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. BordonR. Van Coster, B. N. Lambrecht, B. Menten, R. Beyaert, C. G. Vinuesa, V. Heissmeyer, M. Dullaers, F. Haerynck*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    36 Citations (Scopus)

    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.

    Original languageEnglish
    Article number4779
    JournalNature Communications
    Volume10
    Issue number1
    DOIs
    Publication statusPublished - 1 Dec 2019

    Fingerprint

    Dive into the research topics of 'A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation'. Together they form a unique fingerprint.

    Cite this