PSTPIP1 – Pyogenic Arthritis-Pyoderma Gangrenosum-Acne (PAPA) Syndrome

The association between PSTPIP1 and Pyogenic Arthritis-Pyoderma Gangrenosum-Acne Syndrome is classified as Strong based on multiple independent kindreds, co-segregation in two families, and extensive concordant functional studies. 8 probands were reported across five kindreds (PMID:11971877, PMID:22161697), with segregation of pathogenic variants in two families (PMID:11971877) and consistent mechanistic data.

Inheritance is autosomal dominant with incomplete penetrance. Segregation analysis identified pathogenic missense variants in at least 2 affected relatives. Case series include a multi-generation kindred with co-segregating E250Q and A230T variants, and five additional affected individuals from four kindreds harboring A230T, E250Q, and a novel E250K (PMID:22161697). The variant spectrum is dominated by missense substitutions within the F-BAR and SH3 domains; recurrent de novo mutations (e.g., c.748G>A (p.Glu250Lys) PMID:11971877) and founder alleles contribute to disease prevalence.

Functional studies define a haploinsufficiency/dominant-negative mechanism whereby PAPA-associated PSTPIP1 mutants exhibit enhanced binding to the inflammasome regulator pyrin, leading to hyperactivation of caspase-1 and IL-1β release. Yeast two-hybrid and co-immunoprecipitation assays demonstrated increased pyrin binding for A230T and E250Q mutants (PMID:14595024). Macrophage assays with the SH3-domain R405C mutation revealed dysregulated podosome dynamics and matrix degradation consistent with pyoderma gangrenosum pathology (PMID:24421327).

Conflicting evidence is limited. An intronic PSTPIP1 variant (c.741+33_741+34insGT) occurred at similar frequency in Behçet’s disease cases and controls, indicating polymorphism rather than pathogenicity (PMID:17213252). No other studies have refuted the gene–disease link.

In summary, autosomal dominant PSTPIP1 missense mutations cause PAPA syndrome by dysregulating cytoskeletal adaptor functions and inflammasome activation. Clinical testing for PSTPIP1 should be pursued in patients presenting with early-onset sterile pyogenic arthritis, even before cutaneous manifestations, to enable targeted anti–IL-1 therapy.

References

• Human molecular genetics • 2002 • Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. PMID:11971877
• Arthritis and rheumatism • 2012 • Brief report: genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne). PMID:22161697
• Proceedings of the National Academy of Sciences of the United States of America • 2003 • Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. PMID:14595024
• Blood • 2014 • The F-BAR protein PSTPIP1 controls extracellular matrix degradation and filopodia formation in macrophages. PMID:24421327
• Annals of the rheumatic diseases • 2007 • Autoinflammatory gene mutations in Behçet's disease PMID:17213252

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