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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)
Verlagsversion Forschungsdaten DOI
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Zeitschrift Nature Communications
Quellenangaben Band: 10, Heft: 1, Seiten: , Artikelnummer: 4779 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed