TY - JOUR
T1 - Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases
AU - Holzinger, Dirk
AU - Fassl, Selina Kathleen
AU - de Jager, Wilco
AU - Lohse, Peter
AU - Röhrig, Ute F.
AU - Gattorno, Marco
AU - Omenetti, Alessia
AU - Chiesa, Sabrina
AU - Schena, Francesca
AU - Austermann, Judith
AU - Vogl, Thomas
AU - Kuhns, Douglas B.
AU - Holland, Steven M.
AU - Rodríguez-Gallego, Carlos
AU - López-Almaraz, Ricardo
AU - Arostegui, Juan I.
AU - Colino, Elena
AU - Roldan, Rosa
AU - Fessatou, Smaragdi
AU - Isidor, Bertrand
AU - Poignant, Sylvaine
AU - Ito, Koichi
AU - Epple, Hans Joerg
AU - Bernstein, Jonathan A.
AU - Jeng, Michael
AU - Frankovich, Jennifer
AU - Lionetti, Geraldina
AU - Church, Joseph A.
AU - Ong, Peck Y.
AU - LaPlant, Mona
AU - Abinun, Mario
AU - Skinner, Rod
AU - Bigley, Venetia
AU - Sachs, Ulrich J.
AU - Hinze, Claas
AU - Hoppenreijs, Esther
AU - Ehrchen, Jan
AU - Foell, Dirk
AU - Chae, Jae Jin
AU - Ombrello, Amanda
AU - Aksentijevich, Ivona
AU - Sunderkoetter, Cord
AU - Roth, Johannes
PY - 2014/2/10
Y1 - 2014/2/10
N2 - Background: 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). 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. Astructural 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±1300μg/mL) compared with those with PAPA syndrome (116±74μg/mL) and have a distinct clinical phenotype. Aspecific 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.
AB - Background: 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). 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. Astructural 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±1300μg/mL) compared with those with PAPA syndrome (116±74μg/mL) and have a distinct clinical phenotype. Aspecific 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.
KW - Autoinflammation
KW - Calprotectin
KW - Genotype
KW - Hyperzincemia and hypercalprotectinemia
KW - Myeloid-related protein 8/14
KW - Phenotype
KW - Proline-serine-threonine phosphatase-interacting protein 1
KW - Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome
KW - S100 proteins
KW - Zinc
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U2 - 10.1016/j.jaci.2015.04.016
DO - 10.1016/j.jaci.2015.04.016
M3 - Article
C2 - 26025129
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
ER -