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
  • 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. [email protected].
  • 34. University of Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, Paris, France. [email protected].
  • # 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.