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

objectiveStill 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.

methodsWhole-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.

resultsA 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.

conclusionThis 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.