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1. Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications

Author: Viorica Chelban, Henriette Aksnes, Reza Maroofian, Lauren C. LaMonica, Luis Seabra, Anette Siggervåg, Perrine Devic, Hanan E. Shamseldin, Jana Vandrovcova, David Murphy, Anne-Claire Richard, Olivier Quenez, Antoine Bonnevalle, M. Natalia Zanetti, Rauan Kaiyrzhanov, Vincenzo Salpietro, Stephanie Efthymiou, Lucia V. Schottlaender, Heba Morsy, Annarita Scardamaglia, Ambreen Tariq, Alistair T. Pagnamenta, Ajia Pennavaria, Liv S. Krogstad, Åse K. Bekkelund, Alessia Caiella, Nina Glomnes, Kirsten M. Brønstad, Sandrine Tury, Andrés Moreno De Luca, Anne Boland-Auge, Robert Olaso, Jean-François Deleuze, Mathieu Anheim, Benjamin Cretin, Barbara Vona, Fahad Alajlan, Firdous Abdulwahab, Jean-Luc Battini, Rojan İpek, Peter Bauer, Giovanni Zifarelli, Serdal Gungor, Semra Hiz Kurul, Hanns Lochmuller, Sahar I. Da’as, Khalid A. Fakhro, Alicia Gómez-Pascual, Juan A. Botía, Nicholas W. Wood, Rita Horvath, Andreas M. Ernst, James E. Rothman, Meriel McEntagart, Yanick J. Crow, Fowzan S. Alkuraya, Gaël Nicolas, SYNaPS Study Group, Thomas Arnesen, and Henry Houlden
Subjects: Science
Abstract: Abstract Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.
Published: 2024
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2. ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling

Author: Maximilian Hirschenberger, Alice Lepelley, Ulrich Rupp, Susanne Klute, Victoria Hunszinger, Lennart Koepke, Veronika Merold, Blaise Didry-Barca, Fanny Wondany, Tim Bergner, Tatiana Moreau, Mathieu P. Rodero, Reinhild Rösler, Sebastian Wiese, Stefano Volpi, Marco Gattorno, Riccardo Papa, Sally-Ann Lynch, Marte G. Haug, Gunnar Houge, Kristen M. Wigby, Jessica Sprague, Jerica Lenberg, Clarissa Read, Paul Walther, Jens Michaelis, Frank Kirchhoff, Carina C. de Oliveira Mann, Yanick J. Crow, and Konstantin M. J. Sparrer
Subjects: Science
Abstract: Abstract Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Termination is achieved through autophagic degradation or recycling of STING by retrograde Golgi-to-ER transport. Here, we identify the GTPase ADP-ribosylation factor 1 (ARF1) as a crucial negative regulator of cGAS-STING signalling. Heterozygous ARF1 missense mutations cause a previously unrecognized type I interferonopathy associated with enhanced IFN-stimulated gene expression. Disease-associated, GTPase-defective ARF1 increases cGAS-STING dependent type I IFN signalling in cell lines and primary patient cells. Mechanistically, mutated ARF1 perturbs mitochondrial morphology, causing cGAS activation by aberrant mitochondrial DNA release, and leads to accumulation of active STING at the Golgi/ERGIC due to defective retrograde transport. Our data show an unexpected dual role of ARF1 in maintaining cGAS-STING homeostasis, through promotion of mitochondrial integrity and STING recycling.
Published: 2023
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3. Phenotypes associated with genetic determinants of type I interferon regulation in the UK Biobank: a protocol [version 1; peer review: 2 approved]

Author: Bastien Rioux, Rosie Walker, Michael Chong, Daniel McCartney, Sarah McGlasson, Robin Brown, John McCabe, David Hunt, Kristiina Rannikmäe, Yanick J. Crow, and William Whiteley
Subjects: stroke, dementia, interferonopathy, lupus, inflammation, type I interferon, eng, Medicine, Science
Abstract: Background Type I interferons are cytokines involved in innate immunity against viruses. Genetic disorders of type I interferon regulation are associated with a range of autoimmune and cerebrovascular phenotypes. Carriers of pathogenic variants involved in genetic disorders of type I interferons are generally considered asymptomatic. Preliminary data suggests, however, that genetically determined dysregulation of type I interferon responses is associated with autoimmunity, and may also be relevant to sporadic cerebrovascular disease and dementia. We aim to determine whether functional variants in genes involved in type I interferon regulation and signalling are associated with the risk of autoimmunity, stroke, and dementia in a population cohort. Methods We will perform a hypothesis-driven candidate pathway association study of type I interferon-related genes using rare variants in the UK Biobank (UKB). We will manually curate type I interferon regulation and signalling genes from a literature review and Gene Ontology, followed by clinical and functional filtering. Variants of interest will be included based on pre-defined clinical relevance and functional annotations (using LOFTEE, M-CAP and a minor allele frequency
Published: 2023
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4. Case report: Clinical and neuroradiological longitudinal follow-up in Leukoencephalopathy with Calcifications and Cysts during treatment with bevacizumab

Author: Elena Scaffei, Bianca Buchignani, Rosa Pasquariello, Paola Cristofani, Raffaello Canapicchi, Laura Biagi, Flavio Giordano, Emanuela De Marco, Yanick J. Crow, and Roberta Battini
Subjects: LCC, leukoencephalopathy, cysts, calcifications, Labrune syndrome, MRI, Neurology. Diseases of the nervous system, RC346-429
Abstract: Leukoencephalopathy with Calcifications and Cysts (LCC) is a rare genetic microangiopathy exclusively affecting the central nervous system caused by biallelic mutations in SNORD118. Brain magnetic resonance imaging (MRI) is often diagnostic due to the highly characteristic triad of leukoencephalopathy, intracranial calcifications, and brain cysts. Age at onset, presentation and disease evolution can all vary, ranging from pauci-symptomatic disease to rapid evolution of signs with loss of motor and cognitive abilities. No specific therapies for LCC are currently licensed. According to the literature, bevacizumab might represent an effective modality to improve the clinical and MRI features of the disease. However, uncertainty remains as to the true efficacy of this approach, when to begin therapy, appropriate dosing, and the consequences of drug withdrawal. According to CARE guidelines, we describe the long-term clinical and neuro-radiological follow-up of a 10-year-old child with LCC. We report disease evolution following repeated cycles of treatment with bevacizumab. Our case report suggests that repeated cycles of bevacizumab might effectively modify disease progression, possibly indicating a time-dependent effect.
Published: 2023
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5. Novel compound heterozygous STN1 variants are associated with Coats Plus syndrome

Author: Tanvi Acharya, Helen V. Firth, Shilpa Dugar, Tassos Grammatikopoulos, Luis Seabra, Angharad Walters, Yanick J. Crow, and Alasdair P. J. Parker
Subjects: coats plus, leukodystrophy, stn1, Genetics, QH426-470
Abstract: Abstract Aim Coats plus syndrome (CP) is a rare autosomal recessive disorder, characterised by retinal telangiectasia exudates (Coats disease), leukodystrophy, distinctive intracranial calcification and cysts, as well as extra‐neurological features including abnormal vasculature of the gastrointestinal tract, portal hypertension and osteopenia with a tendency to fractures. CP most frequently occurs due to loss‐of‐function mutations in CTC1. The encoded protein CTC1 constitutes part of the CST (CTC1‐STN1‐TEN1) complex, and three patients have been described with CP due to biallelic mutations in STN1. Together with the identification of homozygosity for a specific loss‐of‐function mutation in POT1 in a sibling pair, these observations highlight a defect in the maintenance of telomere integrity as the cause of CP, although the precise mechanism leading to the micro‐vasculopathy seen at a pathological level remains unclear. Here, we present the investigation of a fourth child who presented to us with retinal exudates, intracranial calcifications and developmental delay, in keeping with a diagnosis of CP, and later went on to develop pancytopenia and gastrointestinal bleeding. Genome sequencing revealed compound heterozygous variants in STN1 as the likely genetic cause of CP in this present case. Methods We assessed the phenotype to be CP and undertook targeted sequencing. Results Whilst sequencing of CTC1 and POT1 was normal, we identified novel compound heterozygous variants in STN1 (previous gene symbol OBFC1): one loss‐of‐function––c.894dup (p.(Asp299Argfs*58)); and one missense––c.707T>C (p.(Leu236Pro)). Conclusion Given the clinical phenotype and identified variants we suggest that this is only the fourth patient reported to date with CP due to mutations in STN1.
Published: 2021
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6. Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease

Author: Alice Lepelley, Timothy Wai, and Yanick J. Crow
Subjects: type I interferonopathy, mitochondrial disease, type I interferon, autoinflammation, mitochondria, mtDNA, Immunologic diseases. Allergy, RC581-607
Abstract: The immune response to viral infection involves the recognition of pathogen-derived nucleic acids by intracellular sensors, leading to type I interferon (IFN), and downstream IFN-stimulated gene, induction. Ineffective discrimination of self from non-self nucleic acid can lead to autoinflammation, a phenomenon implicated in an increasing number of disease states, and well highlighted by the group of rare genetic disorders referred to as the type I interferonopathies. To understand the pathogenesis of these monogenic disorders, and polyfactorial diseases associated with pathogenic IFN upregulation, such as systemic lupus erythematosus and dermatomyositis, it is important to define the self-derived nucleic acid species responsible for such abnormal IFN induction. Recently, attention has focused on mitochondria as a novel source of immunogenic self nucleic acid. Best appreciated for their function in oxidative phosphorylation, metabolism and apoptosis, mitochondria are double membrane-bound organelles that represent vestigial bacteria in the cytosol of eukaryotic cells, containing their own DNA and RNA enclosed within the inner mitochondrial membrane. There is increasing recognition that a loss of mitochondrial integrity and compartmentalization can allow the release of mitochondrial nucleic acid into the cytosol, leading to IFN induction. Here, we provide recent insights into the potential of mitochondrial-derived DNA and RNA to drive IFN production in Mendelian disease. Specifically, we summarize current understanding of how nucleic acids are detected as foreign when released into the cytosol, and then consider the findings implicating mitochondrial nucleic acid in type I interferonopathy disease states. Finally, we discuss the potential for IFN-driven pathology in primary mitochondrial disorders.
Published: 2021
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7. Adult-Onset ANCA-Associated Vasculitis in SAVI: Extension of the Phenotypic Spectrum, Case Report and Review of the Literature

Author: Frederik Staels, Albrecht Betrains, Peter Doubel, Mathijs Willemsen, Vincent Cleemput, Steven Vanderschueren, Anniek Corveleyn, Isabelle Meyts, Ben Sprangers, Yanick J. Crow, Stephanie Humblet-Baron, Adrian Liston, and Rik Schrijvers
Subjects: SAVI, vasculopathy, glomerulonephritis, primary immunodeficiency, interferonopathy, Immunologic diseases. Allergy, RC581-607
Abstract: STING-associated vasculopathy with onset in infancy (SAVI) is an autosomal dominant disorder due to gain-of-function mutations in STING1, also known as TMEM173, encoding for STING. It was reported as a vasculopathy of infancy. However, since its description a wider spectrum of associated manifestations and disease-onset has been observed. We report a kindred with a heterozygous STING mutation (p.V155M) in which the 19-year-old proband suffered from isolated adult-onset ANCA-associated vasculitis. His father suffered from childhood-onset pulmonary fibrosis and renal failure attributed to ANCA-associated vasculitis, and died at the age of 30 years due to respiratory failure. In addition, an overview of the phenotypic spectrum of SAVI is provided highlighting (a) a high phenotypic variability with in some cases isolated manifestations, (b) the potential of adult-onset disease, and (c) a novel manifestation with ANCA-associated vasculitis.
Published: 2020
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8. Type I interferon-mediated autoinflammation due to DNase II deficiency

Author: Mathieu P. Rodero, Alessandra Tesser, Eva Bartok, Gillian I. Rice, Erika Della Mina, Marine Depp, Benoit Beitz, Vincent Bondet, Nicolas Cagnard, Darragh Duffy, Michael Dussiot, Marie-Louise Frémond, Marco Gattorno, Flavia Guillem, Naoki Kitabayashi, Fabrice Porcheray, Frederic Rieux-Laucat, Luis Seabra, Carolina Uggenti, Stefano Volpi, Leo A H. Zeef, Marie-Alexandra Alyanakian, Jacques Beltrand, Anna Monica Bianco, Nathalie Boddaert, Chantal Brouzes, Sophie Candon, Roberta Caorsi, Marina Charbit, Monique Fabre, Flavio Faletra, Muriel Girard, Annie Harroche, Evelyn Hartmann, Dominique Lasne, Annalisa Marcuzzi, Bénédicte Neven, Patrick Nitschke, Tiffany Pascreau, Serena Pastore, Capucine Picard, Paolo Picco, Elisa Piscianz, Michel Polak, Pierre Quartier, Marion Rabant, Gabriele Stocco, Andrea Taddio, Florence Uettwiller, Erica Valencic, Diego Vozzi, Gunther Hartmann, Winfried Barchet, Olivier Hermine, Brigitte Bader-Meunier, Alberto Tommasini, and Yanick J. Crow
Subjects: Science
Abstract: Nucleic acid sensing is important to ensure that an innate immune response is only mounted against microbial nucleic acid. Here, the authors identify loss-of-function mutations in the DNASE2 gene that cause type I interferon-mediated autoinflammation due to enhanced systemic interferon signaling.
Published: 2017
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9. Proceedings of the 23rd Paediatric Rheumatology European Society Congress: part one

Author: F. De Benedetti, J. Anton, M. Gattorno, H. Lachmann, I. Kone-Paut, S. Ozen, J. Frenkel, A. Simon, A. Zeft, E. Ben-Chetrit, H. M. Hoffman, Y. Joubert, K. Lheritier, A. Speziale, J. Guido, Roberta Caorsi, Federica Penco, Alice Grossi, Antonella Insalaco, Maria Alessio, Giovanni Conti, Federico Marchetti, Alberto Tommasini, Silvana Martino, Romina Gallizzi, Annalisa Salis, Francesca Schena, Francesco Caroli, Alberto Martini, Gianluca Damonte, Isabella Ceccherini, Marco Gattorno, Marie-Louise Frémond, Carolina Uggenti, Lien Van Eyck, Isabelle Melki, Darragh Duffy, Vincent Bondet, Yoann Rose, Bénédicte Neven, Yanick Crow, Mathieu P. Rodero, Yvonne Kusche, Johannes Roth, Katarzyna Barczyk-Kahlert, Giovanna Ferrara, Annalisa Chiocchetti, Silvio Polizzi, Josef Vuch, Diego Vozzi, Anna Mondino, Erica Valencic, Serena Pastore, Andrea Taddio, Flavio Faletra, Umberto Dianzani, Ugo Ramenghi, Qing Zhou, Xiaomin Yu, Erkan Demirkaya, Natalie Deuitch, Deborah Stone, Wanxia Tsai, Amanda Ombrello, Tina Romeo, Elaine F. Remmers, JaeJin Chae, Massimo Gadina, Steven Welch, Seza Ozen, Rezan Topaloglu, Mario Abinun, Daniel L. Kastner, Ivona Aksentijevich, Donatella Vairo, Rosalba Monica Ferraro, Giulia Zani, Jessica Galli, Micaela De Simone, Marco Cattalini, Elisa Fazzi, Silvia Giliani, Ebun Omoyinmi, Ariane Standing, Dorota Rowczenio, Annette Keylock, Sonia Melo Gomes, Fiona Price-Kuehne, Sira Nanthapisal, Claire Murphy, Thomas Cullup, Lucy Jenkins, Kimberly Gilmour, Despina Eleftheriou, Helen Lachmann, Philip Hawkins, Nigel Klein, Paul Brogan, Anita Dhanrajani, Mercedes Chan, Stephanie Pau, Janet Ellsworth, Jaime Guzman, Florence A. Aeschlimann, Marinka Twilt, Simon W. Eng, Shehla Sheikh, Ronald M. Laxer, Diane Hebert, Damien Noone, Christian Pagnoux, Susanne M. Benseler, Rae S. Yeung, Christoph Kessel, Katrin Lippitz, Toni Weinhage, Claas Hinze, Helmut Wittkowski, Dirk Holzinger, Niklas Grün, Dirk Föll, Pieter Van Dijkhuizen, Federica Del Chierico, Clara Malattia, Alessandra Russo, Denise Pires Marafon, Nienke M. ter Haar, Silvia Magni-Manzoni, Sebastiaan J. Vastert, Bruno Dallapiccola, Berent Prakken, Fabrizio De Benedetti, Lorenza Putignani, Berna Eren Fidanci, Kenan Barut, Serap Arıcı, Dogan Simsek, Mustafa Cakan, Ezgi D. Batu, Sezgin Şahin, Ayşenur Kısaarslan, Ebru Yilmaz, Özge Basaran, Ferhat Demir, Kubra Ozturk, Zübeyde Gunduz, Betül Sozeri, Balahan Makay, Nuray Ayaz, Onder Yavascan, Ozlem Aydog, Yelda Bilginer, Zelal Ekinci, Dilek Yıldız, Faysal Gök, Muferret Erguven, Erbil Unsal, Ozgur Kasapcopur, For the FMF Arthritis Vasculitis and Orphan Disease Research in Paediatric Rheumatology (FAVOR), Hafize E. Sönmez, Betül Sözeri, Yonatan Butbul, Seza Özen, Claudia Bracaglia, Giusi Prencipe, Manuela Pardeo, Geneviève Lapeyre, Emiliano Marasco, Walter Ferlin, Robert Nelson, Cristina de Min, N. Ruperto, H. I. Brunner, P. Quartier, T. Constantin, E. Alexeeva, K. Marzan, N. Wulffraat, R. Schneider, S. Padeh, V. Chasnyk, C. Wouters, J. B. Kuemmerle-Deschner, T. Kallinich, B. Lauwerys, E. Haddad, E. Nasonov, M. Trachana, O. Vougiouka, K. Leon, E. Vritzali, A. Martini, D. Lovell, PRINTO/PRCSG, Stefano Volpi, Claudia Pastorino, Francesca Kalli, Alessia Omenetti, Sabrina Chiesa, Arinna Bertoni, Paolo Picco, Gilberto Filaci, Elisabetta Traggiai, Marie-Louise Fremond, Naoki Kitabayashi, Olivero Sacco, Isabelle Meyts, Marie-Anne Morren, Carine Wouters, Eric Legius, Isabelle Callebaut, Christine Bodemer, Frederic Rieux-Laucat, Mathieu Rodero, Nadia Jeremiah, Alexandre Belot, Eric Jeziorski, Didier Bessis, Guilhem Cros, Gillian I. Rice, Bruno Charbit, Anne Hulin, Nihel Khoudour, Consuelo Modesto Caballero, Monique Fabre, Laureline Berteloot, Muriel Le Bourgeois, Philippe Reix, Thierry Walzer, Despina Moshous, Stéphane Blanche, Alain Fischer, Brigitte Bader-Meunier, Frédéric Rieux-Laucat, K. Annink, N. ter Haar, S. Al-Mayouf, G. Amaryan, K. Barron, S. Benseler, P. Brogan, L. Cantarini, M. Cattalini, A. Cochino, F. Dedeoglu, A. De Jesus, O. Dellacasa, E. Demirkaya, P. Dolezalova, K. Durrant, G. Fabio, R. Gallizzi, R. Goldbach-Mansky, E. Hachulla, V. Hentgen, T. Herlin, M. Hofer, H. Hoffman, A. Insalaco, A. Jansson, I. Koné-Paut, A. Kozlova, J. Kuemmerle-Deschner, R. Laxer, S. Nielsen, I. Nikishina, A. Ombrello, E. Papadopoulou-Alataki, A. Ravelli, D. Rigante, R. Russo, Y. Uziel, Nienke ter Haar, Jerold Jeyaratnam, Anna Simon, Matteo Doglio, Jordi Anton, Consuelo Modesto, Pierre Quartier, Esther Hoppenreijs, Luca Cantarini, Loredana Lepore, Inmaculada Calvo Penades, Christina Boros, Rita Consolini, Donato Rigante, Ricardo Russo, Jana Pachlopnik Schmid, Thirusha Lane, Nicolino Ruperto, Joost Frenkel, Chiara Passarelli, Elisa Pisaneschi, Virginia Messia, Antonio Novelli, Fabrizio Debenedetti, P. A. Brogan, X. Wei, Martina Finetti, Francesca Orlando, Elisabetta Cortis, Angela Miniaci, Nicola Ruperto, Charlotte Eijkelboom, Pavla Dolezalova, Isabelle Koné-Paut, Marija Jelusic-Drazic, Liliana Bezrodnik, Mari Carmen Pinedo, Valda Stanevicha, Marielle van Gijn, Silvia Federici, Hermann Girschick, Gerd Ganser, Susan Nielsen, Troels Herlin, Sulaiman Mohammed Al-Mayouf, Michael Hofer, Jasmin Kuemmerle-Deschner, Susanne Schalm, Annette Jansson, on behalf of PRINTO and Eurofever registry, Marta Marchi, Chiara Marini, Angelo Ravelli, Alberto Garaventa, Sonia Carta, Enrica Balza, Patrizia Castellani, Caterina Pellecchia, Silvia Borghini, Maria Libera Trotta, Anna Rubartelli, Andrew Henrey, Thomas Loughin, Roberta Berard, Natalie Shiff, Roman Jurencak, Susanne Benseler, Lori Tucker, on behalf of ReACCh-Out Investigators, Charalampia Papadopoulou, Ying Hong, Petra Krol, Yiannis Ioannou, Clarissa Pilkington, Hema Chaplin, Stephania Simou, Marietta Charakida, Lucy Wedderburn, Lynn R. Spiegel, Sara Ahola Kohut, Jennifer Stinson, Paula Forgeron, Miriam Kaufman, Nadia Luca, Khush Amaria, Mary Bell, J Swart, F. Boris, E. Castagnola, A. Groll, G. Giancane, G. Horneff, H. I. Huppertz, T. Wolfs, E. Alekseeva, V. Panaviene, F. Uettwiller, V. Stanevicha, L. M. Ailioaie, E. Tsitami, S. Kamphuis, G. Susic, F. Sztajnbok, B. Flato, A. Pistorio, Stephanie J. W. Shoop, Suzanne M. M. Verstappen, Janet E. McDonagh, Wendy Thomson, Kimme L. Hyrich, CAPS, Maarit Tarkiainen, Pirjo Tynjala, Pekka Lahdenne, Janne Martikainen, Acute-JIA Study Group, Meredyth Wilkinson, Christopher Piper, Georg Otto, Claire T. Deakin, Stefanie Dowle, Stefania Simou, Daniel Kelberman, Claudia Mauri, Elizabeth Jury, David Isenberg, Lucy R. Wedderburn, Kiran Nistala, I. Foeldvari, D. J. Lovell, G. Simonini, M. Bereswill, J. Kalabic, Kiem Oen, Brian M. Feldman, Brenden Dufault, Jennifer Lee, Karen Watanabe Duffy, Ciaran Duffy, ReACCh-Out Investigators, N. Tzaribachev, G. Vega-Cornejo, I. Louw, A. Berman, I. Calvo, R. Cuttica, F. Avila-Zapata, R. Cimaz, E. Solau-Gervais, R. Joos, G. Espada, X. Li, M. Nys, R. Wong, S. Banerjee, For Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology Collaborative Study Group (PRCSG), Rebecca Nicolai, Margherita Verardo, Adele D’Amico, Luisa Bracci-Laudiero, Gian Marco Moneta, Gillian Rice, Anne-Laure Mathieu, Sulliman O. Omarjee, Tracy A. Briggs, James O’Sullivan, Simon Williams, Rolando Cimaz, Eve Smith, Michael W. Beresford, Yanick J. Crow, GENIAL Investigators, UK JSLE Study Group, Madeleine Rooney, Nick Bishop, joyce davidson, Clarissa pilkington, Michael Beresford, Jacqui Clinch, Rangaraj Satyapal, Helen Foster, Janet Gardner Medwin, Janet McDonagh, Sue Wyatt, On Behalf of the British Society for Paediatric and Adolescent Rheumatology, Valentina Litta Modignani, Francesco Baldo, Stefano Lanni, Alessandro Consolaro, Giovanni Filocamo, Helen J. Lachmann, on behalf of Eurofever Registry, Gianmarco Moneta, Camilla Celani, Bilade Cherqaoui, Linda Rossi-Semerano, Perrine Dusser, Véronique Hentgen, Claire Grimwood, Linda Rossi, Isabelle Kone Paut, Veronique Hentgen, Denise Lasigliè, Denise Ferrera, Giulia Amico, Marco Di Duca, Laura Obici, Roberto Ravazzolo, Ryuta Nishikomori, Juan Arostegui, Andrea Petretto, Chiara Lavarello, Elvira Inglese, Federica Vanoni, Michaël Hofer, on behalf of EUROFEVER PROJECT, P. N. Hawkins, T. van der Poll, U. A. Walker, H. H. Tilson, Pascal N. Tyrrell, Raphaela Goldbach-Mansky, Norbert Blank, Hal M. Hoffman, Elisabeth Weissbarth-Riedel, Boris Huegle, Tilmann Kallinich, Ahmet Gul, Marlen Oswald, Fatma Dedeoglu, Aki Hanaya, Takako Miyamae, Manabu Kawamoto, Yumi Tani, Takuma Hara, Yasushi Kawaguchi, Satoru Nagata, Hisashi Yamanaka, Almira Ćosićkić, Fahrija Skokić, Belkisa Čolić, Sanimir Suljendić, Anna Kozlova, Irina Mersiyanova, Mariya Panina, Lily Hachtryan, Vasiliy Burlakov, Elena Raikina, Alexey Maschan, Anna Shcherbina, Banu Acar, Meryem Albayrak, Betul Sozeri, Sezgin Sahin, Amra Adrovic, Nese Inan, Serhan Sevgi, Caroline M. Andreasen, Anne Grethe Jurik, Mia B. Glerup, Christian Høst, Birgitte T. Mahler, Ellen-Margrethe Hauge, Cecilia Lazea, Laura Damian, Calin Lazar, Rodica Manasia, Chloe M. Stephenson, Vimal Prajapati, Paivi M. Miettunen, Dilek Yılmaz, Yavuz Tokgöz, Yasin Bulut, Harun Çakmak, Ferah Sönmez, Elif Comak, Gülşah Kaya Aksoy, Mustafa Koyun, Sema Akman, Yunus Arıkan, Ender Terzioğlu, Osman Nidai Özdeş, İbrahim Keser, Hüseyin Koçak, Ayşen Bingöl, Aygen Yılmaz, Reha Artan, X. Xu, Fatemeh F. Mehregan, Vahid Ziaee, Mohammad H. Moradinejad, Francesco La Torre, Clotilde Alizzi, Pio D’Adamo, G. Junge, J. Gregson, Hasmik Sargsyan, Hulya Zengin, Berna E. Fidanci, Cagla Kaymakamgil, Dilek Konukbay, Dilek Yildiz, Faysal Gok, Iris Stoler, Judith Freytag, Banu Orak, Christine Seib, Lars Esmann, Eva Seipelt, Faekah Gohar, Dirk Foell, Ismail Dursun, Sebahat Tulpar, Sibel Yel, Demet Kartal, Murat Borlu, Funda Bastug, Hakan Poyrazoglu, Zubeyde Gunduz, Kader Kose, Mehmet E. Yuksel, Abdullah Calıskan, Ahmet B. Cekgeloglu, Ruhan Dusunsel, Katerina Bouchalova, Jana Franova, Marcel Schuller, Marie Macku, Katerina Theodoropoulou, Raffaella Carlomagno, Annette von Scheven-Gête, Claudia Poloni, Laura O. Damian, Dan Cosma, Amanda Radulescu, Dan Vasilescu, Liliana Rogojan, Simona Rednic, Mihaela Lupse, Lien De Somer, Pierre Moens, Rocio Galindo Zavala, Laura Martín Pedraz, Esmeralda Núñez Cuadros, Gisela Díaz-Cordovés Rego, Antonio L. Urda Cardona, Ilaria Dal Forno, Sara Pieropan, Ombretta Viapiana, Davide Gatti, Gloria Dallagiacoma, Paola Caramaschi, Domenico Biasi, Daniel Windschall, Ralf Trauzeddel, Hartwig Lehmann, Rainer Berendes, Maria Haller, Manuela Krumrey-Langkammerer, Antje Nimtz-Talaska, Philipp Schoof, Ralf Felix Trauzeddel, Christine Nirschl, Estefania Quesada-Masachs, Carla Aguilar Blancafort, Sara Marsal Barril, Francisca Aguiar, Rita Fonseca, Duarte Alves, Ana Vieira, Alberto Vieira, Jorge A. Dias, Iva Brito, Gordana Susic, Vera Milic, Goran Radunovic, Ivan Boricic, Pauline Marteau, Catherine Adamsbaum, Michel De Bandt, Irène Lemelle, Chantal Deslandre, Tu Anh Tran, Anne Lohse, Elisabeth Solau-Gervais, Pascal Pillet, Julien Wipff, Cécile Gaujoux-Viala, Sylvain Breton, Valérie Devauchelle-Pensec, Sandra Gran, Olesja Fehler, Stefanie Zenker, Michael Schäfers, Thomas Vogl, Severine Guillaume Czitrom, EH Pieter Van Dijkhuizen, Silvia Magni Manzoni, Francesca Magnaguagno, Laura Tanturri de Horatio, Nienke M. Ter Haar, Annemieke S. Littooij, Vitor A. Teixeira, Raquel Campanilho-Marques, Ana F. Mourão, Filipa O. Ramos, Manuela Costa, Wafa A. Madan, Orla G. Killeen, Adriana Rodriguez Vidal, Diana Sueiro Delgado, Maria Isabel Gonzalez Fernandez, Berta Lopez Montesinos, Aleksey Kozhevnikov, Nina Pozdeeva, Mikhail Konev, Evgeniy Melchenko, Vladimir Kenis, Gennadiy Novik, Aysenur Pac Kısaarslan, Butsabong Lerkvaleekul, Suphaneewan Jaovisidha, Witaya Sungkarat, Niyata Chitrapazt, Praman Fuangfa, Thumanoon Ruangchaijatuporn, Soamarat Vilaiyuk, Dan Ø. Pradsgaard, Arne Hørlyck, Anne H. Spannow, Carsten W. Heuck, Talia Diaz, Fernando Garcia, Lorenia De La Cruz, Nadina Rubio, Joanna Świdrowska-Jaros, Elzbieta Smolewska, Mirta Lamot, Lovro Lamot, Mandica Vidovic, Edi Paleka Bosak, Ivana Rados, Miroslav Harjacek, Nikolay Tzaribachev, Polymnia Louka, Romiesa Hagoug, Chiara Trentin, Olga Kubassova, Mark Hinton, Mikael Boesen, Olena A. Oshlianska, Illya A. Chaikovsky, G. Mjasnikov, A. Kazmirchyk, Umberto Garagiola, Irene Borzani, Paolo Cressoni, Fabrizia Corona, Eszter Dzsida, Giampietro Farronato, Antonella Petaccia, Alenka Gagro, Agneza Marija Pasini, Goran Roic, Ozren Vrdoljak, Lucija Lujic, Matija Zutelija-Fattorini, Monika M. Esser, Deepthi R. Abraham, Craig Kinnear, Glenda Durrheim, Mike Urban, Eileen Hoal, Victoria B. Nikolayenko, Kubilay Şahin, Yasar Karaaslan, Adele Civino, Giovanni Alighieri, Sergio Davì, Roberto Rondelli, Andrea Magnolato, Francesca Ricci, Alma Olivieri, Valeria Gerloni, Bianca Lattanzi, Francesca Soscia, Alessandro De Fanti, Stefania Citiso, Lorenzo Quartulli, Maria Cristina Maggio, Manuela Marsili, Maria Antonietta Pelagatti, Valentino Conter, Franca Fagioli, Andrea Pession, Marco Garrone, Mariangela Rinaldi, Jaime De Inocencio, Stella Garay, Daniel J. Lovell, Berit Flato, EPOCA Study Group, Angela Aquilani, Simona Cascioli, Ivan Caiello, Denise Pires-Marafón, Rita Carsetti, Emily Robinson, Salvatore Albani, Wilco de Jager, Sytze de Roock, Trang Duong, Justine Ellis, Kimme Hyrich, Laetitia Jervis, Daniel Lovell, Lucy Marshall, Elizabeth D. Mellins, Kirsten Minden, Jane Munro, Peter A. Nigrovic, Jason Palman, Sunil Sampath, Laura E. Schanberg, Susan D. Thompson, Richard Vesely, Chris Wallace, Chris Williams, Qiong Wu, Nico Wulffraat, Rae S. M. Yeung, M. B. Seyger, D. Arikan, J. K. Anderson, A. Lazar, D. A. Williams, C. Wang, R. Tarzynski-Potempa, J. S. Hymans, Gabriele Simonini, Erika Scoccimarro, Irene Pontikaki, Teresa Giani, Alessandro Ventura, Pier Luigi Meroni, Gaetana Minnone, Marzia Soligo, Luigi Manni, Luisa Bracci Laudiero, Noortje Groot, I. Grein, N. M. Wulffraat, R. Schepp, G. Berbers, C. C. Barbosa Sandoval de Souza, V. Paes Leme Ferriani, G. Pileggi, S. de Roock, Ingrid H. R. Grein, Silvia Scala, Elisa Patrone, Casper Schoemaker, on behalf of Dutch JIA patient organization, Wendy Costello, on behalf of ENCA, Suzanne Parsons, Jean-David Cohen, Damien Bentayou, Marc-Antoine Bernard Brunel, Sonia Trope, Jens Klotsche, Miriam Listing, Martina Niewerth, Gerd Horneff, Angelika Thon, Hans-Iko Huppertz, Kirsten Mönkemöller, Ivan Foeldvari, ICON study group, Achille Marino, Stefano Stagi, Niccolò Carli, Federico Bertini, Adriana S. Díaz-Maldonado, Sally Pino, Pilar Guarnizo, Alfonso Ragnar Torres-Jimenez, Berenice Sanchez-Jara, Eunice Solis-Vallejo, Adriana Ivonne Cespedes-Cruz, Maritza Zeferino-Cruz, Julia Veronica Ramirez-Miramontes, Ankur Kumar, Anju Gupta, Deepti Suri, Amit Rawat, Nandita Kakkar, Surjit Singh, Özge A. Gücenmez, Erbil Ünsal, Bo Magnusson, Karina Mördrup, Anna Vermé, Christina Peterson, Board of the Swedish Pediatric Rheumatology Registry, Caroline Freychet, Jean Louis Stephan, Cathryn E. Harkness, Leanne Foster, Emma Henry, Pauline Taggart, Coskun F. Ozkececi, Esra Kurt, Gokalp Basbozkurt, Daiva Gorczyca, Jacek Postępski, Aleksandra Czajkowska, Bogumiła Szponar, Mariola Paściak, Anna Gruenpeter, Iwona Lachór-Motyka, Daria Augustyniak, Edyta Olesińska, Emediong S. Asuka, Tatyana Golovko, Samuel U. Aliejim, Emilio Inarejos Clemente, Estibaliz Iglesias Jimenez, Joan Calzada Hernandez, Sergi Borlan Fernandez, Clara Gimenez Roca, David Moreno Romo, Natalia Rodriguez Nieva, Juan Manuel Mosquera Angarita, Jordi Anton Lopez, Esmeralda Nuñez-Cuadros, Gisela Diaz-Cordovés, Rocío Galindo-Zavala, Antonio Urda-Cardona, Antonio Fernández-Nebro, Daniel Álvarez de la Sierra, Marina Garcia Prat, Mónica Martínez Gallo, Ricardo Pujol Borrell, Ana M. Marín Sánchez, Etienne Merlin, Sylvie Fraitag, Jean-Louis Stephan, Federico Annoni, Giancarla Di Landro, Sofia Torreggiani, Marta Torcoletti, Georgina Tiller, Jo Buckle, Angela Cox, Peter Gowdie, Roger C. Allen, Jonathan D. Akikusa, Hayde G. Hernández-Huirache, Edel R. Rodea-Montero, William Fahy, Christelle Sordet, Karin B. Berggren, Johanna T. Kembe, Joyce Bos, Wineke Armbrust, Marco van Brussel, Jeanette Cappon, Pieter Dijkstra, Jan Geertzen, Elizabeth Legger, Marion van Rossum, Pieter Sauer, Otto Lelieveld, Levent Buluc, Gur Akansel, Bahar Muezzinoglu, Ljubov Rychkova, Tatyana Knyazeva, Anna Pogodina, Tatyana Belova, Tamara Mandzyak, Ekaterina Kulesh, Alessandro Cafarotti, Cosimo Giannini, Roberta Salvatore, Giuseppe Lapergola, Caterina Di Battista, Maria Loredana Marcovecchio, Raffaella Basilico, Piernicola Pelliccia, Francesco Chiarelli, Luciana Breda, Beverley Almeida, Sarah Tansley, Harsha Gunawardena, Neil McHugh, Juvenile Dermatomyositis Research Group (JDRG), Jessie Aouizerate, Marie De Antonio, Christine Barnerias, Guillaume Bassez, Isabelle Desguerre, Romain Gherardi, Jean-Luc Charuel, François-Jérôme Authier, Cyril Gitiaux, C. H. Spencer, Rabheh Abdul Aziz, Chack-Yung Yu, Brent Adler, Sharon Bout-Tabaku, Katherine Lintner, Melissa Moore-Clingenpeel, Liza McCann, Nicola Ambrose, Mario Cortina-Borja, Juvenile Dermatomyositis Cohort and Biomarker Study (JCDBS), Prasad T. Oommen, Fabian Speth, Johannes-Peter Haas, Working Group “Juvenile Dermatomyositis” of the German Society for Paediatric and Adolescent Rheumatology (GKJR), Claudio Lavarello, Gabriella Giancane, Angela Pistorio, Lisa Rider, Rohit Aggarwal, Sheila K. Oliveira, Ruben Cuttica, Michel Fischbach, Gary Sterba, Karine Brochard, Frank Dressler, Patrizia Barone, Ruben Burgos-Vargas, Elizabeth Candell Chalom, Marine Desjonqueres, Graciela Espada, Anders Fasth, Stella Maris Garay, Rose-Marie Herbigneaux, Claire Hoyoux, Chantal Job Deslandre, Frederick W. Miller, Jiri Vencovsky, Erdal Sag, Gulsev Kale, Haluk Topaloglu, Beril Talim, Francesco Zulian, Tadej Avcin, Roberto Marini, Anne Pagnier, Michel Rodiere, Christine Soler, Rebecca Ten Cate, Yosef Uziel, Jelena Vojinovic, Ana V. Villarreal, Nydia Acevedo, Yuridiana Ramirez, Enrique Faugier, Rocio Maldonado, Bita Arabshahi, John H. Lee, Ian Leibowitz, Lawrence O. Okong’o, Jo Wilmshurst, Monika Esser, Christiaan Scott, Ezgi Deniz Batu, Nagehan Emiroglu, Hafize Emine Sonmez, Gokcen Dilsa Tugcu, Zehra Serap Arici, Ebru Yalcin, Deniz Dogru, Ugur Ozcelik, Mithat Haliloglu, Nural Kiper, Masato Yashiro, Mutsuko Yamada, Toshihiko Yabuuchi, Tomonobu Kikkawa, Nobuyuki Nosaka, Yosuke Fujii, Yukie Saito, Hirokazu Tsukahara, Sulaiman M. Al-Mayouf, Nora AlMutiari, Mohammed Muzaffer, Rawiah shehata, Adel Al-Wahadneh, Reem Abdwani, Safia Al-Abrawi, Mohammed Abu-shukair, Zeyad El-Habahbeh, Abdullah Alsonbul, Aleksandra Szabat, Monika Chęć, Violetta Opoka-Winiarska, Biman Saikia, Ranjana W. Minz, Christine Arango, Clara Malagon, Maria D. P. Gomez, Angela C. Mosquera, Ricardo Yepez, Tatiana Gonzalez, Camilo Vargas, GRIP study group, Marta Balzarin, Biagio Castaldi, Elena Reffo, Francesca Sperotto, Giorgia Martini, Alessandra Meneghel, Ornella Milanesi, Ozgur Kasapçopur, Maria Teresa Terreri, Ekaterina Alexeeva, Maria Katsicas, Mikhail Kostik, Thomas Lehman, W.-Alberto Sifuentes-Giraldo, Vanessa Smith, Flavio Sztajnbok, Tadey Avcin, Maria Jose Santos, Dana Nemcova, Cristina Battagliotti, Liora Harel, Mahesh Janarthanan, Kathryn Torok, Nicola Helmus, Eileen Baildem, Michael Blakley, Kim Fligelstone, Antonia Kienast, Clare Pain, Amanda Saracino, Gabriele Simoni, Lisa Weibel, Maria K. Osminina, Nathalia A. Geppe, Olga V. Niconorova, Olesya V. Karashtina, Oksana V. Abbyasova, Olga V. Shpitonkova, Sinem Durmus, Hafize Uzun, Angela Mauro, Eleonora Fanti, Fabio Voller, Franca Rusconi, Fernando Garcia-Rodriguez, Ana V. Villarreal-Treviño, Angel J. Flores-Pineda, Paola B. Lara-Herrea, Diego R. Salinas-Encinas, Talia Diaz-Prieto, Maria R. Maldonado-Velazquez, Sarbelio Moreno-Espinosa, Enrique Faugier-Fuentes, Mirella Crapanzano, Ilaria Parissenti, Man S. Parihar, Pandiarajan Vignesh, ManojKumar Rohit, Kavitha Gopalan, Savita V. Attri, Alan Salama, David Jayne, Mark Little, Yulia Kostina, Galina Lyskina, Olga Shpitonkova, Alena Torbyak, Olga Shirinsky, Maria Francesca Gicchino, Maria Cristina Smaldone, Mario Diplomatico, Alma Nunzia Olivieri, C H. Spencer, Richard McClead, Hiren Patel, Chung-Yung Yu, Dita Cebecauerová, Tomáš Dallos, Edita Kabíčková, Martin Kynčl, Daniela Chroustová, Jozef Hoza, Dana Němcová, Vladimír Tesař, Pavla Doležalová, Tuncay Hazirolan, Fatih Ozaltin, Fabiola Almeida, Isabela H. Faria de Paula, Maíra M. Sampaio, Fernando N. Arita, Andressa G. Alves, Maria Carolina Santos, Eunice M. Okuda, Silvana B. Sacchetti, Fernanda Falcini, Marini Francesca, Gemma Lepri, Marco Matucci-Cerinic, Maria Luisa Brandi, Hakan Kisaoglu, Sema Misir, Selim Demir, Yuksel Aliyazicioglu, Mukaddes Kalyoncu, Carlos Eduardo Ramalho, Fabiola D. Almeida, Joan Calzada-Hernández, Rosa Bou, Estíbaliz Iglesias, Judith Sánchez-Manubens, Fredy Hermógenes Prada Martínez, Clara Giménez Roca, Sergi Borlan Fernández, Marek Bohm, Kamran Mahmood, Valentina Leone, Mark Wood, Ken-Ichi Yamaguchi, Satoshi Fujikawa, Working Group of Behçet’s Disease, Pediatric Rheumatology Association of Japan (PRAJ), Kyu Yeun Kim, Do Young Kim, Dong Soo Kim, Maka Ioseliani, Ivane Chkhaidze, Maia Lekishvili, Nana Tskhakaia, Shorena Tvalabeishvili, Aleksandre Kajrishvili, Maiko Takakura, Masaki Shimizu, Natsumi Inoue, Mao Mizuta, Akihiro Yachie, Giovanni Corsello, Maryam Piram, Carla Maldini, Sandra Biscardi, Nathalie Desuremain, Catherine Orzechowski, Emilie Georget, Delphine Regnard, Isabelle Kone-Paut, Alfred Mahr, Mihaela Sparchez, Zeno Sparchez, Nydia Acevedo Silva, Ana V. Villarreal Treviño, Yuridiana Ramirez Loyola, Talia Diaz Prieto, Enrique Faugier Fuentes, Maria D. R. Maldonado Velazquez, Pilar Perez, Sagar Bhattad, Ranjana Minz, Jitendra Shandilya, Pediatric Allergy and Immunology Unit, PGIMER, Chandigarh, Ana Villarreal, Yuridiana Ramírez, Zeynep Birsin Özçakar, Suat Fitoz, Fatos Yalcinkaya, Annacarin Horne, Francesca Minoia, Francesca Bovis, Sergio Davi, Priyankar Pal, Kimo Stein, Sandra Enciso, Michael Jeng, Despoina Maritsi, Randy C. Cron, Anne Thorwarth, Sae Lim von Stuckrad, Angela Rösen-Wolff, Hella Luksch, Patrick Hundsdoerfer, Peter Krawitz, Nuray Aktay Ayaz, Doğan Simsek, Şebnem Sara Kılıc, Emine Sonmez, Aysenur Pac Kisaarslan, Ozge Altug Gucenmez, Z. Serap Arıcı, Fatih Kelesoglu, Zelal Ekinci Ekinci, Maria Miranda-Garcia, Carolin Pretzer, Michael Frosch, F. Gohar, Angela McArdle, Niamh Callan, Belinda Hernandez, Miha Lavric, Oliver FitzGerald, Stephen R. Pennington, Joachim Peitz, Joern Kekow, Ariane Klein, Anna C. Schulz, Frank Weller-Heinemann, Anton Hospach, J-Peter Haas, BIKER collaborative group, Karen Put, Jessica Vandenhaute, Anneleen Avau, Annemarie van Nieuwenhuijze, Ellen Brisse, Tim Dierckx, Omer Rutgeerts, Josselyn E. Garcia-Perez, Jaan Toelen, Mark Waer, Georges Leclercq, An Goris, Johan Van Weyenbergh, Adrian Liston, Patrick Matthys, Carine H. Wouters, Yasuo Nakagishi, Michael J. Ombrello, Victoria Arthur, Anne Hinks, Patricia Woo, International Childhood Arthritis Genetics (INCHARGE) Consortium, Barbara Stanimirovic, Biljana Djurdjevic-Banjac, Olivera Ljuboja, Boris Hugle, MArgarita Onoufriou, Olga Vougiouka, Kenza Bouayed, Sanae El Hani, Imane Hafid, Nabiha Mikou, Nunu Shelia, Mari Laan, Jaanika Ilisson, and Chris Pruunsild
Subjects: Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Published: 2017
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10. Altered Nt-acetylation processes, a new disease-mechanism for autosomal recessive primary familial brain calcifications

Author: Viorica, Chelban, primary, Henriette, Aksnes, additional, Lauren, LaMonica, additional, Luis, Seabra, additional, Reza, Maroofian, additional, Rita, Horvath, additional, Yanick J, Crow, additional, Gaël, Nicolas, additional, Thomas, Arnesen, additional, and Henry, Houlden, additional
Published: 2023
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11. Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review

Author: Priyanka Madaan, Yashovardhan Kaushal, Priyanka Srivastava, Yanick J Crow, John H Livingston, Chirag Ahuja, and Naveen Sankhyan
Subjects: Epilepsy, neuroregression, Calcinosis, Neurodegenerative Diseases, Neuroimaging, General Medicine, infantile spasms syndrome, intracranial calcifications, Phenotype, epileptic encephalopathy, Neurology, Seizures, West Syndrome, Humans, Neurology (clinical), Spasms, Infantile
Abstract: Background: Negative regulator of reactive oxygen species (NRROS) related microgliopathy, a rare and recently recognized neurodegenerative condition, is caused by pathogenic variants in the NRROS gene, which plays a major role in the regulation of transforming growth factor-beta 1. Methods: We report a child presenting with infantile spasms syndrome (ISS) with subsequent progressive neurodegeneration who was identified to harbour a novel likely pathogenic NRROS variant (c.1359del; p.Ser454Alafs*11). The previously published reports of patients with this disorder were also reviewed systematically.Results: Including our index patient, 11 children (6 girls) were identified in total. Early development was normal in seven of these eleven children. All had a history of drug-resistant epilepsy, with 3 having epileptic spasms. The median age at seizure onset and developmental regression was 12 months, and the median age at death was 36 months. Intracranial calcifications were described in eight of eleven children. Neuroimaging revealed progressive cerebral atrophy and white matter loss in all children. The most common reported genetic variation was c.1981delC; (p.Leu661Serfs*97) observed in two families (likely due to a founder effect). Conclusions: Pathogenic variants in NRROS should be suspected in children with neuro-regression and drug-resistant epilepsy including ISS with onset in the first two years of life. Punctate or serpiginous calcifications at the grey-white matter junction and acquired microcephaly are further clues towards the diagnosis
Published: 2022

12. Type I interferon–related kidney disorders

Author: Lorenzo Lodi, Maria V. Mastrolia, Federica Bello, Giovanni M. Rossi, Maria L. Angelotti, Yanick J. Crow, Paola Romagnani, and Augusto Vaglio
Subjects: collapsing glomerulopathy, Kidney Glomerulus, interferonopathy, interferon, Kidney, Antiviral Agents, viral nephropathy, systemic lupus erythematosus, Nephrology, Interferon Type I, Humans, Lupus Erythematosus, Systemic, Kidney Diseases, glomerulonephritis
Abstract: Type I interferon (IFN-I) mediates tissue damage in a wide range of kidney disorders, directly affecting the biology and function of several renal cell types including podocytes, mesangial, endothelial, and parietal epithelial cells. Enhanced IFN-I signaling is observed in the context of viral infections, autoimmunity (e.g., systemic lupus erythematosus), and type 1 interferonopathies, rare monogenic disorders characterized by constitutive activation of the IFN-I pathway. All these IFN-I–related disorders can cause renal dysfunction and share pathogenic and histopathological features. Collapsing glomerulopathy, a histopathological lesion characterized by podocyte loss, collapse of the vascular tuft, and parietal epithelial cell proliferation, is commonly associated with viral infections, has been described in type 1 interferonopathies such as Aicardi-Goutières syndrome and stimulator of IFN genes–associated vasculopathy with onset in infancy, and can also be induced by recombinant IFN therapy. In all these conditions, podocytes and parietal epithelial cells seem to be the primary target of IFN-I–mediated damage. Additionally, immune-mediated glomerular injury is common to viral infections, systemic lupus erythematosus, and type 1 interferonopathies such as coatomer subunit-α syndrome (COPA) and DNASE1L3 deficiency, diseases in which IFN-I apparently promotes immune-mediated kidney injury. Finally, kidney pathology primarily characterized by vascular lesions (e.g., thrombotic microangiopathy and vasculitis) is a hallmark of type 1 interferonopathy adenosine deaminase 2 deficiency as well as of systemic lupus erythematosus, viral infections, and IFN therapy. Defining the nosology, pathogenic mechanisms, and histopathological patterns of IFN-I–related kidney disorders has diagnostic and therapeutic implications, especially considering the likely near-term availability of novel drugs targeting the IFN-I pathway.
Published: 2022

13. JAK inhibition in Aicardi-Goutières syndrome: a monocentric multidisciplinary real-world approach study

Author: Marie-Louise Frémond, Marie Hully, Benjamin Fournier, Rémi Barrois, Romain Lévy, Mélodie Aubart, Martin Castelle, Delphine Chabalier, Clarisse Gins, Eugénie Sarda, Buthaina Al Adba, Sophie Couderc, Céline D’ Almeida, Claire-Marine Berat, Chloé Durrleman, Caroline Espil, Laetitia Lambert, Cécile Méni, Maximilien Périvier, Pascal Pillet, Laura Polivka, Manuel Schiff, Calina Todosi, Florence Uettwiller, Alice Lepelley, Gillian I. Rice, Luis Seabra, Sylvia Sanquer, Anne Hulin, Claire Pressiat, Lauriane Goldwirt, Vincent Bondet, Darragh Duffy, Despina Moshous, Brigitte Bader-Meunier, Christine Bodemer, Florence Robin-Renaldo, Nathalie Boddaert, Stéphane Blanche, Isabelle Desguerre, Yanick J. Crow, Bénédicte Neven, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Neurogénétique et neuroinflammation = Neurogenetics and neuroinflammation (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), Sidra Medicine [Doha, Qatar], Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Centre Hospitalier Intercommunal Castres-Mazamet (CHIC-CM), CHU Bordeaux [Bordeaux], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Manchester [Manchester], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hopital Saint-Louis [AP-HP] (AP-HP), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Edinburgh, Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), M.-L. F. received a grant from the Institut National de la Santé et de la Recherche Médicale (reference: 000427993). Y. J. C. acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) 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. C. is supported by a UK Medical Research Council Human Genetics Unit core grant (MRC, U127580972). Y. J. C. and D. D. acknowledge the ANR (grant CE17001002). D. D. thanks ImmunoQure AG for the provision of antibodies for the Simoa assay. The project was supported by MSDAVENIR (Devo-Decode Project)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), and European Project: 786142,ERC-2017-ADG,E-T1IFNs(2018)
Subjects: JAK inhibitors, [SDV]Life Sciences [q-bio], Aicardi-Goutières syndrome (AGS), Immunology, Immunology and Allergy, interferon
Abstract: The paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery.
Published: 2023

14. Type I interferonopathy due to a homozygous loss-of-inhibitory-function mutation in STAT2

Author: Gaofeng Zhu, Mihaly Badonyi, Lina Franklin, Luis Seabra, Gillian I. Rice, null Anne-Boland-Auge, Jean-François Deleuze, Salima El-Chehadeh, Mathieu Anheim, Anne de Saint-Martin, Sandra Pellegrini, Joseph A. Marsh, Yanick J. Crow, and Marie-Therese El-Daher
Subjects: Immunology, Immunology and Allergy
Abstract: Purpose STAT2 is both an effector and negative regulator of type I interferon (IFN-I) signalling. We describe the characterization of a novel homozygous missense STAT2 substitution in a patient with a type I interferonopathy. Methods Whole-genome sequencing (WGS) was used to identify the genetic basis of disease in a patient with features of enhanced IFN-I signalling. After stable lentiviral reconstitution of STAT2-null human fibrosarcoma U6A cells with STAT2 wild type or p.(A219V), we performed quantitative polymerase chain reaction, western blotting, immunofluorescence, and co-immunoprecipitation to functionally characterize the p.(A219V) variant. Results WGS identified a rare homozygous single nucleotide transition in STAT2 (c.656C > T), resulting in a p.(A219V) substitution, in a patient displaying developmental delay, intracranial calcification, and up-regulation of interferon-stimulated gene (ISG) expression in blood. In vitro studies revealed that the STAT2 p.(A219V) variant retained the ability to transduce an IFN-I stimulus. Notably, STAT2 p.(A219V) failed to support receptor desensitization, resulting in sustained STAT2 phosphorylation and ISG up-regulation. Mechanistically, STAT2 p.(A219V) showed defective binding to ubiquitin specific protease 18 (USP18), providing a possible explanation for the chronic IFN-I pathway activation seen in the patient. Conclusion Our data indicate an impaired negative regulatory role of STAT2 p.(A219V) in IFN-I signalling and that mutations in STAT2 resulting in a type I interferonopathy state are not limited to the previously reported R148 residue. Indeed, structural modelling highlights at least 3 further residues critical to mediating a STAT2-USP18 interaction, in which mutations might be expected to result in defective negative feedback regulation of IFN-I signalling.
Published: 2023

15. VEXAS syndrome: expanding the clinical and molecular spectrum

Author: Marie Robert, Marie Berleur, Augustin Gaudemer, Yanick J. Crow, Marie-Louise Frémond, and Karim Sacré
Subjects: Rheumatology
Published: 2023

16. Enhanced Inflammatory Signaling Driven by Metabolic Switch in Aicardi-Goutières Syndrome

Author: Maxime Batignes, Marine Luka, Surabhi Jagtap, Camille de Cevins, Ivan Nemazanyy, Tinhinane Fali, Víctor García-Paredes, Francesco Carbone, Brieuc P. Pérot, Bénédicte Neven, Brigitte Bader-Meunier, Pierre Quartier dit Maire, Marie Hully, Alexandre Belot, Alice Lepelley, Marie-Louise Frémond, Yanick J. Crow, Alain Fischer, and Mickaël M. Ménager
Abstract: SummaryAicardi-Goutières syndrome (AGS) is a genetic type I interferon (IFN)-mediated disease characterised by neurological involvement with onset in childhood. Chronic inflammation in response to uncontrolled type I IFN production is, among other things, associated with IP-10 secretion. We analysed, at the single-cell transcriptomic levels, peripheral blood samples from patients bearing AGS-causing mutations inSAMHD1,RNASEH2BorADAR1genes. Using machine-learning approaches and differential gene expression we identified a drastic loss of transcription factor hypoxia induced factor 1 α (HIF-1α) expression and activity associated with features of a metabolic switch and mitochondrial stress in monocytes/dendritic cells. Chemical stabilization of HIF-1α, with a synthetic drug in anin vitromodel of AGS, allowed us to reverse the energy metabolic switch, attenuate mitochondrial stress and markedly reduce IP-10 production. We therefore propose that energy metabolic switch contributes to exacerbated chronic inflammation in AGS, and that targeting this pathway might represent a promising therapeutic approach.
Published: 2023

17. Juvenile Neuropsychiatric Systemic Lupus Erythematosus: Identification of Novel Central Neuroinflammation Biomarkers

Author: Mathilde Labouret, Stefania Costi, Vincent Bondet, Vincent Trebossen, Enora Le Roux, Alexandra Ntorkou, Sophie Bartoli, Stéphane Auvin, Brigitte Bader-Meunier, Véronique Baudouin, Olivier Corseri, Glory Dingulu, Camille Ducrocq, Cécile Dumaine, Monique Elmaleh, Nicole Fabien, Albert Faye, Isabelle Hau, Véronique Hentgen, Théresa Kwon, Ulrich Meinzer, Naim Ouldali, Cyrielle Parmentier, Marie Pouletty, Florence Renaldo, Isabelle Savioz, Flore Rozenberg, Marie-Louise Frémond, Alice Lepelley, Gillian I. Rice, Luis Seabra, Jean-François Benoist, Darragh Duffy, Yanick J. Crow, Pierre Ellul, Isabelle Melki, Vougny, Marie-Christine, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Definition and characterization of type I interferonopathies - T1-IFN - - EC:FP7:ERC2013-03-01 - 2018-02-28 - 309449 - VALID, Elaboration of the type I interferonopathies - E-T1IFNs - - ERC-2017-ADG2018-11-01 - 2023-10-31 - 786142 - VALID, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de référence des rhumatismes inflammatoires et maladies autoimmunes systémiques rares de l'enfant [Paris] (RAISE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Università degli Studi di Milano = University of Milan (UNIMI), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), Centre d'Investigation Clinique 1426 (CIC 1426), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), CHU Necker - Enfants Malades [AP-HP], Immunogenetics of pediatric autoimmune diseases (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), Centre Hospitalier Sud Francilien, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHI Créteil, Centre Hospitalier de Versailles André Mignot (CHV), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), GHU AP-HP Centre Université de Paris, Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), University of Manchester [Manchester], Université Paris-Saclay, University of Edinburgh, Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Bordeaux [Bordeaux], YJC acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) 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. The project was supported by MSDAVENIR (Devo-Decode Project). YJC and DD acknowledge the Agence Nationale de la Recherche (grant CE17001002)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), European Project: 786142,ERC-2017-ADG,E-T1IFNs(2018), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Institut Pasteur [Paris] (IP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), and Institut Pasteur [Paris] (IP)-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)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.IMM] Life Sciences [q-bio]/Immunology, Central nervous system, Immunology, Immunology and Allergy, Interferon-alpha, [SDV.IMM]Life Sciences [q-bio]/Immunology, Neuropsychiatric, Biomarker, Juvenile systemic lupus erythematosus, Neopterin
Abstract: Introduction Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic autoimmune disease affecting multiple organs. Ranging from minor features, such as headache or mild cognitive impairment, to serious and life-threatening presentations, j-neuropsychiatric SLE (j-NPSLE) is a therapeutic challenge. Thus, the diagnosis of NPSLE remains difficult, especially in pediatrics, with no specific biomarker of the disease yet validated. Objectives To identify central nervous system (CNS) disease biomarkers of j-NPSLE. Methods A 5-year retrospective tertiary reference monocentric j-SLE study. A combination of standardized diagnostic criteria and multidisciplinary pediatric clinical expertise was combined to attribute NP involvement in the context of j-SLE. Neopterin and interferon-alpha (IFN-α) protein levels in cerebrospinal fluid (CSF) were assessed, together with routine biological and radiological investigations. Results Among 51 patients with j-SLE included, 39% presented with j-NPSLE. J-NPSLE was diagnosed at onset of j-SLE in 65% of patients. No specific routine biological or radiological marker of j-NPSLE was identified. However, CSF neopterin levels were significantly higher in active j-NPSLE with CNS involvement than in j-SLE alone (p = 0.0008). Neopterin and IFN-α protein levels in CSF were significantly higher at diagnosis of j-NPSLE with CNS involvement than after resolution of NP features (respectively p = 0.0015 and p = 0.0010) upon immunosuppressive treatment in all patients tested (n = 10). Both biomarkers correlated strongly with each other (Rs = 0.832, p n = 23 paired samples). Conclusion CSF IFN-α and neopterin constitute promising biomarkers useful in the diagnosis and monitoring of activity in j-NPSLE.
Published: 2022

18. Molecular characterization of an intronic RNASEH2B variant in a patient with Aicardi-Goutières syndrome

Author: Marco L. Leung, Whitney Woodhull, Carolina Uggenti, Shauna Schord, Raul Perez Mato, Diana P. Rodriguez, Margie Ream, Yanick J. Crow, and Mari Mori
Subjects: Autoimmune Diseases of the Nervous System/genetics, Mutation, Genetics, Humans, Exome, General Medicine, Nervous System Malformations/genetics, Genetics (clinical)
Abstract: Aicardi-Goutières syndrome (AGS) is a progressive multisystem disorder including encephalopathy with significant impacts on intellectual and physical abilities. An early diagnosis is becoming ever more crucial, as targeted therapies are emerging. A deep understanding of the molecular heterogeneity of AGS can help guide the early diagnosis and clinical management of patients, and inform recurrence risks. Here, we detail the diagnostic odyssey of a patient with an early presentation of AGS. Exome and genome sequencing detected an intronic RNASEH2B variant missed in a conventional leukodystrophy NGS gene panel. RNA studies demonstrated that a c.322-17 A > G variant affected splicing and caused 16-nucleotide intronic retention in the RNASEH2B transcript, introducing an out-of-frame early termination codon. RNASEH2B expression in the patient's blood was reduced when compared to controls. Our study highlights the pathogenicity of this intronic variant and the importance of its inclusion in variant assessment.
Published: 2023

19. STING-Mediated Lung Inflammation and Beyond

Author: Marie-Louise Frémond and Yanick J. Crow
Subjects: 0301 basic medicine, Immunology, Golgi Apparatus, Autoimmunity, Penetrance, Inflammation, Biology, Endoplasmic Reticulum, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Interferon, medicine, Animals, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Endoplasmic reticulum, Disease Management, Membrane Proteins, Pneumonia, Syndrome, Golgi apparatus, Phenotype, Transport protein, Protein Transport, Sting, 030104 developmental biology, Gene Expression Regulation, Mutation, symbols, Disease Susceptibility, medicine.symptom, Signal transduction, Biomarkers, Signal Transduction, 030215 immunology, medicine.drug
Abstract: Mendelian autoinflammatory diseases characterized by constitutive activation of the type I interferon pathway, the so-called type I interferonopathies, constitute a rapidly expanding group of inborn errors of immunity. Among the type I interferonopathies, STING-associated vasculopathy with onset in infancy (SAVI) and COPA syndrome were described in the last 6 years, both manifesting a major inflammatory lung component associated with significant morbidity and increased mortality. There is striking clinical and histopathological overlap between SAVI and COPA syndrome, although distinct features are also present. Of note, there is a remarkably high frequency of clinical non-penetrance among individuals harboring pathogenic COPA mutations. SAVI is caused by, principally heterozygous, gain-of-function mutations in STING1 (previously referred to as TMEM173) encoding STING, a key adaptor of the interferon signaling pathway induced by DNA. COPA syndrome results from heterozygous dominant-negative mutations in the coatomer protein subunit alpha, forming part of a complex involved in intracellular cargo protein transport between the Golgi and the endoplasmic reticulum (ER). Of importance, a role for COPA in regulating the trafficking of STING, an ER-resident protein which translocates to the Golgi during the process of its activation, was recently defined, thereby possibly explaining some aspects of the phenotypic overlap between SAVI and COPA syndrome. Here, we review the expanding phenotype of these diseases, highlighting common as well as specific features, and recent advances in our understanding of STING biology that have informed therapeutic decision-making in both conditions. Beyond these rare Mendelian disorders, DNA sensing through STING is likely relevant to the pathology of several diseases associated with lung inflammation, including systemic lupus erythematosus, dermatomyositis, environmental toxin exposure, and viral infection.
Published: 2021

20. Global mapping of RNA homodimers in living cells

Author: Marta M. Gabryelska, Andrew P. Badrock, Jian You Lau, Raymond T. O'Keefe, Yanick J. Crow, and Grzegorz Kudla
Subjects: Base Sequence, SARS-CoV-2, Zika Virus Infection, Genetics, Animals, COVID-19, RNA, Small Nucleolar, RNA, Viral, Zika Virus, Zebrafish, Genetics (clinical)
Abstract: RNA homodimerization is important for various physiological processes, including the assembly of membraneless organelles, RNA subcellular localization, and packaging of viral genomes. However, understanding RNA dimerization has been hampered by the lack of systematic in vivo detection methods. Here, we show that CLASH, PARIS, and other RNA proximity ligation methods detect RNA homodimers transcriptome-wide as “overlapping” chimeric reads that contain more than one copy of the same sequence. Analyzing published proximity ligation data sets, we show that RNA:RNA homodimers mediated by direct base-pairing are rare across the human transcriptome, but highly enriched in specific transcripts, including U8 snoRNA, U2 snRNA, and a subset of tRNAs. Mutations in the homodimerization domain of U8 snoRNA impede dimerization in vitro and disrupt zebrafish development in vivo, suggesting an evolutionarily conserved role of this domain. Analysis of virus-infected cells reveals homodimerization of SARS-CoV-2 and Zika genomes, mediated by specific palindromic sequences located within protein-coding regions of N gene in SARS-CoV-2 and NS2A gene in Zika. We speculate that regions of viral genomes involved in homodimerization may constitute effective targets for antiviral therapies.
Published: 2022

21. A partial form of inherited human USP18 deficiency underlies infection and inflammation

Author: Marta Martin-Fernandez, Sofija Buta, Tom Le Voyer, Zhi Li, Lasse Toftdal Dynesen, Françoise Vuillier, Lina Franklin, Fatima Ailal, Alice Muglia Amancio, Louise Malle, Conor Gruber, Ibtihal Benhsaien, Jennie Altman, Justin Taft, Caroline Deswarte, Manon Roynard, Alejandro Nieto-Patlan, Kunihiko Moriya, Jérémie Rosain, Nathalie Boddaert, Aziz Bousfiha, Yanick J. Crow, Dragana Jankovic, Alan Sher, Jean-Laurent Casanova, Sandra Pellegrini, Jacinta Bustamante, Dusan Bogunovic, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm 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), Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalo-universitaire Averroes [Casablanca], Université Hassan II [Casablanca] (UH2MC), National Institutes of Health [Bethesda] (NIH), Fundação Cristiano Varella [Muriaé/MG, Brasil] (FCV), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Radiologie et imagerie médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], School of Mathematics - University of Edinburgh, University of Edinburgh, Rockefeller University [New York], Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), This research was in part supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, the National Institute of Allergy and Infectious Diseases (grant numbers R01AI127372, R01AI148963, R01AI151029, 5R01AI089970, and 5R37AI095983), the National Center for Research Resources and the National Center for Advancing Sciences of the National Institutes of Health (grant number 8UL1TR000043), The Rockefeller University, the St. Giles Foundation, The Yale Center for Mendelian Genomics funded by the National Human Genome Research Institute (UM1HG006504), INSERM, University of Paris, the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID) and the French National Research Agency (ANR) under the 'Investments for the future' program (grant number ANR-10-IAHU-01), and GENMSMD (ANR-16-CE17-0005-01 for J. Bustamante). T. LeVoyer is supported by the MD-PhD program of the Imagine Institute with the support of the Bettancourt-Schueller Foundation. Work in Institut Pasteur was supported by grants from Association de la Recherche sur le Cancer (ARC no. 20141201864) and Fondation pour la Recherche Médicale (grant DEQ. 2017033741) and by institutional funding from Institut Pasteur and INSERM. Z. Li was supported by Centre national de la recherche scientifique. L.T. Dynesen was supported by the EU Erasmus+ program. L. Franklin was supported by la Fondation de France (Prix Thérèse Lebrasseur to S. Pellegrini). L. Malle and C. Gruber were supported by National Institute of Child Health and Human Development-Interdisciplinary Training in Systems and Developmental Biology and Birth Defects T32HD075735., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), Vuillier, Françoise, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, and Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme - - GENMSMD2016 - ANR-16-CE17-0005 - AAPG2016 - VALID
Subjects: MESH: Inflammation, MESH: Interleukin-12, MESH: Interleukin-23, Inflammation, MESH: Cytokines, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Immunology, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Ubiquitin Thiolesterase, Interleukin-12, Interleukin-23, [SDV] Life Sciences [q-bio], MESH: Ubiquitins, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Humans, Immunology and Allergy, Ubiquitin Thiolesterase, Ubiquitins
Abstract: International audience; Human USP18 is an interferon (IFN)-stimulated gene product and a negative regulator of type I IFN (IFN-I) signaling. It also removes covalently linked ISG15 from proteins, in a process called deISGylation. In turn, ISG15 prevents USP18 from being degraded by the proteasome. Autosomal recessive complete USP18 deficiency is life-threatening in infancy owing to uncontrolled IFN-I–mediated autoinflammation. We report three Moroccan siblings with autoinflammation and mycobacterial disease who are homozygous for a new USP18 variant. We demonstrate that the mutant USP18 (p.I60N) is normally stabilized by ISG15 and efficient for deISGylation but interacts poorly with the receptor-anchoring STAT2 and is impaired in negative regulation of IFN-I signaling. We also show that IFN-γ–dependent induction of IL-12 and IL-23 is reduced owing to IFN-I–mediated impairment of myeloid cells to produce both cytokines. Thus, insufficient negative regulation of IFN-I signaling by USP18-I60N underlies a specific type I interferonopathy, which impairs IL-12 and IL-23 production by myeloid cells, thereby explaining predisposition to mycobacterial disease.
Published: 2022

22. An Indian child with Coats plus syndrome due to mutations in <scp> STN1 </scp>

Author: Yanick J. Crow, Surabhi Rathore, Gouri Rao Passi, Aradhana Mathur, Pooja Sharma, Uzma Shamim, Shaista Parveen, Mohammed Faruq, and Aditi Joshi
Subjects: Genome instability, Proband, Mutation, Norethisterone, Blood transfusion, business.industry, medicine.medical_treatment, media_common.quotation_subject, Nonsense, medicine.disease_cause, Bioinformatics, Compound heterozygosity, Genetics, medicine, business, Genetics (clinical), Exome sequencing, medicine.drug, media_common
Abstract: The role of the CTC1-STN1-TEN1 (CST) complex in Coats plus syndrome (CP), as well as other telomeropathy-phenotypes and disorders of genome instability is well documented. We report an Indian child with a clinical diagnosis of CP who presented to us with retinal exudates, extensive cerebral calcification, developmental delay and severe anemia consequent upon chronic gastrointestinal (GI) bleeding. Whole exome sequencing revealed compound heterozygous variants in STN1 as the probable genetic cause leading to CP in the present case. Of the two variants, the nonsense variant c.397C>T (p.Arg133*) was a truncating variant leading to loss of full protein length whereas the second variant c.985G>C (p.Ala329Pro) was novel and neither reported in ExAC, 1KGP or gnomAD. The deleteriousness of the novel variant was explored through molecular dynamics simulation analysis where p.Ala329Pro mutation affected C-terminal domain interaction between STN1 and TEN1 complex. Hormonal therapy using ethinyl estradiol and norethisterone was apparently associated with a clinically useful, although poorly sustained, decrease in blood transfusion requirement in the proband.
Published: 2020

23. The 2021 Eurpean Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type i interferonopathies: CANDLE/PRAAS, SAVI and AGS

Author: Kader Cetin Gedik, Lovro Lamot, Micol Romano, Erkan Demirkaya, David Piskin, Sofia Torreggiani, Laura A Adang, Thais Armangue, Kathe Barchus, Devon R Cordova, Yanick J Crow, Russell C Dale, Karen L Durrant, Despina Eleftheriou, Elisa M Fazzi, Marco Gattorno, Francesco Gavazzi, Eric P Hanson, Min Ae Lee-Kirsch, Gina A Montealegre Sanchez, Bénédicte Neven, Simona Orcesi, Seza Ozen, M Cecilia Poli, Elliot Schumacher, Davide Tonduti, Katsiaryna Uss, Daniel Aletaha, Brian M Feldman, Adeline Vanderver, Paul A Brogan, and Raphaela Goldbach-Mansky
Subjects: Immunology, immune system diseases, Nervous System Malformations, Skin Diseases, Pediatrics, General Biochemistry, Genetics and Molecular Biology, Settore MED/39 - Neuropsichiatria Infantile, Article, polymorphism, Fingers, Type I Interferonopathies, CANDLE/PRAAS, SAVI, AGS, Autoimmune Diseases of the Nervous System, Erythema Nodosum, Rheumatology, genetic, inflammation, Quality of Life, Immunology and Allergy, Humans
Abstract: ObjectiveAutoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) and Aicardi-Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of ‘points to consider’ to improve diagnosis, treatment and long-term monitoring of patients with these rare diseases.MethodsMembers of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates and an allied healthcare professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires and consensus methodology, ‘points to consider’ to guide patient management were developed.ResultsThe Task Force devised consensus and evidence-based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment and long-term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI and AGS.ConclusionThese points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment and management of patients with CANDLE/PRAAS, SAVI and AGS and aim to standardise and improve care, quality of life and disease outcomes.
Published: 2022

24. Autosomal Dominant ADAR c.3019G>A (p.(G1007R)) Variant is an Important Mimic of Hereditary Spastic Paraplegia and Cerebral Palsy

Author: Gladys Ho, Hannah F. Jones, Yanick J. Crow, Shekeeb S. Mohammad, Christopher Troedson, Kavitha Kothur, Russell C. Dale, Kirsty Stewart, Marion Stoll, Simon P Paget, Velda X Han, Dugald O'Neill, and Jennifer Lewis
Subjects: business.industry, Hereditary spastic paraplegia, General Medicine, medicine.disease, Penetrance, Dyschromatosis symmetrica hereditaria, Cerebral palsy, Developmental Neuroscience, Pediatrics, Perinatology and Child Health, ADAR, Spastic diplegia, Immunology, medicine, Spastic, Aicardi–Goutières syndrome, Neurology (clinical), business
Abstract: Background The type 1 interferonopathy, Aicardi-Goutieres syndrome 6 (AGS6), is classically caused by biallelic ADAR mutations whereas dominant ADAR mutations are associated with dyschromatosis symmetrica hereditaria (DSH). The unique dominant ADAR c.3019G>A variant is associated with neurological manifestations which mimic spastic paraplegia and cerebral palsy (CP). Case summaries We report three cases of spastic paraplegia or CP diagnosed with AGS6 caused by the ADAR c.3019G>A variant. Two children inherited the variant from an asymptomatic parent, and each child had a different clinical course. The youngest case demonstrated relentless progressive symptoms but responded to immunomodulation using steroids and ruxolitinib. Conclusion The ADAR c.3019G>A variant has incomplete penetrance and is a likely underrecognized imitator of spastic paraplegia and dystonic CP. A high level of clinical suspicion is required to diagnose this form of AGS, and disease progression may be ameliorated by immunomodulatory treatment with selective Janus kinase inhibitors.
Published: 2021

25. The type I interferonopathies 10 years on

Author: Daniel B. Stetson and Yanick J. Crow
Subjects: History, Innate immune system, COVID-19, Cellular homeostasis, Review Article, Computational biology, Disease, Biology, Immunity, Innate, Computer Science Applications, Education, Immune system, Downregulation and upregulation, Interferon, Immunity, Nucleic Acids, Interferon Type I, Nucleic acid, medicine, Humans, Interferons, Pandemics, Immunological disorders, medicine.drug
Abstract: As brutally demonstrated by the COVID-19 pandemic, an effective immune system is essential for survival. Developed over evolutionary time, viral nucleic acid detection is a central pillar in the defensive armamentarium used to combat foreign microbial invasion. To ensure cellular homeostasis, such a strategy necessitates the efficient discrimination of pathogen-derived DNA and RNA from that of the host. In 2011, it was suggested that an upregulation of type I interferon signalling might serve as a defining feature of a novel set of Mendelian inborn errors of immunity, where antiviral sensors are triggered by host nucleic acids due to a failure of self versus non-self discrimination. These rare disorders have played a surprisingly significant role in informing our understanding of innate immunity and the relevance of type I interferon signalling for human health and disease. Here we consider what we have learned in this time, and how the field may develop in the future., The term ‘type I interferonpathy’ was coined 10 years ago to describe rare genetic diseases that are caused by an aberrant upregulation of type I interferon signalling. Here, Crow and Stetson discuss our current understanding of the type I interferonpathies, 10 years on.
Published: 2021

26. Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease

Author: Yanick J. Crow, Alice Lepelley, Timothy Wai, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Biologie mitochondriale – Mitochondrial biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Edinburgh, AL is supported by funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 892311. YC acknowledges that work relating to this manuscript has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 786142) and State funding from the Agence Nationale de la Recherche under 'Investissements d’avenir' program (ANR-10-IAHU-01). TW acknowledges funding from the ERC (grant agreement No. 714472)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 786142,ERC-2017-ADG,E-T1IFNs(2018), European Project: 714472,ERC-2016-STG,Mitomorphosis(2017), European Project: 892311,H2020-MSCA-IF-2019,MitoFeron(2020), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris]-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Lemesle, Marie, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Elaboration of the type I interferonopathies - E-T1IFNs - - ERC-2017-ADG2018-11-01 - 2023-10-31 - 786142 - VALID, Metabolic regulation of mitochondrial morphology - Mitomorphosis - - ERC-2016-STG2017-04-01 - 2022-03-31 - 714472 - VALID, and Mitochondrial integrity and autoinflammation - MitoFeron - - H2020-MSCA-IF-20192020-07-01 - 2022-06-30 - 892311 - VALID
Subjects: Mitochondrial DNA, Mitochondrial Diseases, RNA, Mitochondrial, Mini Review, Mitochondrial disease, Immunology, Autoimmunity, Mitochondrion, Biology, DNA, Mitochondrial, 03 medical and health sciences, 0302 clinical medicine, Mitophagy, medicine, Animals, Humans, Immunology and Allergy, innate immunity MINI REVIEW, Inner mitochondrial membrane, Gene, innate immunity, 030304 developmental biology, 0303 health sciences, mtDNA, RNA, type I interferonopathy, RC581-607, autoinflammation, medicine.disease, Immunity, Innate, Up-Regulation, 3. Good health, Cell biology, mitochondria, mitochondrial disease, mtRNA, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Nucleic acid, type I interferon, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Interferons, Immunologic diseases. Allergy, 030217 neurology & neurosurgery, Signal Transduction
Abstract: International audience; The immune response to viral infection involves the recognition of pathogen-derived nucleic acids by intracellular sensors, leading to type I interferon (IFN), and downstream IFN-stimulated gene, induction. Ineffective discrimination of self from non-self nucleic acid can lead to autoinflammation, a phenomenon implicated in an increasing number of disease states, and well highlighted by the group of rare genetic disorders referred to as the type I interferonopathies. To understand the pathogenesis of these monogenic disorders, and polyfactorial diseases associated with pathogenic IFN upregulation, such as systemic lupus erythematosus and dermatomyositis, it is important to define the self-derived nucleic acid species responsible for such abnormal IFN induction. Recently, attention has focused on mitochondria as a novel source of immunogenic self nucleic acid. Best appreciated for their function in oxidative phosphorylation, metabolism and apoptosis, mitochondria are double membrane-bound organelles that represent vestigial bacteria in the cytosol of eukaryotic cells, containing their own DNA and RNA enclosed within the inner mitochondrial membrane. There is increasing recognition that a loss of mitochondrial integrity and compartmentalization can allow the release of mitochondrial nucleic acid into the cytosol, leading to IFN induction. Here, we provide recent insights into the potential of mitochondrial-derived DNA and RNA to drive IFN production in Mendelian disease. Specifically, we summarize current understanding of how nucleic acids are detected as foreign when released into the cytosol, and then consider the findings implicating mitochondrial nucleic acid in type I interferonopathy disease states. Finally, we discuss the potential for IFN-driven pathology in primary mitochondrial disorders.
Published: 2021

27. Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A

Author: Stéphanie Chhun, Yanick J. Crow, Henna Tyynismaa, Bert Callewaert, Gillian I. Rice, Manju A Kurian, Christine Bodemer, Edwin Carter, Lien De Somer, Luis Seabra, Simon Holden, Hugh J. McMillan, Brigitte Bader-Meunier, Kristin Suetens, Timothy Wai, Lucy Grove, Sylvie Fraitag, Erika Della Mina, Ashish Dhir, Fran Faes, Marie Hully, Mathieu P Rodero, Pascale de Lonlay, Marie-Louise Frémond, Alice Lepelley, Daniela Buhas, David A. Dyment, Carine Wouters, Erika Van Nieuwenhove, Lise Waumans, STEMM - Stem Cells and Metabolism Research Program, Centre of Excellence in Stem Cell Metabolism, Staff Services, Henna Tyynismaa / Principal Investigator, Neuroscience Center, Helsinki Institute of Life Science HiLIFE, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre national de Référence (CNR) des Hantavirus [UZ Leuven, Belgium], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Manchester [Manchester], University of Edinburgh, McGill University Health Center [Montreal] (MUHC), McGill University = Université McGill [Montréal, Canada], Ghent University Hospital, 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 (UPC), Children's Hospital of Eastern Ontario [Ottawa, Canada], West Suffolk Hospital Foundation Trust [Bury St Edmunds, UK] (WSHFT), Addenbrooke's Hospital, Cambridge University NHS Trust, University College of London [London] (UCL), University of Ottawa [Ottawa], University of Helsinki, Université Paris Descartes - Paris 5 (UPD5), Biologie mitochondriale – Mitochondrial biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Y.J. Crow acknowledges that this project has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement 786142), a state subsidy managed by the National Research Agency (France) under the 'Investments for the Future' program bearing the reference ANR-10-IAHU-01, and the National Institute for Health Research UK Rare Genetic Disease Research Consortium. The project was supported by MSDAVENIR (Devo-Decode Project). E. Van Nieuwenhove acknowledges the Research Foundation Flanders (Fonds voor Wetenschappelijk Onderzoek Vlaanderen, grant 1S22716N). B. Callewaert is a Senior Clinical Investigator of the Research Foundation Flanders. Ghent University Hospital, University Hospital Leuven, and Hôpital Universitaire, ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 786142,ERC-2017-ADG,E-T1IFNs(2018), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris]-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Lepelley, alice, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, and Elaboration of the type I interferonopathies - E-T1IFNs - - ERC-2017-ADG2018-11-01 - 2023-10-31 - 786142 - VALID
Subjects: Male, MITOCHONDRIAL-DNA, THP-1 Cells, [SDV]Life Sciences [q-bio], medicine.disease_cause, DNA, Mitochondrial/genetics, 0302 clinical medicine, Interferon, DUPLICATIONS, Medicine and Health Sciences, Immunology and Allergy, Child, Genes, Dominant, AICARDI-GOUTIERES SYNDROME, 0303 health sciences, Mutation, Gene knockdown, I INTERFERON, MEMBRANE-PROTEIN, CHOLESTEROL, INDUCTION, Scleroderma, Systemic/genetics, Nucleotidyltransferases, 3. Good health, [SDV] Life Sciences [q-bio], Stimulator of interferon genes, Child, Preschool, Mitochondrial Proteins/genetics, Female, Signal transduction, RNASEH2B, medicine.drug, RECURRENT DE-NOVO, Signal Transduction, Mitochondrial DNA, Interferons/genetics, Mitochondrial disease, Immunology, Biology, DNA, Mitochondrial, ATPases Associated with Diverse Cellular Activities/genetics, Mitochondrial Proteins, 03 medical and health sciences, Young Adult, medicine, Humans, Membrane Proteins/genetics, Gene, 030304 developmental biology, Scleroderma, Systemic, Membrane Proteins, medicine.disease, Molecular biology, DYSFUNCTION, Nucleotidyltransferases/genetics, ATPases Associated with Diverse Cellular Activities, Interferons, 3111 Biomedicine, 030217 neurology & neurosurgery
Abstract: Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up-regulated ISG expression and interferon α protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy. ispartof: JOURNAL OF EXPERIMENTAL MEDICINE vol:218 issue:10 ispartof: location:United States status: published
Published: 2021

28. Cerebrospinal fluid neopterin as a biomarker of treatment response to Janus kinase inhibition in Aicardi-Goutières syndrome

Author: Velda X Han, Shekeeb S. Mohammad, Russell C. Dale, Hannah F Jones, Sushil Bandodkar, and Yanick J. Crow
Subjects: Male, medicine.medical_specialty, Treatment response, Adolescent, Nervous System Malformations, Gastroenterology, Neopterin, chemistry.chemical_compound, Cerebrospinal fluid, Autoimmune Diseases of the Nervous System, Developmental Neuroscience, Interferon, Internal medicine, Medicine, Humans, Janus Kinase Inhibitors, Child, Retrospective Studies, business.industry, Janus Kinase 1, medicine.disease, Treatment efficacy, chemistry, Child, Preschool, Pediatrics, Perinatology and Child Health, Biomarker (medicine), Aicardi–Goutières syndrome, Female, Neurology (clinical), business, Janus kinase, Biomarkers, medicine.drug
Abstract: Janus kinase (JAK) 1 inhibition represents a precision medicine approach in the treatment of Aicardi-Goutieres syndrome (AGS), through targeting of type I interferon-mediated cell signalling. Blood interferon mRNAseq has been proposed as a biomarker of disease with utility in therapeutic monitoring. Objective cerebrospinal fluid (CSF) biomarkers tracking treatment efficacy are currently lacking. Here, we report a retrospective case series of 13 patients (median age 6y, range 2y 6mo-17y; five females, eight males) with AGS demonstrating significantly elevated CSF neopterin levels at first sampling (median 200nmol/L, range 45-2024nmol/L), compared to 13 age-matched controls with non-inflammatory neurological conditions (median 23nmol/L, range 5-34nmol/L, p
Published: 2021

29. Opsoclonus-myoclonus in Aicardi-Goutières syndrome

Author: Cynthia Sharpe, Odile Boespflug-Tanguy, Isabelle Melki, Russell C. Dale, Domitille Gras, Hannah F Jones, Salam Alburaiky, Evangeline Wassmer, Yanick J. Crow, and Jeremy Do Cao
Subjects: Male, congenital, hereditary, and neonatal diseases and abnormalities, 030506 rehabilitation, Context (language use), Nervous System Malformations, Irritability, medicine.disease_cause, Neopterin, Pathogenesis, 03 medical and health sciences, Autoimmune Diseases of the Nervous System, 0302 clinical medicine, Developmental Neuroscience, mental disorders, medicine, Humans, Opsoclonus-Myoclonus Syndrome, business.industry, Brain, Infant, Opsoclonus, Immune dysregulation, medicine.disease, Magnetic Resonance Imaging, White Matter, nervous system diseases, Pediatrics, Perinatology and Child Health, Immunology, Aicardi–Goutières syndrome, Female, Neurology (clinical), medicine.symptom, 0305 other medical science, business, Developmental regression, Myoclonus, Biomarkers, 030217 neurology & neurosurgery
Abstract: Aicardi-Goutières syndrome (AGS) is a rare genetic neuroinflammatory disorder caused by abnormal upregulation of type 1 interferon signalling. Opsoclonus-myoclonus syndrome is a rare autoimmune phenotype demonstrating a disturbance in the humoral immune response mostly seen in the context of paraneoplastic or postinfectious states, although its pathophysiology is incompletely understood. We report the first three children described with AGS demonstrating transient opsoclonus and myoclonus after irritability and/or developmental regression, suggesting a pathological association. We describe the presentation, clinical features, progress, cerebrospinal fluid (CSF) inflammatory markers, electroencephalogram (EEG), and magnetic resonance imaging (MRI) findings in these children. Two patients had developmental regression but demonstrated a positive response to JAK1/2 inhibition clinically and on serial examination of CSF inflammatory markers. These findings suggest that AGS should be considered in children presenting with opsoclonus-myoclonus, and that the association between AGS and opsoclonus-myoclonus further supports the role of immune dysregulation as causal in the rare neurological phenomenon opsoclonus and myoclonus. What this paper adds There is a phenotypic association between opsoclonus-myoclonus syndrome and Aicardi-Goutières syndrome. There is clinical evidence of immune dysregulation in the pathogenesis of opsoclonus and myoclonus.
Published: 2021

30. Novel compound heterozygous STN1 variants are associated with Coats Plus syndrome

Author: Angharad Walters, Shilpa Dugar, Helen V. Firth, Luis Seabra, Tanvi Acharya, Yanick J. Crow, Tassos Grammatikopoulos, Alasdair Parker, Acharya, Tanvi [0000-0003-0330-6585], and Apollo - University of Cambridge Repository
Subjects: Male, Models, Molecular, 0301 basic medicine, Pathology, leukodystrophy, Protein Conformation, DNA Mutational Analysis, 030105 genetics & heredity, QH426-470, Compound heterozygosity, medicine.disease_cause, Leukoencephalopathies, Medicine, Coats' disease, Central Nervous System Cysts, Child, Genetics (clinical), CLINICAL REPORTS, Mutation, Gastrointestinal tract, Brain Neoplasms, stn1, coats plus, Calcinosis, Phenotype, Pancytopenia, Retinal telangiectasia, Muscle Spasticity, CLINICAL REPORT, Heterozygote, medicine.medical_specialty, Telomere-Binding Proteins, Neuroimaging, Structure-Activity Relationship, 03 medical and health sciences, Retinal Diseases, Seizures, Genetics, Humans, Genetic Predisposition to Disease, Molecular Biology, Alleles, Genetic Association Studies, business.industry, Leukodystrophy, medicine.disease, 030104 developmental biology, Ataxia, Tomography, X-Ray Computed, business, Magnetic Resonance Angiography
Abstract: Funder: Wellcome, Aim: Coats plus syndrome (CP) is a rare autosomal recessive disorder, characterised by retinal telangiectasia exudates (Coats disease), leukodystrophy, distinctive intracranial calcification and cysts, as well as extra‐neurological features including abnormal vasculature of the gastrointestinal tract, portal hypertension and osteopenia with a tendency to fractures. CP most frequently occurs due to loss‐of‐function mutations in CTC1. The encoded protein CTC1 constitutes part of the CST (CTC1‐STN1‐TEN1) complex, and three patients have been described with CP due to biallelic mutations in STN1. Together with the identification of homozygosity for a specific loss‐of‐function mutation in POT1 in a sibling pair, these observations highlight a defect in the maintenance of telomere integrity as the cause of CP, although the precise mechanism leading to the micro‐vasculopathy seen at a pathological level remains unclear. Here, we present the investigation of a fourth child who presented to us with retinal exudates, intracranial calcifications and developmental delay, in keeping with a diagnosis of CP, and later went on to develop pancytopenia and gastrointestinal bleeding. Genome sequencing revealed compound heterozygous variants in STN1 as the likely genetic cause of CP in this present case. Methods: We assessed the phenotype to be CP and undertook targeted sequencing. Results: Whilst sequencing of CTC1 and POT1 was normal, we identified novel compound heterozygous variants in STN1 (previous gene symbol OBFC1): one loss‐of‐function––c.894dup (p.(Asp299Argfs*58)); and one missense––c.707T>C (p.(Leu236Pro)). Conclusion: Given the clinical phenotype and identified variants we suggest that this is only the fourth patient reported to date with CP due to mutations in STN1.
Published: 2021

31. Apparent Radiological Improvement in an Infant With Labrune Syndrome Treated With Bevacizumab

Author: Juan Antonio Cerón, Ana Victoria Marco-Hernández, Yanick J. Crow, Francisco Martínez-Castellano, Jesús José Ferre-Fernández, Laia Pedrola, Miguel Tomás-Vila, Marina Martinez-Matilla, and María José Aparisi
Subjects: calcification and cysts, medicine.medical_specialty, Bevacizumab, business.industry, Infant, Leukoencephalopathy with intracranial, Labrune Syndrome, SNORD118, Developmental Neuroscience, Neurology, Radiological weapon, Pediatrics, Perinatology and Child Health, medicine, Neurology (clinical), Radiology, business, medicine.drug
Published: 2020

32. Use of ruxolitinib in COPA syndrome manifesting as life-threatening alveolar haemorrhage

Author: Yanick J. Crow, Hugues Begueret, Serge Amselem, Hubert Ducou Le Pointe, Michael Fayon, Marie-Louise Frémond, Gillian I. Rice, Nadia Nathan, Darragh Duffy, Emilie Filhol-Blin, Laura Berdah, Nicolas Richard, Vincent Bondet, Chiara Sileo, Annick Clement, Marie Legendre, Aurore Coulomb, Bénédicte Neven, Sylvie Roullaud, 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 Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier d'Angoulême (CH Angoulême), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Immunobiologie des Cellules dendritiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], 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), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Edinburgh, 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), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des maladies génétiques d'expression pédiatrique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Hospitalier d'Angoulême, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Service de Pneumologie Pédiatrique [CHU Trousseau], Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), and ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016)
Subjects: Lung Diseases, massive haemoptysis, Pulmonary and Respiratory Medicine, Ruxolitinib, Hemosiderosis, paediatric interstitial lung disease, Arthritis, Hemorrhage, Disease, 03 medical and health sciences, 0302 clinical medicine, Interferon, Nitriles, medicine, Humans, 030212 general & internal medicine, Child, rare lung diseases, business.industry, Interstitial lung disease, medicine.disease, 3. Good health, systemic disease and lungs, Pyrimidines, 030228 respiratory system, Pulmonary haemosiderosis, Coatomer, Mutation (genetic algorithm), Immunology, Pyrazoles, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, paediatric lung disaese, business, medicine.drug
Abstract: COPA (coatomer subunit α) syndrome is a newly recognised cause of interstitial lung disease in children and adults, frequently associated with arthritis and renal dysfunction. We report a 11-year-old girl with disease limited to major pulmonary haemosiderosis manifesting at the age of 2 years, due to a heterozygous p.(Arg233His) mutation in COPA. Her interferon (IFN) signature was elevated (10.312 and 12.429, healthy COPA screening. Functional tests can help to personalise patient therapy.
Published: 2019

33. Conséquences pathologiques d’un excès d’interféron in vivo

Author: Yanick J. Crow, Pierre Lebon, Jean-Laurent Casanova, Ion Gresser, Laboratoire de Virologie, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), and University of Edinburgh-Medical Research Council
Subjects: 030203 arthritis & rheumatology, 0301 basic medicine, Gynecology, medicine.medical_specialty, Lupus erythematosus, business.industry, [SDV]Life Sciences [q-bio], General Medicine, medicine.disease, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, In vivo, Interferon, medicine, business, Pathological, medicine.drug
Abstract: International audience; Dans cette brève revue, nous montrons les liens entre les différentes recherches qui ont conduit à la mise en évidence d’un rôle délétère d’un excès d’interféron de type 1, depuis la découverte de son activité antivirale en 1957 par A. Isaacs et J. Lindemann jusqu’au concept d’interféronopathie introduit par Y. Crow en 2011.
Published: 2019

34. DDX58 and Classic Singleton-Merten Syndrome

Author: Carlos Ferreira, Michele Nehrebecky, Yanick J. Crow, Ji Woo Park, Adriana Almeida de Jesus, William A. Gahl, Tracy A Briggs, Sun Hur, Pamela J. Gardner, and Raphaela Goldbach-Mansky
Subjects: 0301 basic medicine, Male, Pathology, Interferonopathy, Lydia Becker Institute, medicine.disease_cause, 0302 clinical medicine, Interferon, Odontodysplasia, Immunology and Allergy, Receptors, Immunologic, Promoter Regions, Genetic, retinoic acid-inducible gene I, Mutation, Middle Aged, Phenotype, Singleton-Merten syndrome, Gain of Function Mutation, Interferon Type I, type I interferon, DEAD Box Protein 58, Original Article, Dental Enamel Hypoplasia, Female, Metacarpus, medicine.drug, Adult, medicine.medical_specialty, Singleton Merten syndrome, Immunology, Aortic Diseases, Cell Line, 03 medical and health sciences, Muscular Diseases, Psoriasis, ResearchInstitutes_Networks_Beacons/lydia_becker_institute_of_immunology_and_inflammation, Arthropathy, medicine, Humans, Vascular Calcification, business.industry, Sequela, medicine.disease, Type I interferon production, 030104 developmental biology, HEK293 Cells, Osteoporosis, business, 030215 immunology
Abstract: Purpose Singleton-Merten syndrome manifests as dental dysplasia, glaucoma, psoriasis, aortic calcification, and skeletal abnormalities including tendon rupture and arthropathy. Pathogenic variants in IFIH1 have previously been associated with the classic Singleton-Merten syndrome, while variants in DDX58 has been described in association with a milder phenotype, which is suggested to have a better prognosis. We studied a family with severe, “classic” Singleton-Merten syndrome. Methods We undertook clinical phenotyping, next-generation sequencing, and functional studies of type I interferon production in patient whole blood and assessed the type I interferon promoter activity in HEK293 cells transfected with wild-type or mutant DDX58 stimulated with Poly I:C. Results We demonstrate a DDX58 autosomal dominant gain-of-function mutation, with constitutive upregulation of type I interferon. Conclusions DDX58 mutations may be associated with the classic features of Singleton-Merten syndrome including dental dysplasia, tendon rupture, and severe cardiac sequela.
Published: 2018

35. DNASE1L3 deficiency, new phenotypes, and evidence for a transient type I IFN signaling

Author: Maud Tusseau, Ema Lovšin, Charlotte Samaille, Rémi Pescarmona, Anne-Laure Mathieu, Maria-Cristina Maggio, Velma Selmanović, Marusa Debeljak, Angelique Dachy, Gregor Novljan, Alexandre Janin, Louis Januel, Jean-Baptiste Gibier, Emilie Chopin, Isabelle Rouvet, David Goncalves, Nicole Fabien, Gillian I Rice, Gaétan Lesca, Audrey Labalme, Paola Romagnani, Thierry Walzer, Sebastien Viel, Magali Perret, Yanick J. Crow, Tadej Avčin, Rolando Cimaz, Alexandre Belot, Tusseau M., Lovsin E., Samaille C., Pescarmona R., Mathieu A.-L., Maggio M. C., Selmanovic V., Debeljak M., Dachy A., Novljan G., Janin A., Januel L., Gibier J.-B., Chopin E., Rouvet I., Goncalves D., Fabien N., Rice G.I., Lesca G., Labalme A., Romagnani P., Walzer T., Viel S., Perret M., Crow Y.J., Avcin T., Cimaz R., and Belot A.
Subjects: Vasculitis, Endodeoxyribonucleases, Immunology, DNA, Inflammatory Bowel Diseases, Lupus Nephritis, Chromatin, ANCA, Apoptosis, DNASE1L3, Interferon-stimulated genes, Nucleic acids, Systemic lupus erythematosus, Type I interferon, Antibodies, Antineutrophil Cytoplasmic, Settore MED/38 - Pediatria Generale E Specialistica, Phenotype, Interferon Type I, Immunology and Allergy, Humans, Lupus Erythematosus, Systemic, Interferons
Abstract: Background: Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3 pathogenic variants have been associated with a lupus phenotype. It is unclear whether interferon signaling is sustained in DNASE1L3 deficiency in humans. Objectives: To explore interferon signaling in DNASE1L3 deficient patients. To depict the characteristic features of DNASE1L3 deficiencies in human. Methods: We identified, characterized, and analyzed five new patients carrying biallelic DNASE1L3 variations. Whole or targeted exome and/or Sanger sequencing was performed to detect pathogenic variations in five juvenile systemic erythematosus lupus (jSLE) patients. We measured interferon-stimulated gene (ISG) expression in all patients. We performed a systematic review of all published cases available from its first description in 2011 to March 24th 2022. Results: We identified five new patients carrying biallelic DNASE1L3 pathogenic variations, including three previously unreported mutations. Contrary to canonical type I interferonopathies, we noticed a transient increase of ISGs in blood, which returned to normal with disease remission. Disease in one patient was characterized by lupus nephritis and skin lesions, while four others exhibited hypocomplementemic urticarial vasculitis syndrome. The fourth patient presented also with early-onset inflammatory bowel disease. Reviewing previous reports, we identified 35 additional patients with DNASE1L3 deficiency which was associated with a significant risk of lupus nephritis and a poor outcome together with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Lung lesions were reported in 6/35 patients. Conclusions: DNASE1L3 deficiencies are associated with a broad phenotype including frequently lupus nephritis and hypocomplementemic urticarial vasculitis with positive ANCA and rarely, alveolar hemorrhages and inflammatory bowel disease. This report shows that interferon production is transient contrary to anomalies of intracellular DNA sensing and signaling observed in Aicardi-Goutières syndrome or STING-associated vasculitis in infancy (SAVI).
Published: 2021

36. Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A

Author: David A. Dyment, Stéphanie Chhun, Carine Wouters, Kristin Suetens, Hugh J. McMillan, Manju A. Kurian, P. de Lonlay, Gillian I. Rice, Bert Callewaert, Lise Waumans, Christine Bodemer, L. De Somer, E. Della Mina, F. Faes, Edwin Carter, S. Holden, Luis Seabra, E. van Nieuwenhove, Brigitte Bader-Meunier, Lucy Grove, Sylvie Fraitag, Yanick J. Crow, Marie-Louise Frémond, Timothy Wai, Ashish Dhir, Marie Hully, Daniela Buhas, Alice Lepelley, Henna Tyynismaa, and Mathieu P Rodero
Subjects: 0303 health sciences, Mitochondrial DNA, Gene knockdown, Mitochondrial disease, Alpha interferon, Biology, medicine.disease, Molecular biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Interferon, Mitochondrial Membrane Protein, Stimulator of interferon genes, medicine, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, medicine.drug
Abstract: Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype, and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A, and recorded up-regulated ISG expression and interferon alpha protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.SummaryDominant-negative mutations in ATAD3A, a ubiquitously expressed mitochondrial protein, cause mitochondrial DNA-dependent up-regulation of type I interferon signaling in the context of neurological disease and autoimmunity, thereby defining a novel type I interferonopathy.
Published: 2021

37. 05 How interferonopathies inform SLE pathogenesis

Author: Yanick J. Crow
Subjects: lcsh:Immunologic diseases. Allergy, Innate immune system, business.industry, Molecular pathology, Context (language use), Disease, medicine.disease_cause, Autoimmunity, Pathogenesis, Immune system, Interferon, Immunology, Medicine, business, lcsh:RC581-607, medicine.drug
Abstract: Type I interferon (IFN) is a potent substance. As such, the induction, transmission and resolution of the type I IFN-mediated immune response are tightly regulated. The type I interferonopathies represent discrete examples of a disturbance of the homeostatic control of this system due to Mendelian mutations, and their molecular definition has the potential to dissect fundamental aspects of IFN control in the human context. Of note, the recognition of type I interferonopathies is becoming of increasing clinical importance as treatment options are developed based on an understanding of disease pathology and innate immune signaling. Definition of the type I interferonopathies indicates that autoinflammation can be both IFN and non-IFN related, and that a primary disturbance of the innate immune system can ‘spill-over’ into autoimmunity in some cases. Indeed, the fact that a number of non-Mendelian disorders, particularly systemic lupus erythematosus (SLE) and dermatomyositis, are also characterized by an upregulation of type I IFN signaling suggests the possibility that insights derived from this work will have relevance to a broader field of clinical medicine. Learning Objectives Describe the phenotypic breadth of the type I interferonopathies Describe the molecular basis of the type I interferonopathies Describe the status of interferon signalling in the type I interferonopathies Describe the clinical link between the type I interferonopathies and SLE Describe the link between the molecular pathology of the type I interferonopathies and SLE
Published: 2021

38. Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients

Author: Olivier Brocq, Pere Soler-Palacín, Jérôme Sirvente, Brigitte Bader-Meunier, Rawane Dagher, Naoki Kitabayashi, Laureline Berteloot, Sophie Willcocks, Nadia Jeremiah, Laura Barnabei, Stefano Volpi, Eline Van Aerde, Sylvain Breton, Damien Chan, Alice Hadchouel, Vincent Bondet, Eric Jeziorski, Despina Moshous, Antonella Insalaco, Jean-Christophe Dubus, Thierry Jo Molina, Isabelle Melki, Nathalie Stremler-Le Bel, Stéphane Blanche, Marie-Anne Morren, Alain Fischer, Mireia Lopez-Corbeto, Gillian I. Rice, Marie-Louise Frémond, Carine Wouters, Yanick J. Crow, Séverine Feuillet-Soummer, Jacques G. Rivière, Françoise Mazingue, Violaine Bresson, Bénédicte Neven, Alexandre Belot, Mathieu Fusaro, Guillaume Thouvenin, Darragh Duffy, Frédéric Rieux-Laucat, Caroline Thumerelle, Luis Seabra, Marco Gattorno, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service d'immuno-hématologie 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), Service de Pneumologie Allergologie [CHU Necker], 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), Service de radiologie pédiatrique [CHU Necker], AP-HP Hôpital universitaire Robert-Debré [Paris], Urgences pédiatriques [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Hospices Civils de Lyon (HCL), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Immunologie Translationnelle - Translational Immunology lab, Hôpital Princesse Grace [Monaco], Women’s and Children’s Hospital [Adelaide], CHU Notre Dame des Secours [Jbeil], Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre chirurgical Marie Lannelongue, CHU Necker - Enfants Malades [AP-HP], IRCCS Istituto Giannina Gaslini [Genoa, Italy], IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Vall d'Hebron University Hospital [Barcelona], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University Hospitals Leuven [Leuven], Lausanne University Hospital, Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Service de Pneumologie pédiatrique [CHU Trousseau], 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), Queensland Children's Hospital, Partenaires INRAE, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Service de pathologie [CHU Necker], Collège de France (CdF (institution)), MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, M.-L. Frémond received a grant from the Institut National de la Santé et de la Recherche Médicale (reference: 000427993). Y. J. Crow acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) 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 (France) (grant CE17001002)., The authors wish to thank the patients and their families for their cooperation in this study. The authors are grateful to Elvira Duchesne (NP) and Samira Plassart (PhD) for their very helpful technical assistance. They thank Thomas Blauwblomme (MD, PhD, Neurosurgery Unit, Necker Hospital, Paris, France) for providing CSF from children with idiopathic hydrocephalus., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Centre Chirurgical Marie Lannelongue (CCML), Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université des Antilles (UA)-Etablissement français du don du sang [Montpellier], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Adult, medicine.medical_specialty, Adolescent, Late onset, Interstitial lung disease, Vasculopathy, Systemic inflammation, Gastroenterology, Nephropathy, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Lymphopenia, medicine, Immunology and Allergy, Humans, 030212 general & internal medicine, Vascular Diseases, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Child, Type I interferonopathy, Immunodeficiency, Inflammation, STING1, JAK inhibitors, business.industry, Infant, Membrane Proteins, medicine.disease, 3. Good health, Polyarthritis, 030228 respiratory system, Failure to thrive, Mutation, Aicardi–Goutières syndrome, medicine.symptom, Stimulator of interferon genes, business, Lung Diseases, Interstitial
Abstract: BACKGROUND: Gain-of-function mutations in STING1 underlie a type I interferonopathy termed SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD).OBJECTIVE: To describe a cohort of patients with SAVI.METHODS: Assessment of clinical, radiological and immunological data from 21 patients (17 families) was carried out.RESULTS: Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most were symptomatic from infancy, but late onset in adulthood occurred in 1 patient. Systemic inflammation, skin vasculopathy, and ILD were observed in 19, 18, and 21 patients, respectively. Extensive tissue loss occurred in 4 patients. Severity of ILD was highly variable with insidious progression up to end-stage respiratory failure reached at teenage in 6 patients. Lung imaging revealed early fibrotic lesions. Failure to thrive was almost constant, with severe growth failure seen in 4 patients. Seven patients presented polyarthritis, and the phenotype in 1 infant mimicked a combined immunodeficiency. Extended features reminiscent of other interferonopathies were also found, including intracranial calcification, glaucoma and glomerular nephropathy. Increased expression of interferon-stimulated genes and interferon α protein was constant. Autoantibodies were frequently found, in particular rheumatoid factor. Most patients presented with a T-cell defect, with low counts of memory CD8+ cells and impaired T-cell proliferation in response to antigens. Long-term follow-up described in 8 children confirmed the clinical benefit of ruxolitinib in SAVI where the treatment was started early in the disease course, underlying the need for early diagnosis. Tolerance was reasonably good.CONCLUSION: The largest worldwide cohort of SAVI patients yet described, illustrates the core features of the disease and extends the clinical and immunological phenotype to include overlap with other monogenic interferonopathies.
Published: 2021

39. Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies

Author: Alice Hadchouel, Odile Boespflug-Tanguy, Eric Jeziorski, Thomas Blauwblomme, Buthaina Al Adba, Alice Lepelley, Isabelle Desguerre, Gillian I. Rice, Edwin Carter, Véronique Hentgen, Christine Bodemer, Lorenzo Lodi, Sandrine Passemard, Yanick J. Crow, Marie Hully, Fanny Mochel, Camille Ducrocq, Magalie Barth, Jay Shetty, Brigitte Bader-Meunier, Isabelle Melki, Florence Renaldo, Vincent Bondet, Miguel Hie, Marie Pouletty, Russell C. Dale, Romain Lévy, Pierre Ellul, Simona Orcesi, Bénédicte Neven, Cécile Dumaine, Luis Seabra, Darragh Duffy, Fabienne Dulieu, Marie-Louise Frémond, Stéphane Blanche, Rainer Seidl, Maria José Martin-Niclos, Pierre Quartier, Laboratory of neurogenetics and neuroinflammation (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), Azienda Ospedaliero Universitaria A. Meyer [Firenze, Italy], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), University of Manchester [Manchester], University of Edinburgh, Sidra Medicine [Doha, Qatar], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie pédiatrique [CHU Necker], Service de dermatologie [CHU Necker], The University of Sydney, Service de neurologie pédiatrique [CHU Necker], Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Pneumologie Allergologie [CHU Necker], Centre Hospitalier de Versailles André Mignot (CHV), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département Pédiatrie [CHRU Montpellier], Pôle Femme Mère Enfant [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Università degli Studi di Pavia = University of Pavia (UNIPV), CHU Trousseau [APHP], Medizinische Universität Wien = Medical University of Vienna, Royal Hospital for Sick Children [Edinburgh], Y.J.C. acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) and a state subsidy managed by the National Research Agency (France) under the ‘Investments for the Future’ programme bearing the reference ANR-10-IAHU-01. The project was supported by MSDAVENIR (Devo-Decode Project). Y.J.C. and D.D. acknowledge the Agence Nationale de la Recherche (grant CE17001002)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), 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), Institut Pasteur [Paris], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Centre National de Référence du Lupus Systémique, Syndrome des Anticorps Anti-phospholipides et Maladies Auto-immunes Systémiques Rares [CHU Pitié Salpêtrière], Service de Médecine Interne 2, maladies auto-immunes et systémiques [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], 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 Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UF Neurométabolique Bioclinique et Génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Pavia, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (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)-CHU Pitié-Salpêtrière [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)-Institut E3M [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Sorbonne Université (SU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Immunology, Central nervous system, Alpha interferon, Aicardi-Goutières syndrome, cerebrospinal fluid, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Medical microbiology, Downregulation and upregulation, systemic lupus erythematosus, Interferon, Humans, Immunology and Allergy, Medicine, Child, Retrospective Studies, business.industry, Infant, Interferon-alpha, medicine.disease, 3. Good health, Hydrocephalus, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, Organ Specificity, Case-Control Studies, Child, Preschool, Interferon Type I, Mutation, Aicardi–Goutières syndrome, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Disease Susceptibility, STING-associated vasculopathy with onset in infancy, business, 030215 immunology, medicine.drug
Abstract: International audience; Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.
Published: 2021

40. Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1

Author: Lucy Bizien, Eystein S. Husebye, Edwin Carter, Maria Pavlova, Jérémie Rosain, Fanny Vuoto, Bénédicte Neven, Thomas DiMaggio, Monica M. Schmitt, Agnès Linglart, Luigi D. Notarangelo, Kai Kisand, Adrian Gervais, Michail S. Lionakis, Mark S. Anderson, Olov Ekwall, Nathalie Cheikh, Sébastien Humbert, Yulia Rodina, Olivier Hermine, Pierre Rohrlich, Lucia Ghizzoni, Romain Lévy, Anya Rothenbuhler, Tom Le Voyer, Paul Bastard, Laurent Abel, Brigite Mignot, Anna-Lena Neehus, Sebastian Ochoa, Steven M. Holland, Helen C. Su, Quentin Philippot, Emmanuelle Jouanguy, Karine Faure, Martin Mcintyre, Mélanie Migaud, Elana Shaw, Maria Kareva, Arthur Pavot, Aurélie Comte, Nelli Y Kann, Elise M. N. Ferré, Anna Shcherbina, Katarina Trebušak Podkrajšek, Alyssa James, Leila S. Sozaeva, Lars Breivik, Yanick J. Crow, Primož Kotnik, Guglielmo Beccuti, Stefan Berg, Nizar Mahlaoui, Tadej Battelino, Gérard Thiriez, Anne Puel, Alain Coaquette, Cécile Goujard, Marie-Louise Frémond, Shen-Ying Zhang, Jean-Laurent Casanova, Lindsey B. Rosen, Peter D. Burbelo, Anna Kolodkina, and Elizaveta Orlova
Subjects: 0301 basic medicine, Male, Autoimmunity, Disease, medicine.disease_cause, Medical and Health Sciences, law.invention, 0302 clinical medicine, law, Immunology and Allergy, 030212 general & internal medicine, Young adult, Child, Polyendocrinopathies, Autoimmune, Lung, education.field_of_study, Middle Aged, Intensive care unit, Infectious Diseases, Autoimmune polyendocrine syndrome, Interferon Type I, Pneumonia & Influenza, Female, Adult, medicine.medical_specialty, Adolescent, Immunology, Population, Innate Immunity and Inflammation, Autoimmune Disease, Infectious Disease and Host Defense, 03 medical and health sciences, Young Adult, Rare Diseases, Clinical Research, Internal medicine, medicine, Humans, education, Autoantibodies, business.industry, SARS-CoV-2, Prevention, Autoantibody, Brief Definitive Report, COVID-19, Pneumonia, medicine.disease, 030104 developmental biology, Polyendocrinopathies, business, Autoimmune
Abstract: Patients with autoimmune polyendocrine syndrome type-1 (APS-1) have circulating auto-Abs neutralizing most type I interferons. These auto-Abs can underlie life-threatening COVID-19 pneumonia in the general population. The authors report 22 APS-1 patients infected with SARS-CoV-2, including 15 (68%) who developed life-threatening disease., Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.
Published: 2021

41. Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum

Author: Calvin Soh, Sophie Calvert, Ram L. Kumar, Isabelle Desguerre, Kevin Talbot, Evangeline Wassmer, Axel Panzer, Andrea Berger, Anna de Burca, Anu Jacob, Andrea Whitney, Andrew P. Badrock, Frances Gibbon, Shelley MacDonald, Rhys H. Thomas, Reza Maroofian, Heather Burnett, Elizabeth Jones, Thomas Blauwblomme, Francois V. Bolduc, Jamal Ghoumid, Mickaël Ferrand, Yanick J. Crow, Emma M. Jenkinson, Camilo Toro, Diana Chiang, Roseline Caumes, Gillian I. Rice, Gemma Fisher, Gopinath M. Subramanian, Edoardo Monfrini, Renaud Touraine, Hilde T. Hilmarsen, Sarju G. Mehta, Imelda Hughes, Sumit Parikh, Edward Blair, Mary O'Driscoll, Sarah Dyack, Himanshu Goel, Kristin W. Barañano, Prab Prabhakar, Luis Seabra, Roberta Battini, John H. Livingston, Russell P. Saneto, Richard J. Leventer, Katrin Õunap, Heather Marshall, Andy Cheuk Him Ng, Duccio Maria Cordelli, Natasha Demic, Daniela Neumann, Natalie Boddaert, Michael J. Noetzel, S. Richard Dunham, Ehsan Ghayoor Karimiani, Johannes A. Buckard, Frances Elmslie, Raymond T. O'Keefe, Chloe A Stutterd, Richard Sandford, Imke Metz, Francis Ramond, Liesbeth De Waele, Alessio Di Fonzo, Emma Wakeling, David B. Clifford, Crow Y.J., Marshall H., Rice G.I., Seabra L., Jenkinson E.M., Baranano K., Battini R., Berger A., Blair E., Blauwblomme T., Bolduc F., Boddaert N., Buckard J., Burnett H., Calvert S., Caumes R., Ng A.C.-H., Chiang D., Clifford D.B., Cordelli D.M., de Burca A., Demic N., Desguerre I., De Waele L., Di Fonzo A., Dunham S.R., Dyack S., Elmslie F., Ferrand M., Fisher G., Karimiani E.G., Ghoumid J., Gibbon F., Goel H., Hilmarsen H.T., Hughes I., Jacob A., Jones E.A., Kumar R., Leventer R.J., MacDonald S., Maroofian R., Mehta S.G., Metz I., Monfrini E., Neumann D., Noetzel M., O'Driscoll M., Ounap K., Panzer A., Parikh S., Prabhakar P., Ramond F., Sandford R., Saneto R., Soh C., Stutterd C.A., Subramanian G.M., Talbot K., Thomas R.H., Toro C., Touraine R., Wakeling E., Wassmer E., Whitney A., Livingston J.H., O'Keefe R.T., and Badrock A.P.
Subjects: Male, 0301 basic medicine, Proband, 030105 genetics & heredity, Gene mutation, ribosomopathy, Compound heterozygosity, Genetic analysis, Loss of heterozygosity, Leukoencephalopathy, Consanguinity, Leukoencephalopathies, Pathology, Molecular, Child, Zebrafish, Genetics (clinical), Genetics, Molecular pathology, C/D box snoRNA U8, coats plus, Labrune syndrome, leukoencephalopathy with calcifications and cysts, SNORD118, Calcinosis, Middle Aged, 3. Good health, Child, Preschool, Female, Adult, Heterozygote, Adolescent, coats plu, Biology, Young Adult, 03 medical and health sciences, medicine, Animals, Humans, RNA, Small Nucleolar, Genetic Association Studies, Aged, leukoencephalopathy with calcifications and cyst, Infant, Newborn, Infant, medicine.disease, Disease Models, Animal, 030104 developmental biology
Abstract: Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.
Published: 2021

42. cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing

Author: Jennifer Doig, Hélio van der Linden, Ram Kumar, Waad Albawardi, Mathieu P Rodero, Caroline A Salmon, Angus Dobbie, Hilde Van Esch, Marie Vermelle, Cristina Cereda, Nick Gilbert, Marine Depp, Andrew P. Jackson, Kevin Rostasy, Robert Olaso, Jean-François Deleuze, Luis Seabra, Frances Elmslie, Davide Tonduti, Diane Doummar, Somdutta Dhir, Duncan Sproul, Alice Lepelley, John H. Livingston, Kate Webb, Yanick J. Crow, Alejandro Rubio-Roldan, Marie-Louise Frémond, Christiaan Scott, Simona Orcesi, Ashish Dhir, Sylviane Peudenier, Guy Touati, Anirban Majumdar, Kate Lamb, Jose L. Garcia-Perez, Vanessa Cavallera, Liesbeth De Waele, Maria José Martin-Niclos, Julien Baruteau, Marie-Thérèse El-Daher, Jonny Hertzog, Jonathan Buckley, Martin A M Reijns, Charles Marques Lorenço, Erika Della Mina, Marialuisa Valente, Karine Brochard, Anne Boland-Auge, Andrew P. Badrock, Ann P. Wheeler, Natalie F. Blair, Carolina Uggenti, Gillian I. Rice, Margarete Koch-Hogrebe, Jan Rehwinkel, University of Edinburgh, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Manchester [Manchester], Centre for Genomics and Oncological Research Pfizer [Granada, Spain], Universidad de Granada = University of Granada (UGR)-Andalusian Regional Government [Granada, Spain], University of Oxford, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Saclay, University College of London [London] (UCL), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), University of Cape Town, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), University Hospitals Leuven [Leuven], Chapel Allerton Hospital, Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of London [London], Witten/Herdecke University, Alder Hey Children's Hospital, Gloucestershire Hospitals, Partenaires INRAE, Leeds Teaching Hospitals NHS Trust, Bristol Royal Hospital for Children, Università degli Studi di Pavia = University of Pavia (UNIPV), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Royal Surrey County Hospital (ROYAL SURREY COUNTY HOSPITAL), Royal Surrey County Hospital, Children's Hospital 'V. Buzzi' [Milan, Italy], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), CH Dunkerque, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Granada [Granada]-Andalusian Regional Government [Granada, Spain], University of Oxford [Oxford], Hôpital des Enfants, CHU Toulouse [Toulouse], and University of Pavia
Subjects: [SDV]Life Sciences [q-bio], Guanosine, Nervous System Malformations, Cell Line, Histones, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Autoimmune Diseases of the Nervous System, Interferon, medicine, RNA Precursors, Genetics, Humans, Gene, 030304 developmental biology, Ribonucleoprotein, 0303 health sciences, biology, ATP synthase, Ribonucleoprotein, U7 Small Nuclear, HEK 293 cells, Hereditary Autoinflammatory Diseases, Membrane Proteins, RNA-Binding Proteins, DNA, HCT116 Cells, Nucleotidyltransferases, Chromatin, 3. Good health, Cell biology, Histone, HEK293 Cells, chemistry, Gene Expression Regulation, Interferon Type I, biology.protein, Nucleotides, Cyclic, 030217 neurology & neurosurgery, medicine.drug
Abstract: International audience; Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.
Published: 2020

43. Expanding the clinical spectrum of Fowler syndrome: Three siblings with survival into adulthood and systematic review of the literature

Author: Martin Lammens, Hilde Van Esch, Anne Rochtus, Gillian I. Rice, Paul De Cock, Chiara De Luca, Mathieu P Rodero, Melek Ahmed, Lieven Lagae, Yanick J. Crow, 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), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes - Paris 5 (UPD5), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Antwerp University Hospital [Edegem] (UZA), Centre for Human Genetics, University Hospitals Leuven [Leuven], Department of Pediatric Neurology, and University of Leuven Medical School, University Hospitals KULeuven
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, Cerebral calcification, [SDV]Life Sciences [q-bio], Disease, 030105 genetics & heredity, Hydranencephaly, 03 medical and health sciences, Neuroimaging, Genetics, medicine, Humans, Sibling, Genetics (clinical), Genetic Association Studies, ComputingMilieux_MISCELLANEOUS, Fetus, Neovascularization, Pathologic, business.industry, Fowler syndrome, Brain, Membrane Transport Proteins, medicine.disease, Phenotype, 3. Good health, 030104 developmental biology, Mutation, Receptors, Virus, Human medicine, business, Ventriculomegaly
Abstract: Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH, OMIM 225790), also known as Fowler syndrome, is a rare autosomal recessive disorder of brain angiogenesis. PVHH has long been considered to be prenatally lethal. We evaluated the phenotypes of the first three siblings with survival into adulthood, performed a systematic review of the Fowler syndrome literature and delineated genotype-phenotype correlations using a scoring system to rate the severity of the disease. Thirty articles were included, describing 69 individual patients. To date, including our clinical reports, 72 patients have been described with Fowler syndrome. Only 6/72 (8%) survived beyond birth. Although our three patients carry the same mutations (c.327T>A-p.Asn109Lys and c.887C>T-p.Ser296Leu) in FLVCR2, only two of them presented with the same cerebral features, ventriculomegaly and cerebral calcifications, as affected fetuses. The third sibling has a surprisingly milder clinical and radiological phenotype, suggesting intrafamilial variability. Although no clear phenotype-genotype correlation exists, some variants appear to be associated with a less severe phenotype compatible with life. As such, it is important to consider Fowler syndrome in patients with gross ventriculomegaly, cortical malformations and/or cerebral calcifications on brain imaging.
Published: 2020

44. Elevated antiviral, myeloid and endothelial inflammatory markers in severe COVID-19

Author: Graham P. Taylor, Ashley Sanchez Sevilla Uruchurtu, Malcolm G Semple, Felicity Liew, Thilipan Thaventhiran, Emma Bergstrom, Shona C Moore, Clark D Russell, Charlotte-Eve Short, Peter J. M. Openshaw, Yanick J. Crow, Matthew K. Siggins, Annemarie B Docherty, David M. Hunt, Simon T. Abrams, Ewen M Harrison, Stephanie Ascough, Christopher Chiu, J Kenneth Baillie, Zoe Gardener, Edwin Carter, Tom Solomon, Ryan S Thwaites, and Lance Turtle
Subjects: Innate immune system, Myeloid, Coronavirus disease 2019 (COVID-19), business.industry, medicine.medical_treatment, Lung injury, Proinflammatory cytokine, Endothelial stem cell, Cytokine, medicine.anatomical_structure, Immunology, medicine, CXCL10, business
Abstract: Introductory paragraphThe mechanisms that underpin COVID-19 disease severity, and determine the outcome of infection, are only beginning to be unraveled. The host inflammatory response contributes to lung injury, but circulating mediators levels fall below those in classical ‘cytokine storms’. We analyzed serial plasma samples from 619 patients hospitalized with COVID-19 recruited through the prospective multicenter ISARIC clinical characterization protocol U.K. study and 39 milder community cases not requiring hospitalization. Elevated levels of numerous mediators including angiopoietin-2, CXCL10, and GM-CSF were seen at recruitment in patients who later died. Markers of endothelial injury (angiopoietin-2 and von-Willebrand factor A2) were detected early in some patients, while inflammatory cytokines and markers of lung injury persisted for several weeks in fatal COVID-19 despite decreasing antiviral cytokine levels. Overall, markers of myeloid or endothelial cell activation were associated with severe, progressive, and fatal disease indicating a central role for innate immune activation and vascular inflammation in COVID-19.
Published: 2020

45. Cerebral Microangiopathy in Leukoencephalopathy With Cerebral Calcifications and Cysts: A Pathological Description

Author: John R. Cottrell, Sarah Woidill, Angela N. Viaene, Asako Takanohashi, Adeline Vanderver, Marianna Bugiani, Cas Simons, Rebecca Berger, Marjolein Breur, Guy Helman, Yanick J. Crow, Raphael Schiffmann, VU University medical center, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Pathology, and Pediatric surgery
Subjects: 0301 basic medicine, Male, Pathology, medicine.medical_specialty, Proteolipid protein 1, Adolescent, H&E stain, Autopsy, Luxol fast blue stain, Leukoencephalopathy, White matter, 03 medical and health sciences, 0302 clinical medicine, Fatal Outcome, Leukoencephalopathies, medicine, Van Gieson's stain, Humans, Central Nervous System Cysts, Child, Glial fibrillary acidic protein, biology, business.industry, Brain, Calcinosis, medicine.disease, Magnetic Resonance Imaging, 030104 developmental biology, medicine.anatomical_structure, Cerebral Small Vessel Diseases, Pediatrics, Perinatology and Child Health, biology.protein, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Leukoencephalopathy with calcifications and cysts (LCC) is a neurological syndrome recently associated with pathogenic variants in SNORD118. We report autopsy neuropathological findings from an individual with genetically confirmed LCC. Histologic studies included staining of formalin-fixed paraffin-embedded tissue sections by hematoxylin and eosin, elastic van Gieson, and luxol fast blue. Immunohistochemistry stains against glial fibrillary acidic protein, proteolipid protein, phosphorylated neurofilament, CD31, alpha-interferon, LN3, and inflammatory markers were performed. Gross examination revealed dark tan/gray appearing white matter with widespread calcifications. Microscopy revealed a diffuse destructive process due to a vasculopathy with secondary ischemic lesions and mineralization. The vasculopathy involved clustered small vessels, resembling vascular malformations, and sporadic lymphocytic infiltration of vessel walls. The white matter was also diffusely abnormal, with concurrent loss of myelin and axons, tissue rarefaction with multifocal cystic degeneration, and the presence of foamy macrophages, secondary calcifications, and astrogliosis. The midbrain, pons, and cerebellum were diffusely involved. It is not understood why variants in SNORD118 result in a disorder that predominantly causes neurological disease and significantly disrupts the cerebral vasculature. Clinical and radiological benefit was recently reported in an LCC patient treated with Bevacizumab; it is important that these patients are rapidly diagnosed and trial of this treatment modality is considered in appropriate circumstances.
Published: 2020

46. Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling

Author: Florence Uettwiller, Makoto Miyara, François-Jérôme Authier, Maria José Martin-Niclos, Pierre Quartier, Alice Lepelley, Nicole Fabien, Alexandre Belot, Yanick J. Crow, Alice Hadchouel, Isabelle Melki, Emmanuelle Bourrat, Albert Faye, Darragh Duffy, Theresa Kwon, Brigitte Bader-Meunier, Carolina Uggenti, Sasi Mudumba, Lucile Musset, Gillian I. Rice, Vincent Bondet, Jean-Luc Charuel, Cyril Gitiaux, Naoki Kitabayashi, Cécile Dumaine, Marie-Louise Frémond, Christine Bodemer, Luis Seabra, Sébastien Viel, Plamen Bokov, Mathieu P Rodero, Yves Allenbach, Hervé Devilliers, Ahmed Kheniche, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de référence des rhumatismes inflammatoires et maladies autoimmunes systémiques rares de l'enfant [Paris] (RAISE), AP-HP Hôpital universitaire Robert-Debré [Paris], Service de médecine interne et maladies systémiques (SOC 2) [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Necker - Enfants Malades [AP-HP], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie Translationnelle - Translational Immunology, Institut Pasteur [Paris], Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Pédiatrique des Pathologies du Sommeil [AP-HP Hôpital Robert Debré], Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Médecine Interne (SOC 1 et SOC 2) [CHU de Dijon], Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), CHU Henri Mondor, Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Centre de référence national des Maladies Génétiques à Expression Cutanée (MAGEC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), 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, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University of Edinburgh, Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes - Paris 5 (UPD5), Y.J.C. and D.D. acknowledge support from the ANR (CE17001002) and thank Immunoqure for provision of mAbs for the Simoa assay. I.M. acknowledges support from the Bettencourt Schueler foundation through the Programme Santé-Sciences MD/PhD of Imagine Institute. F.-J.A. and C.G. acknowledge support from the AFM (CE17001002), The work was previously presented at PReS meeting 2018 (O18) and GCOM 2019 (O20), ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche en Myologie, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Henri Mondor [Créteil], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence national des Maladies Génétiques à Expression Cutanée - National Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], École normale supérieure - Lyon (ENS 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)-École normale supérieure - Lyon (ENS 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), Vougny, Marie-Christine, and Investigation des interferonopathies type I humaine - - IFNX2016 - ANR-16-CE17-0010 - AAPG2016 - VALID
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Interferon-Induced Helicase, IFIH1, [SDV.IMM] Life Sciences [q-bio]/Immunology, Adolescent, anti-MDA5 autoantibodies, [SDV]Life Sciences [q-bio], Arthritis, Alpha interferon, Gastroenterology, 03 medical and health sciences, Simoa, 0302 clinical medicine, Rheumatology, Internal medicine, medicine, Humans, interferon alpha, Pharmacology (medical), Prospective Studies, Child, Muscle, Skeletal, Myositis, ComputingMilieux_MISCELLANEOUS, Autoantibodies, Retrospective Studies, 030203 arthritis & rheumatology, Systemic lupus erythematosus, business.industry, interstitial lung disease (ILD), Autoantibody, Interstitial lung disease, Interferon-alpha, Skin ulcer, medicine.disease, 3. Good health, 030104 developmental biology, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, juvenile idiopathic inflammatory myopathies (JIIM), medicine.symptom, business, Signal Transduction
Abstract: Objectives JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2). Methods This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes. Results Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported. Conclusion This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target.
Published: 2020

47. Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling

Author: Nicolas Manel, Siham Boulisfane-El Khalifi, Mary Brennan, Darragh Duffy, Nadia Nathan, Serge Amselem, Kathryn J. McKenzie, Maria José Martin-Niclos, Jonny Hertzog, Carolina Uggenti, Marie Legendre, Stéphanie Chhun, Caroline Thumerelle, Luis Seabra, Marie-Louise Frémond, Vincent Bondet, Bénédicte Neven, Joseph A. Marsh, Marie Wislez, Catherine McDougall, Marine Depp, Jan Rehwinkel, Gillian I. Rice, Aurore Coulomb L'Hermine, Yanick J. Crow, Lucienne Chatenoud, Melvin Le Bihan, Thierry Jo Molina, Karen J. Mackenzie, Alice Lepelley, Edwin Carter, Jonathan Marey, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Radcliffe Department of Medicine [Oxford], University of Oxford [Oxford], Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Royal Hospital for Sick Children [Edinburgh], 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), Service de pathologie [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), Sorbonne Université (SU), Service de pneumologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Royal Infirmary of Edinburgh, Département de Pathologie [CHU Necker], Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-CHU Necker - Enfants Malades [AP-HP], Service d'immuno-hématologie 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), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), M.-L. Frémond received a grant from the Institut National de la Santé et de la Recherche Médicale (000427993) and acknowledges La Fondation Square. Y.J. Crow acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs), and a state subsidy managed by the Agence Nationale de la Recherche under the 'Investments for the Future' program (ANR-10-IAHU-01). Y.J. Crow and D. Duffy acknowledge the Agence Nationale de la Recherche (grant CE17001002). J.A. Marsh is supported by a Medical Research Council Career Development Award (MR/M02122X/1) and is a Lister Institute of Preventive Medicine Research Prize Fellow. N. Manel was supported by LABEX DCBIOL (ANR-10-IDEX-0001-02 PSL* and ANR-11-LABX-0043), ANR-17-CE15-0025-01, ANR-18-CE92-0022-01, Fondation BMS, Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ECTZ71745), Sidaction (VIH2016126002), and Ile-de-France Emergence. M. Le Bihan received a doctoral fellowship from Ile-de-France ARDoc. The project was supported by MSDAVENIR (Devo-Decode Project)., We thank Immunoqure AG for provision of antibodies for the Simoa assay., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-17-CE15-0025,STINGCHECK,Mécanismes des points de contrôle du senseur de l'immunité innée STING(2017), ANR-18-CE92-0022,cGAS-Vac,Analyses fonctionnelles de la voie cGAS/STING au cours d'infections bactériennes et infections virales et implications pour le développement de vaccins innovants(2018), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Oxford, Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), UF de Génétique moléculaire [CHU Trousseau], Service de Pneumologie pédiatrique [CHU Trousseau], Vougny, Marie-Christine, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Mécanismes des points de contrôle du senseur de l'immunité innée STING - - STINGCHECK2017 - ANR-17-CE15-0025 - AAPG2017 - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Analyses fonctionnelles de la voie cGAS/STING au cours d'infections bactériennes et infections virales et implications pour le développement de vaccins innovants - - cGAS-Vac2018 - ANR-18-CE92-0022 - AAPG2018 - VALID, and Definition and characterization of type I interferonopathies - T1-IFN - - EC:FP7:ERC2013-03-01 - 2018-02-28 - 309449 - VALID
Subjects: 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Protein subunit, Immunology, Mutant, Biology, medicine.disease_cause, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Interferon, medicine, Immunology and Allergy, Gene silencing, Mutation, HEK 293 cells, Golgi apparatus, eye diseases, 3. Good health, Cell biology, Sting, 030104 developmental biology, 030220 oncology & carcinogenesis, symbols, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.drug
Abstract: International audience; Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER-Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome.
Published: 2020

48. Cardiac valve involvement in ADAR -related type I interferonopathy

Author: Alessandro Giardini, Jacques Patrick Barbet, Gillian I. Rice, Shamima Rahman, Charlotte Boussard, Cyril Gitiaux, Vincent Bondet, Nathalie Dedieu, Marie Hully, Brigitte Bader-Meunier, Nandaki Keshavan, Yanick J. Crow, Geanina Bercu, Darragh Duffy, Luis Seabra, University of Edinburgh, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Great Ormond Street Hospital for Children [London] (GOSH), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunobiologie des Cellules dendritiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], University of Manchester [Manchester], Rheumatism and autoimmune diseases (RAISE), Mother and Children University Hospital, YJC acknowledges funding from the European Research Council (GA 309449), fellowship and a state subsidy managed by the National Research Agency (ANR, France) under the 'Investments for the Future' (ANR-10-IAHU-01). SR acknowledges funding from the Great Ormond Street Hospital Children’s Charity, the NIHR Great Ormond Street Hospital Biomedical Research Centre and the Lily Foundation., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vougny, Marie-Christine, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, and Definition and characterization of type I interferonopathies - T1-IFN - - EC:FP7:ERC2013-03-01 - 2018-02-28 - 309449 - VALID
Subjects: 0301 basic medicine, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Encephalopathy, Context (language use), Disease, 03 medical and health sciences, 0302 clinical medicine, Aortic valve replacement, Internal medicine, Genetics, Medicine, metabolic disorders, immunology (including allergy), Genetics (clinical), business.industry, medicine.disease, 3. Good health, Stenosis, 030104 developmental biology, cardiovascular medicine, Cardiology, Etiology, cardiovascular system, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, Paraplegia, 030217 neurology & neurosurgery, clinical genetics, Calcification
Abstract: BackgroundAdenosine deaminases acting on RNA (ADAR) mutations cause a spectrum of neurological phenotypes ranging from severe encephalopathy (Aicardi-Goutières syndrome) to isolated spastic paraplegia and are associated with enhanced type I interferon signalling. In children, non-neurological involvement in the type I interferonopathies includes autoimmune and rheumatological phenomena, with calcifying cardiac valve disease only previously reported in the context of MDA5 gain-of-function.ResultsWe describe three patients with biallelic ADAR mutations who developed calcifying cardiac valvular disease in late childhood (9.5–14 years). Echocardiography revealed progressive calcification of the valvular leaflets resulting in valvular stenosis and incompetence. Two patients became symptomatic with biventricular failure after 5–6.5 years. In one case, disease progressed to severe cardiac failure despite maximal medical management, with death occurring at 17 years. Another child received mechanical mitral and aortic valve replacement at 16 years with good postoperative outcome. Histological examination of the affected valves showed fibrosis and calcification.ConclusionsType I interferonopathies of differing genetic aetiology demonstrate an overlapping phenotypic spectrum which includes calcifying cardiac valvular disease. Individuals with ADAR-related type I interferonopathy may develop childhood-onset multivalvular stenosis and incompetence which can progress insidiously to symptomatic, and ultimately fatal, cardiac failure. Regular surveillance echocardiograms are recommended to detect valvular disease early.
Published: 2020

49. Catatonia in a patient with Aicardi-Goutières syndrome efficiently treated with immunoadsorption

Author: Flore Rozenberg, Richard Delorme, Pierre Ellul, Odile Boespflug-Tanguy, Vincent Bondet, Yanick J. Crow, Theresa Kwon, Darragh Duffy, Isabelle Melki, Monique Elmaleh-Bergès, Séverine Drunat, Anaël Ayrolles, Florence Renaldo, Service Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Centre de référence des leucodystrophies et leucoencéphalopathies de cause rare [AP-HP Hôpital Robert-Debré] (LEUKOFRANCE), Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de radiologie pédiatrique [AP-HP Hôpital Robert Debré], 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 Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), 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), MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, Centre de référence des rhumatismes inflammatoires et maladies autoimmunes systémiques rares de l'enfant [Paris] (RAISE), Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], CHU Necker - Enfants Malades [AP-HP], We acknowledge the contribution of the General Paediatrics, Infectious Disease and Internal Medicine Department, the Child and Adolescent Psychiatry Department, the Child Neurology Department, the Pediatric Nephrology Department and the Genetics Department of Robert Debre Hospital. We thank the patient and his family members for allowing us to report the findings of his case., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and 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)
Subjects: Pathology, medicine.medical_specialty, Catatonia, Alpha interferon, Interstitial lung disease, Aicardi-Goutières syndrome, Nervous System Malformations, 03 medical and health sciences, Autoimmune Diseases of the Nervous System, 0302 clinical medicine, medicine, Humans, Immunoadsorption, Biological Psychiatry, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, Interferon-alpha, medicine.disease, 3. Good health, Psychiatry and Mental health, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Aicardi–Goutières syndrome, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, 030217 neurology & neurosurgery
Abstract: International audience; Letter to the Editor
Published: 2020

50. Biallelic mutations in NRROS cause an early onset lethal microgliopathy

Author: Yanick J. Crow, Jeremy Armishaw, Leslie R. Bridges, Anirudh Patir, Barry W. McColl, Colin Smith, Jack Barrington, Antonia Clarke, Vivienne Hobbs, Iona Jeffrey, Luis Seabra, Jenny Eaton, Mathieu P Rodero, John H. Livingston, Melinda Nolan, Gillian I. Rice, Sahar Mansour, Carolina Uggenti, 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), and SW Thames Regional Genetics Service, St Georgeâ™s University of London, London
Subjects: Male, [SDV]Life Sciences [q-bio], MEDLINE, Bioinformatics, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Text mining, Correspondence, Medicine, Animals, Humans, Allele, Age of Onset, ComputingMilieux_MISCELLANEOUS, Alleles, 030304 developmental biology, Early onset, Mice, Knockout, 0303 health sciences, business.industry, Brain, 3. Good health, Pedigree, Latent TGF-beta Binding Proteins, Mutation, Female, Neurology (clinical), Age of onset, business, 030217 neurology & neurosurgery
Abstract: Microglia are tissue-resident macrophages playing essential roles in central nervous system (CNS) development and homeostasis [14, 17]. The importance of microglia for brain health in humans has been highlighted by the definition of Mendelian disorders associated with dysfunction of microglia-related proteins. These so-called microgliopathies [20] comprise a diverse set of neurological phenotypes including disease due to mutations in CSF1R [5, 8, 13], DAP12 and TYROBP/TREM2 [4, 7], USP18 [3, 11, 16, 18], and IRF8 [2, 6]. Here, we describe a novel early onset lethal encephalopathy due to mutations in the microglial-associated protein NRROS.
Published: 2020

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