Dirk Holzinger1, Selina Kathleen Fassl2, Wilco de Jager3, Peter Lohse4, Ute F Röhrig5, Marco Gattorno6, Alessia Omenetti6, Sabrina Chiesa6, Francesca Schena6, Judith Austermann7, Thomas Vogl7, Douglas B Kuhns8, Steven M Holland9, Carlos Rodríguez-Gallego10, Ricardo López-Almaraz11, Juan I Arostegui12, Elena Colino13, Rosa Roldan14, Smaragdi Fessatou15, Bertrand Isidor16, Sylvaine Poignant17, Koichi Ito18, Hans-Joerg Epple19, Jonathan A Bernstein20, Michael Jeng20, Jennifer Frankovich20, Geraldina Lionetti21, Joseph A Church22, Peck Y Ong22, Mona LaPlant23, Mario Abinun24, Rod Skinner25, Venetia Bigley26, Ulrich J Sachs27, Claas Hinze28, Esther Hoppenreijs29, Jan Ehrchen30, Dirk Foell31, Jae Jin Chae32, Amanda Ombrello32, Ivona Aksentijevich32, Cord Sunderkoetter30, Johannes Roth33. 1. Institute of Immunology, University of Muenster, Muenster, Germany; Interdisciplinary Centre for Clinical Research IZKF, University Hospital Muenster, University of Muenster, Muenster, Germany; Department of Paediatric Rheumatology and Immunology, University Children's Hospital Muenster, University of Muenster, Muenster, Germany. 2. Institute of Immunology, University of Muenster, Muenster, Germany. 3. Laboratory for Translational Immunology, Department of Paediatric Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands. 4. Department of Clinical Chemistry Großhadern, University of Munich, Munich, Germany. 5. Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, Switzerland. 6. 2nd Division of Pediatrics "G. Gaslini" Scientific Institute, Genoa, Italy. 7. Institute of Immunology, University of Muenster, Muenster, Germany; Interdisciplinary Centre for Clinical Research IZKF, University Hospital Muenster, University of Muenster, Muenster, Germany. 8. Leidos Biomedical Research, Frederick, Md. 9. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. 10. Department of Immunology, Hospital Universitario Son Espases, Palma de Mallorca, Spain. 11. Department of Pediatrics, Hospital Universitario de Canarias, La Laguna, Spain. 12. Department of Immunology-CDB, Hospital Clinic-IDIBAPS, Barcelona, Spain. 13. Department of Paediatrics, Complejo Hospitalario Universitario Insular Materno Infantil, Las Palmas de Gran Canaria, Spain. 14. Department of Pediatric Rheumatology Hospital Universitario Reina Sofia, Cordoba, Spain. 15. 3rd Department of Pediatrics, Athens University Medical School, "ATTIKON" Hospital, Athens, Greece. 16. Service de Génétique Médicale, Centre Hospitalo-Universitaire, Nantes, France. 17. Service de Pédiatrie, CH Cholet, Cholet, France. 18. Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan. 19. Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany. 20. Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif. 21. Department of Pediatrics, University of California, San Francisco, Calif. 22. Division of Clinical Immunology and Allergy, Children's Hospital Los Angeles and Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, Calif. 23. Children's Hospital and Clinics of Minnesota, Saint Paul, Minn. 24. Department of Paediatric Immunology and Children's BMT Unit, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom; Institute of Clinical Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom. 25. Department of Paediatric and Adolescent Haematology and Oncology and Children's BMT Unit, Great North Children's Hospital, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom; Northern Institute of Cancer Research, University of Newcastle, Newcastle upon Tyne, United Kingdom. 26. Human Dendritic Cell Laboratory, Newcastle University Medical School, Newcastle upon Tyne, United Kingdom. 27. Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, Giessen, Germany. 28. Interdisciplinary Centre for Clinical Research IZKF, University Hospital Muenster, University of Muenster, Muenster, Germany; Deutsches Zentrum für Kinder-und Jugendrheumatologie, Garmisch-Partenkirchen, Germany. 29. Department of Paediatrics/Paediatric Rheumatology, St Maartenskliniek and Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 30. Interdisciplinary Centre for Clinical Research IZKF, University Hospital Muenster, University of Muenster, Muenster, Germany; Department of Dermatology, University Hospital Muenster, Muenster, Germany; Department for Translational Dermatoinfectiology, University Hospital Muenster, Muenster, Germany. 31. Interdisciplinary Centre for Clinical Research IZKF, University Hospital Muenster, University of Muenster, Muenster, Germany; Department of Paediatric Rheumatology and Immunology, University Children's Hospital Muenster, University of Muenster, Muenster, Germany. 32. National Human Genome Research Institute, National Institutes of Health, Bethesda, Md. 33. Institute of Immunology, University of Muenster, Muenster, Germany; Interdisciplinary Centre for Clinical Research IZKF, University Hospital Muenster, University of Muenster, Muenster, Germany. Electronic address: rothj@uni-muenster.de.
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 μg/mL) compared with those with PAPA syndrome (116 ± 74 μg/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.
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 μg/mL) compared with those with PAPA syndrome (116 ± 74 μg/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.
Authors: Pei Dai; Tim Furlong; Gary Gracie; Min Li Huang; Tao Yang; Kathy H C Wu; Mark Danta; Melanie Wong; Andrew Williams; Lyn March; Marie Hetherington; David Heyworth-Smith; Tri Giang Phan Journal: J Clin Immunol Date: 2019-05-22 Impact factor: 8.317