Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.

Autor: Rice GI; Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK., Del Toro Duany Y; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.; Boston Children's Hospital, Boston, MA 02115, USA., Jenkinson EM; Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK., Forte GM; Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK., Anderson BH; Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK., Ariaudo G; Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy.; Department of Brain and Behavioral Sciences, Unit of Child Neurology and Psychiatry, University of Pavia, Pavia, Italy., Bader-Meunier B; Department of pediatric Immunology and Rheumatology, INSERM U 768, Imagine Foundation, APHP, Hôpital Necker, Paris, France., Baildam EM; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK., Battini R; Department of Developmental Neuroscience, IRCCS Stella Maris, Pisa, Italy., Beresford MW; Institute of Translational Medicine, University of Liverpool; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK., Casarano M; Department of Developmental Neuroscience, IRCCS Stella Maris, Pisa, Italy., Chouchane M; Service de Pédiatrie 1, CHU de Dijon, Dijon, France., Cimaz R; AOU Meyer and University of Florence, Italy., Collins AE; Department of Pediatrics, Division of Pediatric Neurology, University of Colorado, Denver, School of Medicine, USA., Cordeiro NJ; Department of Paediatrics, Rainbow House NHS Ayrshire & Arran, Scotland, UK., Dale RC; Neuroimmunology group, the Children's Hospital at Westmead, University of Sydney, Australia., Davidson JE; Department of Paediatric Rheumatology, Royal Hospital for Sick Children, Glasgow, UK., De Waele L; Department of Development and Regeneration, KU Leuven, Paediatric Neurology, University Hospitals Leuven, Leuven, Belgium., Desguerre I; Department of pediatric Immunology and Rheumatology, INSERM U 768, Imagine Foundation, APHP, Hôpital Necker, Paris, France., Faivre L; Centre de Génétique, Hôpital d'Enfants, CHU de Dijon et Université de Bourgogne, Dijon, France., Fazzi E; Child Neurology and Psychiatry Unit. Civil Hospital. Department of Clinical and Experimental Sciences, University of Brescia, Italy., Isidor B; Service de Génétique Médicale, Inserm, CHU Nantes, UMR-S 957, Nantes, France., Lagae L; Department of Development and Regeneration, KU Leuven, Paediatric Neurology, University Hospitals Leuven, Leuven, Belgium., Latchman AR; Division of General Pediatrics, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Canada., Lebon P; Université et Faculté de Medecine Paris Descartes, Paris, France., Li C; Department of Pediatrics, Clinical Genetics Program, McMaster Children's Hospital, McMaster University, Hamilton, Canada., Livingston JH; Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK., Lourenço CM; Clinics Hospital of Ribeirao Preto, University of São Paulo, Brasil., Mancardi MM; O.U. Child Neuropsychiatry, Department of Neuroscience, Giannina Gaslini Institute, Genoa, Italy., Masurel-Paulet A; Centre de Génétique, Hôpital d'Enfants, CHU de Dijon et Université de Bourgogne, Dijon, France., McInnes IB; Institute of Infection Immunity and Inflammation, University of Glasgow, Glasgow, UK., Menezes MP; Institute for Neuroscience and Muscle Research, the Children's Hospital at Westmead, University of Sydney, Australia., Mignot C; AP-HP, Department of Genetics, Groupe Hospitalier Pitié Salpêtrière, F-75013, Paris, France., O'Sullivan J; Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK., Orcesi S; Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy., Picco PP; Paediatric Rheumatology, Giannina Gaslini Institute, Genoa, Italy., Riva E; Clinical Department of Pediatrics, San Paolo Hospital, University of Milan, Italy., Robinson RA; Department of Neurology, Great Ormond Street Hospital for Children, London, UK., Rodriguez D; AP-HP, Service de Neuropédiatrie & Centre de Référence de Neurogénétique, Hôpital A. Trousseau, HUEP, F-75012 Paris, France.; UPMC Univ Paris 06, F-75012 Paris; Inserm U676, F-75019 Paris, France., Salvatici E; Clinical Department of Pediatrics, San Paolo Hospital, University of Milan, Italy., Scott C; University of Cape Town, Red Cross War Memorial Children's Hospital, Republic of South Africa., Szybowska M; Department of Pediatrics, Clinical Genetics Program, McMaster Children's Hospital, McMaster University, Hamilton, Canada., Tolmie JL; Department of Clinical Genetics, Southern General Hospital, Glasgow, Scotland, UK., Vanderver A; Department of Paediatric Neurology, Children's National Medical Center, Washington DC, USA., Vanhulle C; Service de Néonatalogie et Réanimation, Hôpital Charles Nicolle, CHU Rouen, F-76031 Rouen, France., Vieira JP; Neurology Department. Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Portugal., Webb K; University of Cape Town, Red Cross War Memorial Children's Hospital, Republic of South Africa., Whitney RN; Division of Pediatric Neurology, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Canada., Williams SG; Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK., Wolfe LA; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD, USA., Zuberi SM; Paediatric Neurosciences Research Group, Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow, UK.; School of Medicine, College of Medical, Veterinary & Life Sciences, University of Glasgow, UK., Hur S; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.; Boston Children's Hospital, Boston, MA 02115, USA., Crow YJ; Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2014 May; Vol. 46 (5), pp. 503-509. Date of Electronic Publication: 2014 Mar 30.
DOI: 10.1038/ng.2933
Abstrakt: The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.
Databáze: MEDLINE