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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.*

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

Nat. Commun. 10:4779 (2019)
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Open Access Gold
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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 immuneregulatory 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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Publication type Article: Journal article
Document type Scientific Article
Keywords Helper T-cells; Macrophage Activation Syndrome; Constitutive-decay Element; Messenger-rna Decay; Hemophagocytic Lymphohistiocytosis; Roq Domain; Complex; Recognition; Disease; Regnase-1
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Quellenangaben Volume: 10, Issue: 1, Pages: , Article Number: 4779 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed