A novel mutatioin in the PSTPIP1 gene is associated with an autoinflammatory disease distinct from classical PAPA syndrome

Background

Hyperzincaemia and hypercalprotectinaemia, a rare condition within the spectrum of autoinflammatory diseases, is associated with recurrent infections, hepatosplenomegaly, arthritis, anemia, cutaneous inflammation, and failure to thrive. So far, no genetic cause has been identified in these patients. While the clinical appearance is heterogeneous, all affected individuals present with extremely elevated S100A8/S100A9 (calprotectin) serum concentrations (0.9-12.0 g/l (normal range < 0.001 g/l)).

Aim

The clinical phenotype of 8 patients was characterized. Screening of candidate genes PSTPIP1 and MEFV was performed in 7 hyperzincaemia and hypercalprotectinaemia patients to identify disease-causing mutations.

Methods

Serum concentrations of S100A8/S100A9 were analyzed by an ELISA assay in 8 patients with hyperzincaemia and hypercalprotectinaemia and compared to PAPA patients with and without treatment. Candidate exons were amplified by PCR and sequenced on an ABI 3130 Genetic Analyzer.

Results

Seven of the eight patients were heterozygous carriers of a glutamic acid 250 (GAG)→lysine (AAG)/p.Glu250Lys/E250K substitution in exon 11 of the PSTPIP1 gene. S100A8/S100A9 concentrations were extremely elevated in these patients (0.9-12 g/l) compared to seven patients presenting with classical PAPA symptoms (0.02-0.35 g/l), whose levels again were significantly higher compared to normal controls.

Conclusion

The PSTPIP1 E250K mutation causes an autoinflammatory disorder known as hyperzincaemia and hypercalprotectinaemia. The disease causes a heterogeneous spectrum of symptoms that only partially overlaps with the presentation of the classical PAPA syndrome. Elevated S100A8/A9 levels are a common hallmark and biomarker of disorders caused by mutations in the PSTPIP1 gene.