A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation

• Published in: Nature communications Vol. 10; no. 1; pp. 4779 - 16
• Main Authors: Tavernier, S. J., Athanasopoulos, V., Verloo, P., Behrens, G., Staal, J., Bogaert, D. J., Naesens, L., De Bruyne, M., Van Gassen, S., Parthoens, E., Ellyard, J., Cappello, J., Morris, L. X., Van Gorp, H., Van Isterdael, G., Saeys, Y., Lamkanfi, M., Schelstraete, P., Dehoorne, J., Bordon, V., Van Coster, R., Lambrecht, B. N., Menten, B., Beyaert, R., Vinuesa, C. G., Heissmeyer, V., Dullaers, M., Haerynck, F.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.10.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 14/1; 14/19; 38/77; 42/35; 42/44; 45/23; 45/90; 631/208/248/144; 631/250/256; 631/337/1645/2020; 64/60; 692/699/249/2512; 82/29; 96/31; Adolescent; Animals; Cell activation; Codon, Nonsense; Consanguinity; Cyclosporine - therapeutic use; Cytokines; Cytotoxicity; Damage accumulation; Eosinophilia - genetics; Eosinophilia - immunology; Histiocytosis; Homozygote; Humanities and Social Sciences; Humans; Immune response; Immune system; Immunophenotyping; Immunosuppressive Agents - therapeutic use; Inducible T-Cell Co-Stimulator Protein - genetics; Inducible T-Cell Co-Stimulator Protein - immunology; Inducible T-Cell Co-Stimulator Protein - metabolism; Lymphocytosis; Lymphohistiocytosis, Hemophagocytic - drug therapy; Lymphohistiocytosis, Hemophagocytic - genetics; Lymphohistiocytosis, Hemophagocytic - immunology; Male; Mice; Monocytes - immunology; mRNA turnover; multidisciplinary; Mutation; Negative feedback; Post-transcription; Receptors, OX40 - genetics; Receptors, OX40 - immunology; Receptors, OX40 - metabolism; Recurrence; Regulatory proteins; RNA-Binding Proteins - genetics; Science; Science (multidisciplinary); T-Lymphocytes - immunology; T-Lymphocytes, Regulatory - immunology; Toxicity; Tumor necrosis factor; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - immunology
• DOI: 10.1038/s41467-019-12704-6
• ISSN: 2041-1723

Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation. Roquin-1 is a posttranscriptional regulator that controls the expression of many immune-related genes such as ICOS and TNFA . Here, the authors report a homozygous R688* loss of function mutation in Roquin-1 in a patient with syndromic uncontrolled hyperinflammation associated with immune cell activation and hypercytokinemia.