splicing mutation identified in five related individuals with Seckel syndrome. Here, we report the first case of primary microcephaly with compound heterozygous mutations in ATR: a 540 kb genomic deletion on one allele and a missense mutation leading to splice dysregulation on the other, which ultimately lead to a sharp decrease in ATR expression. DNA combing technology revealed a profound spontaneous alteration of several DNA replication parameters in patient's cells and FISH analyses highlighted the genomic instability caused by ATR deficiency. Collectively, our results emphasize the crucial role for ATR in the control of DNA replication, and reinforce the complementary and nonredundant contributions of ATM and ATR in human cells to face DNA damages and warrant genome integrity.

Published
2012

50. Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ('FILS syndrome')

Author

Patrick Nitschke, Marianne Debré, Anne Durandy, Capucine Picard, Geneviève de Saint Basile, Christine Bole-Feysot, Jana Pachlopnik Schmid, Annick Lim, Alain Fischer, Patrick Revy, Roxane Lemoine, Nadine Nehme, Laurence Legeai-Mallet, Valéry Cormier-Daire, Franck Debeurme, and Jean-Pierre de Villartay

Subjects
Male, DNA polymerase, DNA Mutational Analysis, Gene Expression, medicine.disease_cause, Consanguinity, Immunology and Allergy, Child, Poly-ADP-Ribose Binding Proteins, Growth Disorders, Polymerase, Genetics, 0303 health sciences, Mutation, biology, 030302 biochemistry & molecular biology, Genetic disorder, Syndrome, Pedigree, 3. Good health, Child, Preschool, Female, France, medicine.symptom, Adult, Adolescent, DNA repair, Immunology, Genes, Recessive, Short stature, Facial Bones, Young Adult, 03 medical and health sciences, medicine, Humans, Point Mutation, Gene, Cell Proliferation, Livedo Reticularis, 030304 developmental biology, Chromosomes, Human, Pair 12, Base Sequence, Point mutation, Immunologic Deficiency Syndromes, Brief Definitive Report, DNA Polymerase II, medicine.disease, G1 Phase Cell Cycle Checkpoints, Molecular biology, Body Height, Introns, body regions, Alternative Splicing, biology.protein
Abstract

Homozygous missense mutations in POLE1 caused an inherited disorder characterized by facial dysmorphism, immunodeficiency, livedo, and short stature., DNA polymerase ε (Polε) is a large, four-subunit polymerase that is conserved throughout the eukaryotes. Its primary function is to synthesize DNA at the leading strand during replication. It is also involved in a wide variety of fundamental cellular processes, including cell cycle progression and DNA repair/recombination. Here, we report that a homozygous single base pair substitution in POLE1 (polymerase ε 1), encoding the catalytic subunit of Polε, caused facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”) in a large, consanguineous family. The mutation resulted in alternative splicing in the conserved region of intron 34, which strongly decreased protein expression of Polε1 and also to a lesser extent the Polε2 subunit. We observed impairment in proliferation and G1- to S-phase progression in patients’ T lymphocytes. Polε1 depletion also impaired G1- to S-phase progression in B lymphocytes, chondrocytes, and osteoblasts. Our results evidence the developmental impact of a Polε catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder.

Published
2012

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