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

S. J. Tavernier, V. Athanasopoulos, P. Verloo, G. Behrens, J. Staal, D. J. Bogaert, L. Naesens, M. De Bruyne, S. Van Gassen, E. Parthoens, J. Ellyard, J. Cappello, L. X. Morris, H. Van Gorp, G. Van Isterdael, Y. Saeys, M. Lamkanfi, P. Schelstraete, J. Dehoorne, V. Bordon, R. Van Coster, B. N. Lambrecht, B. Menten, R. Beyaert, C. G. Vinuesa, V. Heissmeyer, M. Dullaers and F. Haerynck ()
Additional contact information
S. J. Tavernier: Ghent University Hospital
V. Athanasopoulos: Australian National University
P. Verloo: Ghent University Hospital
G. Behrens: Ludwig-Maximilians-Universität München
J. Staal: VIB Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation
D. J. Bogaert: Ghent University Hospital
L. Naesens: Ghent University Hospital
M. De Bruyne: Ghent University Hospital
S. Van Gassen: VIB Center for Inflammation Research, Unit of Data Mining and Modeling for Biomedicine
E. Parthoens: VIB Bioimaging Core, VIB Center for Inflammation Research
J. Ellyard: Australian National University
J. Cappello: Australian National University
L. X. Morris: Australian National University
H. Van Gorp: Ghent University Hospital
G. Van Isterdael: Ghent University
Y. Saeys: VIB Center for Inflammation Research, Unit of Data Mining and Modeling for Biomedicine
M. Lamkanfi: Ghent University Hospital
P. Schelstraete: Ghent University Hospital
J. Dehoorne: Ghent University Hospital
V. Bordon: Ghent University Hospital
R. Van Coster: Ghent University Hospital
B. N. Lambrecht: Ghent University Hospital
B. Menten: Ghent University Hospital
R. Beyaert: VIB Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation
C. G. Vinuesa: Australian National University
V. Heissmeyer: Ludwig-Maximilians-Universität München
M. Dullaers: Ghent University Hospital
F. Haerynck: Ghent University Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12704-6

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