2. Academic Validation
  3. cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing

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

  • Nat Genet. 2020 Dec;52(12):1364-1372. doi: 10.1038/s41588-020-00737-3.
Carolina Uggenti 1,  Alice Lepelley # 2,  Marine Depp # 1,  Andrew P Badrock # 1,  Mathieu P Rodero 2,  Marie-Thérèse El-Daher 1,  Gillian I Rice 3,  Somdutta Dhir 1,  Ann P Wheeler 4,  Ashish Dhir 1,  Waad Albawardi 4,  Marie-Louise Frémond 2,  Luis Seabra 2,  Jennifer Doig 1,  Natalie Blair 1,  Maria José Martin-Niclos 2,  Erika Della Mina 2,  Alejandro Rubio-Roldán 5,  Jose L García-Pérez 4 5,  Duncan Sproul 4 6,  Jan Rehwinkel 7,  Jonny Hertzog 7,  Anne Boland-Auge 8,  Robert Olaso 8,  Jean-François Deleuze 8,  Julien Baruteau 9,  Karine Brochard 10,  Jonathan Buckley 11,  Vanessa Cavallera 12,  Cristina Cereda 13,  Liesbeth M H De Waele 14,  Angus Dobbie 15,  Diane Doummar 16,  Frances Elmslie 17,  Margarete Koch-Hogrebe 18,  Ram Kumar 19,  Kate Lamb 20,  John H Livingston 21,  Anirban Majumdar 22,  Charles Marques Lorenço 23,  Simona Orcesi 12 24,  Sylviane Peudenier 25,  Kevin Rostasy 18,  Caroline A Salmon 26,  Christiaan Scott 27,  Davide Tonduti 28,  Guy Touati 29,  Marialuisa Valente 13,  Hélio van der Linden Jr 30,  Hilde Van Esch 31,  Marie Vermelle 32,  Kate Webb 27,  Andrew P Jackson 4,  Martin A M Reijns 4,  Nick Gilbert 4,  Yanick J Crow 33 34
Affiliations

Affiliations

  • 1 Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
  • 2 University of Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, Paris, France.
  • 3 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
  • 4 Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
  • 5 Centre for Genomics and Oncological Research (GENyO), Pfizer-University of Granada-Andalusian Regional Government, Parque Tecnico de la Ciencia de Salud, Granada, Spain.
  • 6 Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
  • 7 Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • 8 Université Paris-Saclay, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Centre National de Recherche en Génomique Humaine, Évry, France.
  • 9 University College London Great Ormond Street Institute of Child Health, London, UK.
  • 10 Service de Médecine Interne Néphrologie Pédiatrique, Hôpital des Enfants, Toulouse, France.
  • 11 Department of Paediatric Nephrology, University of Cape Town, Red Cross War Memorial Children's Hospital, Cape Town, South Africa.
  • 12 Child Neurology and Psychiatry Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Mondino Foundation, Pavia, Italy.
  • 13 Genomic and Post-Genomic Center, Istituto di Ricovero e Cura a Carattere Scientifico, Mondino Foundation, Pavia, Italy.
  • 14 Department of Paediatric Neurology, University Hospitals Leuven, Leuven, Belgium.
  • 15 Yorkshire Clinical Genetics Service, Chapel Allerton Hospital, Leeds, UK.
  • 16 Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Département de Neuropédiatrie, Centre de Référence de Neurogénétique et Mouvements Anormaux de l'Enfant, Hôpital Armand Trousseau, Paris, France.
  • 17 South West Thames Regional Genetics Service, St George's, University of London, London, UK.
  • 18 Department of Paediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, Datteln, Germany.
  • 19 Department of Paediatric Neurology, Alder Hey Children's National Health Service Foundation Trust, Liverpool, UK.
  • 20 Department of Paediatrics, Gloucestershire Royal Hospital, Gloucester, UK.
  • 21 Department of Paediatric Neurology, Leeds Teaching Hospitals National Health Service Trust, Leeds, UK.
  • 22 Department of Paediatric Neurology, Bristol Children's Hospital, Bristol, UK.
  • 23 Faculdade de Medicina - Centro Universitário Estácio de Ribeirão Preto, Ribeirão Preto, Brazil.
  • 24 Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.
  • 25 Centre de Référence des Déficiences Intellectuelles de Causes Rares et Polyhandicap, Centre Hospitalier Régional Universitaire de Brest, Brest, France.
  • 26 Department of Paediatrics, Royal Surrey County Hospital, Guildford, UK.
  • 27 University of Cape Town, Red Cross War Memorial Children's Hospital, Cape Town, South Africa.
  • 28 Center for diagnosis and treatment of Leukodystrophies, Pediatric Neurology Unit, V. Buzzi Children's Hospital, Milano, Italy.
  • 29 Reference Center for Inborn Errors of Metabolism-Department of Pediatrics, Hôpital des Enfants-Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
  • 30 Department of Paediatric Neurology, Neurological Institute of Goiânia, Goiânia, Brazil.
  • 31 Center for Human Genetics, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium.
  • 32 Department of Paediatrics, Centre Hospitalier de Dunkerque, Dunkerque, France.
  • 33 Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK. yanickcrow@mac.com.
  • 34 University of Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, Paris, France. yanickcrow@mac.com.
  • # Contributed equally.
PMID: 33230297 DOI: 10.1038/s41588-020-00737-3
Abstract

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.

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