Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 136, Issue 5, Pages 1337-1345Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2015.04.016
Keywords
Hyperzincemia and hypercalprotectinemia; myeloid-related protein 8/14; calprotectin; S100 proteins; zinc; proline-serine-threonine phosphatase-interacting protein 1; pyogenic arthritis; pyoderma gangrenosum, and acne syndrome; genotype; phenotype; autoinflammation
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Funding
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Instituters of Health, Department of Health and Haman Services
- National Cancer Institute, National Institutes of Health [HHSN261200800001E]
- Fondo de Investigaciones Sanitarias,'' Ministerio de Economia y Competitividad [PI06/1031, PI10/01718]
- European Regional Development Fund European Social Fund FEDER-FSE
- Interdisciplinary Centre for Clinical Research University of Munster
- German Research Foundation [SFB1009]
- Bundesministerium fur Bildung und Forschung (AID-NET) [01GM08100]
- Wellcome Trust [101155/Z/13/Z] Funding Source: researchfish
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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.
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