Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus

Yanick J Crow^1, 2, Bruce E Hayward¹, Rekha Parmar¹, Peter Robins³, Andrea Leitch⁴, Manir Ali¹, Deborah N Black⁵, Hans van Bokhoven⁶, Han G Brunner⁶, Ben C Hamel⁶, Peter C Corry⁷, Frances M Cowan⁸, Suzanne G Frints⁹, Joerg Klepper¹⁰, John H Livingston¹¹, Sally Ann Lynch¹², Roger F Massey¹³, Jean François Meritet¹⁴, Jacques L Michaud¹⁵, Gerard Ponsot¹⁶, Thomas Voit¹⁰, Pierre Lebon¹⁴, David T Bonthron¹, Andrew P Jackson⁴, Deborah E Barnes³ & Tomas Lindahl³

¹  Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK.

²  Department of Paediatrics, St Luke's Hospital, Little Horton Lane, Bradford BD5 0NA, UK.

³  Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK.

⁴  Medical Research Council (MRC) Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.

⁵  Department of Neurogenetics, Montreal Neurological Institute, Montreal, Quebec, Canada.

⁶  Radboud University Nijmegen Medical Center, Department of Human Genetics 417, Geert Grooteplein 20, 6525GA Nijmegen, The Netherlands.

⁷  Bradford Child Development Centre, St Luke's Hospital, Little Horton Lane, Bradford BD5 0NA, UK.

⁸  Department of Paediatrics, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 OHS, UK.

⁹  Department of Clinical Genetics, University Hospital azM Maastricht, Postbox 5800, 6202 AZ Maastricht, The Netherlands.

¹⁰  Department of Pediatrics and Pediatric Neurology, University Hospital Essen, Hufelandstrasse 55; D-45122, Essen, Germany.

¹¹  Department of Paediatric Neurology, Leeds General Infirmary, Great George Street, Leeds, LS1 3EX, UK.

¹²  National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland.

¹³  Department of Paediatrics, Hull Royal Infirmary, Anlaby Road, Hull HU3 2JZ, UK.

¹⁴  Service de Virologie, Hôpital Cochin, St Vincent de Paul, 82 Avenue Denfert Rochereau and Université René Descartes, 75674, Paris, France.

¹⁵  Research Center, Hôpital Sainte-Justine, 3175 Cote Ste-Catherine, Montréal, Quebec H3T 1C5, Canada.

¹⁶  Service de Neuropediatrie, Hôpital Cochin, St. Vincent de Paul, 82 Avenue Denfert Rochereau and Université René Descartes, 75674, Paris, France.

Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection^{1, 2}. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype³. Here, we show that TREX1, encoding the major mammalian 3' 5' DNA exonuclease⁴, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1 ^-/- mouse leads to an inflammatory phenotype⁵. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response.

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