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

Lookup NU author(s): Dr Mario Abinun, Professor Roderick Skinner, Dr Venetia BigleyORCiD


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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.

Publication metadata

Author(s): Holzinger D, Fassl SK, de Jager W, Lohse P, Rohrig UF, Gattorno M, Omenetti A, Chiesa S, Schena F, Austermann J, Vogl T, Kuhns DB, Holland SM, Rodriguez-Gallego C, Lopez-Almaraz R, Arostegui JI, Colino E, Roldan R, Fessatou S, Isidor B, Poignant S, Ito K, Epple HJ, Bernstein JA, Jeng M, Frankovich J, Lionetti G, Church JA, Ong PY, LaPlant M, Abinun M, Skinner R, Bigley V, Sachs UJ, Hinze C, Hoppenreijs E, Ehrchen J, Foell D, Chae JJ, Ombrello A, Aksentijevich I, Sunderkoetter C, Roth J

Publication type: Article

Publication status: Published

Journal: Journal of Allergy and Clinical Immunology

Year: 2015

Volume: 136

Issue: 5

Pages: 1337-1345

Print publication date: 01/11/2015

Online publication date: 27/05/2015

Acceptance date: 08/04/2015

ISSN (print): 0091-6749

ISSN (electronic): 1097-6825

Publisher: Elsevier


DOI: 10.1016/j.jaci.2015.04.016


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Funder referenceFunder name
Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Instituters of Health, Department of Health and Haman Services
European Regional Development Fund European Social Fund FEDER-FSE
Interdisciplinary Centre for Clinical Research University of Munster
01GM08100Bundesministerium fur Bildung und Forschung (AID-NET)
HHSN261200800001ENational Cancer Institute, National Institutes of Health
PI06/1031"Fondo de Investigaciones Sanitarias,'' Ministerio de Economia y Competitividad
PI10/01718"Fondo de Investigaciones Sanitarias,'' Ministerio de Economia y Competitividad
SFB1009German Research Foundation