4.7 Article

Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases

Journal

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 136, Issue 5, Pages 1337-1345

Publisher

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

Funding

  1. Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Instituters of Health, Department of Health and Haman Services
  2. National Cancer Institute, National Institutes of Health [HHSN261200800001E]
  3. Fondo de Investigaciones Sanitarias,'' Ministerio de Economia y Competitividad [PI06/1031, PI10/01718]
  4. European Regional Development Fund European Social Fund FEDER-FSE
  5. Interdisciplinary Centre for Clinical Research University of Munster
  6. German Research Foundation [SFB1009]
  7. Bundesministerium fur Bildung und Forschung (AID-NET) [01GM08100]
  8. 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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