6533b822fe1ef96bd127ce0a
RESEARCH PRODUCT
Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.
Catherine VanhulleLynne A. WolfeChumei LiEileen BaildamBertrand IsidorJohn TolmieYoandris Del Toro DuanyYoandris Del Toro DuanyYanick J. CrowGabriella M A ForteGillian I. RiceSimona OrcesiMondher ChouchaneMichael W. BeresfordNuno CordeiroBeverley AndersonLiesbeth De WaelePierre LebonDiana RodriguezDiana RodriguezJames O'sullivanMarta SzybowskaRolando CimazIsabelle DesguerreGiada AriaudoManoj P. MenezesKate WebbRobyn WhitneySun HurSun HurSimon G. WilliamsJoyce DavidsonRussell C. DaleAndrew LatchmanLaurence FaivreAbigail CollinsRobert RobinsonAdeline VanderverChristiaan ScottIain B. McinnesEnrica RivaCyril MignotRoberta BattiniJosé Pedro VieiraBrigitte Bader-meunierEmma M. JenkinsonElisa FazziPaolo PiccoLieven LagaeElisabetta SalvaticiManuela CasaranoSameer M. ZuberiSameer M. ZuberiCharles Marques LourençoMaria Margherita MancardiAlice Masurel-pauletJohn H. Livingstonsubject
Models MolecularInterferon-Induced Helicase IFIH1Molecular Sequence DataHDE NEU PEDElectrophoretic Mobility Shift AssayBiologymedicine.disease_causeNervous System MalformationsReal-Time Polymerase Chain ReactionArticleDEAD-box RNA HelicasesImmune systemAutoimmune Diseases of the Nervous SystemDownregulation and upregulationAnalysis of Variance; Autoimmune Diseases of the Nervous System; Base Sequence; DEAD-box RNA Helicases; Electrophoretic Mobility Shift Assay; Exome; HEK293 Cells; Humans; Interferon Type I; Microsatellite Repeats; Molecular Sequence Data; Mutation; Nervous System Malformations; Real-Time Polymerase Chain Reaction; Sequence Analysis DNA; Signal Transduction; Spectrum Analysis; Models Molecular; Phenotype; GeneticsModelsInterferonGeneticsmedicineHumansExomeMutationAnalysis of VarianceBase SequenceSpectrum AnalysisMolecularRNAMDA5DNASequence Analysis DNAMolecular biology3. Good healthInterferon Tipo IHEK293 CellsPhenotypeInterferon Type IMutationCancer researchSignal transductionSequence AnalysisInterferon type Imedicine.drugMicrosatellite RepeatsSignal Transductiondescription
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 patients with 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 (MDA5) cause a spectrum of neuro-immunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer a gain-of-function - so 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2014-03-30 | Nature genetics |