Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.
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Vavassori Stefano, Chou Janet, Faletti Laura Eva, Haunerdinger Veronika, Opitz Lennart, Joset Pascal, Fraser Christopher J, Prader Seraina, Gao Xianfei, Schuch Luise A, Wagner Matias, Hoefele Julia, Maccari Maria Elena, Zhu Ying, Elakis George, Gabbett Michael T, Forstner Maria, Omran Heymut, Kaiser Thomas, Kessler Christina, Olbrich Heike, Frosk Patrick, Almutairi Abduarahman, Platt Craig D, Elkins Megan, Weeks Sabrina, Rubin Tamar, Planas Raquel, Marchetti Tommaso, Koovely Danil, Klämbt Verena, Soliman Neveen A, von Hardenberg Sandra, Klemann Christian, Baumann Ulrich, Lenz Dominic, Klein-Franke Andreas, Schwemmle Martin, Huber Michael, Sturm Ekkehard, Hartleif Steffen, Häffner Karsten, Gimpel Charlotte, Brotschi Barbara, Laube Guido, Güngör Tayfun, Buckley Michael F, Kottke Raimund, Staufner Christian, Hildebrandt Friedhelm, Reu-Hofer Simone, Moll Solange, Weber Achim, Kaur Hundeep, Ehl Stephan, Hiller Sebastian, Geha Raif, Roscioli Tony, Griese Matthias, Pachlopnik Schmid Jana
Аннотация
OBJECTIVE: We studied 15 patients from 8 families with an autosomal recessive immunodeficiency characterized by severe infections by both RNA and DNA viruses and virally triggered inflammatory episodes with hemophagocytic lymphohistiocytosis-like disease, early-onset seizures, and renal and lung disease.
METHODS: Whole exome sequencing was performed on 13 patients from 8 families. We investigated the transcriptome, posttranscriptional regulation of interferon-stimulated genes (ISGs) and predisposition to viral infections in primary cells from patients and controls stimulated with synthetic double-stranded nucleic acids.
RESULTS: Deleterious homozygous and compound heterozygous ZNFX1 variants were identified in all 13 patients. Stimulation of patient-derived primary cells with synthetic double-stranded nucleic acids was associated with a deregulated pattern of expression of ISGs and alterations in the half-life of the mRNA of ISGs and also associated with poorer clearance of viral infections by monocytes.
CONCLUSION: ZNFX1 is an important regulator of the response to double-stranded nucleic acids stimuli following viral infections. ZNFX1 deficiency predisposes to severe viral infections and a multisystem inflammatory disease.