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.
Highlights
1234567890():,; Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms
We performed whole exome sequencing (WES) to identify causal mutations in the case of an 18-year-old male, who was referred to our center at age 11 suffering from hyperinflammation clinically resembling hemophagocytic lymphohistiocytosis (HLH) (Table 1)
We describe the consequences of a homozygous nonsense R688* RC3H1 mutation in a patient suffering from an immune dysregulation syndrome with uncontrolled systemic inflammation
Summary
1234567890():,; Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. 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. In familial HLH (FHL), progress has been made to identify the underlying disease-causing genes These variants are mostly situated in pathways that regulate cytotoxic granule function (e.g., PRF1) or exocytosis (e.g., RAB27A, LYST). Roquin-1, encoded by RC3H1, recognizes and binds to RNA by the virtue of its ROQ domain and the adjacent C3H1 zinc finger[8,9,10,11,12,13,14] It acts as a post-transcriptional regulator that typically promotes mRNA degradation[15] and protein translation inhibition has been reported[16]. As a consequence of its function, Roquin-1 can colocalize with P-bodies, cytoplasmic regions in which stalled mRNA storage and post-transcriptional regulation occurs[22]
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