Journalartikel

Jahr der Veröffentlichung: 2015

Seiten: 1337-1345

Zeitschrift: Journal of Allergy and Clinical Immunology

Bandnummer: 136

Heftnummer: 5

ISSN: 0091-6749

eISSN: 1097-6825

DOI Link: https://doi.org/10.1016/j.jaci.2015.04.016

Verlag: Elsevier

Abstract: 

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. 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 mu g/mL) compared with those with PAPA syndrome (116 +/- 74 mu g/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.

Harvard-Zitierstil: Holzinger, D., Fassl, S., de Jager, W., Lohse, P., Roehrig, U., Gattorno, M., et al. (2015) Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases, Journal of Allergy and Clinical Immunology, 136(5), pp. 1337-1345. https://doi.org/10.1016/j.jaci.2015.04.016

APA-Zitierstil: Holzinger, D., Fassl, S., de Jager, W., Lohse, P., Roehrig, U., Gattorno, M., Omenetti, A., Chiesa, S., Schena, F., Austermann, J., Vogl, T., Kuhns, D., Holland, S., Rodriguez-Gallego, C., Lopez-Almaraz, R., Arostegui, J., Colino, E., Roldan, R., Fessatou, S., ...Roth, J. (2015). Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases. Journal of Allergy and Clinical Immunology. 136(5), 1337-1345. https://doi.org/10.1016/j.jaci.2015.04.016