A Rare RIPK3 Variant Enhances Necroptosis and Promotes Inflammation in a Still Disease–Like Autoinflammatory Syndrome

Abstract

Objective

Still disease represents a prototypical polygenic systemic autoinflammatory disease, characterized by recurrent systemic inflammation and dysregulation of innate immunity. Despite extensive clinical characterization, familial clustering Still disease remains unreported. This study investigates a novel variant underlying a distinct Still disease–like autoinflammatory syndrome.

Methods

Whole-exome sequencing was performed in a three-generation family with three affected individuals. Functional analyses were conducted to assess the impact of the receptor-interacting protein kinase 3 (RIPK3) p.Q134K variant on kinase activity, necroptosis, and inflammatory signaling. Transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) and in vitro cytokine assays were used to characterize inflammatory responses.

Results

A heterozygous RIPK3 p.Q134K variant was identified in all affected individuals. Functional analyses demonstrated that this variant exhibits gain-of-function activity, characterized by enhanced RIPK3 kinase activity and increased RIPK3 self-association, which in turn promote mixed-lineage kinase domain-like protein phosphorylation and necroptosis. RNA sequencing of PBMCs from one patient revealed marked up-regulation of NF-κB and MAPK signaling pathways and elevated expression of interleukin-6, and tumor necrosis factor-α, which was effectively suppressed by pharmacologic inhibition of RIPK3.

Conclusion

This study describes a familial Still disease–like autoinflammatory syndrome caused by a gain-of-function RIPK3 variant. Our findings establish aberrant RIPK3 activation as a driver of autoinflammation and expand the spectrum of human RIPK3-associated diseases.