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

Carolina Uggenti; Alice Lepelley; Marine Depp; Andrew P Badrock; Mathieu P Rodero; Marie-Thérèse El-Daher; Gillian I Rice; Somdutta Dhir; Ann P Wheeler; Ashish Dhir; Waad Albawardi; Marie-Louise Frémond; Luis Seabra; Jennifer Doig; Natalie Blair; Maria José Martin-Niclos; Erika Della Mina; Alejandro Rubio-Roldán; Jose L García-Pérez; Duncan Sproul; Jan Rehwinkel; Jonny Hertzog; Anne Boland-Auge; Robert Olaso; Jean-François Deleuze; Julien Baruteau; Karine Brochard; Jonathan Buckley; Vanessa Cavallera; Cristina Cereda; Liesbeth M H De Waele; Angus Dobbie; Diane Doummar; Frances Elmslie; Margarete Koch-Hogrebe; Ram Kumar; Kate Lamb; John H Livingston; Anirban Majumdar; Charles Marques Lorenço; Simona Orcesi; Sylviane Peudenier; Kevin Rostasy; Caroline A Salmon; Christiaan Scott; Davide Tonduti; Guy Touati; Marialuisa Valente; Hélio van der Linden Jr; Hilde Van Esch; Marie Vermelle; Kate Webb; Andrew P Jackson; Martin A M Reijns; Nick Gilbert; Yanick J Crow

doi:10.1038/s41588-020-00737-3

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. Epub 2020 Nov 23.

Authors

Carolina Uggenti¹, Alice Lepelley^#², Marine Depp^#¹, Andrew P Badrock^#¹, Mathieu P Rodero², Marie-Thérèse El-Daher¹, Gillian I Rice³, Somdutta Dhir¹, Ann P Wheeler⁴, Ashish Dhir¹, Waad Albawardi⁴, Marie-Louise Frémond², Luis Seabra², Jennifer Doig¹, Natalie Blair¹, Maria José Martin-Niclos², Erika Della Mina², Alejandro Rubio-Roldán⁵, Jose L García-Pérez^{4

5}, Duncan Sproul^{4

6}, Jan Rehwinkel⁷, Jonny Hertzog⁷, Anne Boland-Auge⁸, Robert Olaso⁸, Jean-François Deleuze⁸, Julien Baruteau⁹, Karine Brochard¹⁰, Jonathan Buckley¹¹, Vanessa Cavallera¹², Cristina Cereda¹³, Liesbeth M H De Waele¹⁴, Angus Dobbie¹⁵, Diane Doummar¹⁶, Frances Elmslie¹⁷, Margarete Koch-Hogrebe¹⁸, Ram Kumar¹⁹, Kate Lamb²⁰, John H Livingston²¹, Anirban Majumdar²², Charles Marques Lorenço²³, Simona Orcesi^{12

24}, Sylviane Peudenier²⁵, Kevin Rostasy¹⁸, Caroline A Salmon²⁶, Christiaan Scott²⁷, Davide Tonduti²⁸, Guy Touati²⁹, Marialuisa Valente¹³, Hélio van der Linden Jr³⁰, Hilde Van Esch³¹, Marie Vermelle³², Kate Webb²⁷, Andrew P Jackson⁴, Martin A M Reijns⁴, Nick Gilbert⁴, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autoimmune Diseases of the Nervous System / genetics
Autoimmune Diseases of the Nervous System / immunology
Cell Line
Chromatin / metabolism*
DNA / immunology
Gene Expression Regulation / genetics
Gene Expression Regulation / immunology
HCT116 Cells
HEK293 Cells
Hereditary Autoinflammatory Diseases / genetics
Hereditary Autoinflammatory Diseases / immunology
Histones / metabolism*
Humans
Interferon Type I / biosynthesis*
Membrane Proteins / metabolism
Nervous System Malformations / genetics
Nervous System Malformations / immunology
Nucleotides, Cyclic / biosynthesis
Nucleotidyltransferases / metabolism
RNA Precursors / metabolism*
RNA-Binding Proteins / genetics*
Ribonucleoprotein, U7 Small Nuclear / genetics*

Substances

Chromatin
Histones
Interferon Type I
Lsm11 protein, human
Membrane Proteins
Nucleotides, Cyclic
RNA Precursors
RNA-Binding Proteins
Ribonucleoprotein, U7 Small Nuclear
STING1 protein, human
cyclic guanosine monophosphate-adenosine monophosphate
DNA
Nucleotidyltransferases
cGAS protein, human

Supplementary concepts

Aicardi-Goutieres syndrome

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding