Title |
Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)–associated inflammatory diseases
|
---|---|
Published in |
The Journal of Allergy and Clinical Immunology, May 2015
|
DOI | 10.1016/j.jaci.2015.04.016 |
Pubmed ID | |
Authors |
Dirk Holzinger, Selina Kathleen Fassl, Wilco de Jager, Peter Lohse, Ute F. Röhrig, Marco Gattorno, Alessia Omenetti, Sabrina Chiesa, Francesca Schena, Judith Austermann, Thomas Vogl, Douglas B. Kuhns, Steven M. Holland, Carlos Rodríguez-Gallego, Ricardo López-Almaraz, Juan I. Arostegui, Elena Colino, Rosa Roldan, Smaragdi Fessatou, Bertrand Isidor, Sylvaine Poignant, Koichi Ito, Hans-Joerg Epple, Jonathan A. Bernstein, Michael Jeng, Jennifer Frankovich, Geraldina Lionetti, Joseph A. Church, Peck Y. Ong, Mona LaPlant, Mario Abinun, Rod Skinner, Venetia Bigley, Ulrich J. Sachs, Claas Hinze, Esther Hoppenreijs, Jan Ehrchen, Dirk Foell, Jae Jin Chae, Amanda Ombrello, Ivona Aksentijevich, Cord Sunderkoetter, Johannes Roth |
Abstract |
Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin). We sought to characterize the genetic cause and clinical spectrum of Hz/Hc. 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. 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. 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 1 | 100% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 87 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 22 | 25% |
Student > Doctoral Student | 9 | 10% |
Student > Master | 8 | 9% |
Other | 8 | 9% |
Student > Bachelor | 6 | 7% |
Other | 13 | 15% |
Unknown | 21 | 24% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 23 | 26% |
Immunology and Microbiology | 12 | 14% |
Biochemistry, Genetics and Molecular Biology | 9 | 10% |
Agricultural and Biological Sciences | 7 | 8% |
Chemistry | 3 | 3% |
Other | 10 | 11% |
Unknown | 23 | 26% |