Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases.
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Holzinger Dirk, Fassl Selina Kathleen, de Jager Wilco, Lohse Peter, Röhrig Ute F, Gattorno Marco, Omenetti Alessia, Chiesa Sabrina, Schena Francesca, Austermann Judith, Vogl Thomas, Kuhns Douglas B, Holland Steven M, Rodríguez-Gallego Carlos, López-Almaraz Ricardo, Arostegui Juan I, Colino Elena, Roldan Rosa, Fessatou Smaragdi, Isidor Bertrand, Poignant Sylvaine, Ito Koichi, Epple Hans-Joerg, Bernstein Jonathan A, Jeng Michael, Frankovich Jennifer, Lionetti Geraldina, Church Joseph A, Ong Peck Y, LaPlant Mona, Abinun Mario, Skinner Rod, Bigley Venetia, Sachs Ulrich J, Hinze Claas, Hoppenreijs Esther, Ehrchen Jan, Foell Dirk, Chae Jae Jin, Ombrello Amanda, Aksentijevich Ivona, Sunderkoetter Cord, Roth Johannes
Аннотация
OBJECTIVE: We sought to characterize the genetic cause and clinical spectrum of Hz/Hc.
METHODS: Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA.
RESULTS: Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation resulting in p.E257K. Both mutations substantially alter the electrostatic potential of the PSTPIP1 dimer model in a region critical for protein-protein interaction. Patients with Hz/Hc have extremely high MRP8/14 concentrations (2045 ± 1300 μg/mL) compared with those with PAPA syndrome (116 ± 74 μg/mL) and have a distinct clinical phenotype. A specific cytokine profile is associated with Hz/Hc. Hz/Hc mutations altered protein binding of PSTPIP1, increasing interaction with pyrin through phosphorylation of PSTPIP1.
CONCLUSION: Mutations resulting in charge reversal in the y-domain of PSTPIP1 (E→K) and increased interaction with pyrin cause a distinct autoinflammatory disorder defined by clinical and biochemical features not found in patients with PAPA syndrome, indicating a unique genotype-phenotype correlation for mutations in the PSTPIP1 gene. This is the first inborn autoinflammatory syndrome in which inflammation is driven by uncontrolled release of members of the alarmin family.