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Nat Commun. 2019 Oct 21;10(1):4779. doi: 10.1038/s41467-019-12704-6.

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

Author information

1
Primary Immune Deficiency Research Lab, Department of Internal Medicine and Pediatrics, Centre for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium.
2
VIB Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, Ghent, Belgium.
3
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
4
Department of Immunology and Infectious Disease and Center for Personalised Immunology (NHMRC Centre for Research Excellence), John Curtin School of Medical Research, Australian National University, Canberra, Australia.
5
Centre for Personalised Immunology (CACPI), Shanghai Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
6
Department of Internal Medicine and Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium.
7
Institute for Immunology, Biomedical Center, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany.
8
Research Unit Molecular Immune Regulation, Helmholtz Zentrum München, Munich, Germany.
9
Department of Internal Medicine and Pediatrics, Division of Pediatric Immunology and Pulmonology, Ghent University Hospital, Ghent, Belgium.
10
Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium.
11
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
12
VIB Center for Inflammation Research, Unit of Data Mining and Modeling for Biomedicine, Ghent, Belgium.
13
Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Gent, Belgium.
14
VIB Bioimaging Core, VIB Center for Inflammation Research, Ghent, Belgium.
15
The Australian Phenomics Facility, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
16
VIB Center for Inflammation Research, Ghent, Belgium.
17
VIB Flow Core, VIB Center for Inflammation Research, Ghent, Belgium.
18
Department of Internal Medicine and Pediatrics, Division of Pediatric Rheumatology, Ghent University Hospital, Ghent, Belgium.
19
Department of Internal Medicine and Pediatrics, Division of Pulmonology, Ghent University Hospital, Ghent, Belgium.
20
VIB Center for Inflammation Research, Unit for Immunoregulation and Mucosal Immunology, Ghent, Belgium.
21
Department of Pulmonary Medicine, ErasmusMC, Rotterdam, The Netherlands.
22
Ablynx, a Sanofi Company, Zwijnaarde, Belgium.
23
Primary Immune Deficiency Research Lab, Department of Internal Medicine and Pediatrics, Centre for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium. Filomeen.Haerynck@ugent.be.
24
Department of Internal Medicine and Pediatrics, Division of Pediatric Immunology and Pulmonology, Ghent University Hospital, Ghent, Belgium. Filomeen.Haerynck@ugent.be.

Abstract

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.

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