Autoinflammatory disease and severe neutropenia due to de novo variant of PSTPIP1 with increased binding to pyrin.

Mutations in the gene PSTPIP1 may cause several different autoinflammatory syndromes, but the mechanisms by which distinct PSTPIP1 mutations lead to these differing phenotypes are not fully understood. The two best characterized autoinflammatory conditions resulting from PSTPIP1 mutation are pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome and PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome. Here, we report a novel gain-of-function PSTPIP1 mutation (p.N236K) causing PAMI syndrome in a patient with systemic autoinflammation and severe neutropenia. This mutant form of PSTPIP1 shows increased binding to pyrin and leads to heightened inflammasome formation, relative to WT PSTPIP1. We also identify a transcriptional signature in blood from PAMI patients suggestive of enhanced T cell activation and altered neutrophil survival and/or function. Further research on PSTPIP1-related autoinflammatory conditions is needed to more deeply understand the genetic and immunological drivers of disease and contribute to improving patient outcomes.