role of the nuclear pore component ranbp2 in inflammatory responses to viral infections

Conditions: Rare Genetic Disease; Acute Necrotizing Encephalopathy

Summary: the goal of this controlled, pathophysiological, exploratory interventional study is to compare the inflammatory phenotype of circulating immune cells, basal and following stimulation, from acute necrotizing encephalopathy type 1 (ane1) patients with those from sex- and age-matched donors who do not carry the mutation.to date, no study has investigated the molecular mechanisms regulating the inflammatory response in ane1 disease directly on patient samples. the primary endpoint in individuals in the "mutated ranbp2" arm is an inflammatory phenotype (hyperinflammatory monocytes, secretion of pro-inflammatory cytokines, anti-glycoprotein autoantibodies), significantly exacerbated basal and/or post-stimulation production of pro-inflammatory cytokines compared with the control arm. the secondary objective is to examine the allelic expression of mutant ranbp2 and characterize genetic variants by whole-exome sequencing, in order to associate them with ranbp2 protein localization and ane crisis severity the researchers will compare the group of ane1 patients with age- and sex-matched control groups, divided into two subgroups: unrelated controls and controls with familial ties. the aim is to study the different types of inflammatory responses and correlate them with the localization of the ranbp2 protein and the severity of ane episodes. participants will participate in a single visit during which demographic data, clinical history and a blood test will be collected with one (unrelated control) or two blood tubes (ane1 and related control).

the nucleoporin ranbp2, also known as nup358, is a component of the cytoplasmic filaments of nuclear pore complexes (npcs), which regulate the transport of macromolecules between the cytoplasm and the nucleus. mutations in the ranbp2 gene are associated with a rare genetic predisposition to acute necrotizing encephalopathy (ane1), a predominantly pediatric disease characterized by multiple, symmetrical hemorrhagic lesions of the brain following febrile infection, most often with influenza a virus (iav). given the presumed inflammatory nature of ane1, first-line treatment includes intravenous administration of high-dose pharmacological corticosteroids with or without immunoglobulins. in addition, two clinical cases report that il-6 inhibition by tocilumizab may have a beneficial role. the research team have recently demonstrated that iav infection disrupts the localization of ranbp2 and key inflammatory mediators such as inflammasome components. we have also shown that ranbp2 regulates the expression of pro-inflammatory cytokines at both transcriptional and post-translational levels. the researchers hypothesis is that mutation of ranbp2 in ane1 patients weakens nuclear pore control of innate immune signaling pathways, leading to an exacerbated inflammatory response to infections.

Eligibility criteria:
inclusion criteria: * obtaining written consent from adult participants * obtaining written consent from legal guardians of minors with their assent * subjects aged 1 to 90 * subject with a t585m mutation in ranbp2 for the ranbp2 mutation arm. * subjects matched on age (+/- 10 years) and gender for the "control" arm. exclusion criteria: * patient not affiliated to a social security scheme or not a beneficiary of such a scheme. (for example, a european health insurance card (ehic)) * absence of written informed consent * person unable to give consent * legally protected adult (guardianship, curatorship) * person deprived of liberty * person participating in another research study with an exclusion period still in progress * chronic or infectious disease affecting the immune system * immunomodulating treatment (e.g. corticosteroids, immunoglobulins)

Keywords: ranbp2 nuclear pore