ABSTRACT
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.
Subject(s)
Autoimmune Diseases of the Nervous System/genetics , DEAD-box RNA Helicases/genetics , Interferon Type I/immunology , Models, Molecular , Mutation/genetics , Nervous System Malformations/genetics , Phenotype , Signal Transduction/genetics , Analysis of Variance , Autoimmune Diseases of the Nervous System/immunology , Base Sequence , DEAD-box RNA Helicases/chemistry , Electrophoretic Mobility Shift Assay , Exome/genetics , HEK293 Cells , Humans , Interferon-Induced Helicase, IFIH1 , Microsatellite Repeats/genetics , Molecular Sequence Data , Nervous System Malformations/immunology , Real-Time Polymerase Chain Reaction , Sequence Analysis, DNA , Spectrum AnalysisABSTRACT
BACKGROUND: Red ear syndrome (RES), first described by Lance in 1996 in an adult series, may be primary or associated with headache syndromes, upper cervical disorders or vascular anomalies. Clinically the disease is characterised by recurrent episodes of reddening and burning pain in the auricle, usually elicited by different triggers. The prevalence of RES in the paediatric age group remains poorly understood. Several therapeutic approaches have been tried with heterogeneous clinical response. CASE RESULTS: We report a paediatric patient suffering from primary RES associated with debilitating cochleo-vestibular symptomatology causing severe discomfort. Three years after the disease onset, the patient also developed headache, with clinical features of migraine. DISCUSSION: The temporal and spatial association could suggest shared pathogenetic features between neurological (cochleo-vestibular) and vascular (red and burning ear) symptomatology, likely related to trigeminal autonomic reflex activation, although further studies are required for full comprehension of RES pathogenesis.
