Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)–associated inflammatory diseases - 06/11/15

Doi : 10.1016/j.jaci.2015.04.016

Dirk Holzinger, MD ^a,^b,^c, Selina Kathleen Fassl, MSc ^a, Wilco de Jager, PhD ^d, Peter Lohse, MD ^e, Ute F. Röhrig, PhD ^f, Marco Gattorno, MD ^g, Alessia Omenetti, MD ^g, Sabrina Chiesa, MD ^g, Francesca Schena, PhD ^g, Judith Austermann, PhD ^a,^b, Thomas Vogl, PhD ^a,^b, Douglas B. Kuhns, PhD ^h, Steven M. Holland, MD ⁱ, Carlos Rodríguez-Gallego, PhD ^j, Ricardo López-Almaraz, MD ^k, Juan I. Arostegui, MD, PhD ^l, Elena Colino, MD ^m, Rosa Roldan, MD, PhD ⁿ, Smaragdi Fessatou, MD ^o, Bertrand Isidor, MD ^p, Sylvaine Poignant, MD ^q, Koichi Ito, MD ^r, Hans-Joerg Epple, MD ^s, Jonathan A. Bernstein, MD, PhD ^t, Michael Jeng, MD ^t, Jennifer Frankovich, MD ^t, Geraldina Lionetti, MD ^u, Joseph A. Church, MD ^v, Peck Y. Ong, MD, PhD ^v, Mona LaPlant, MD ^w, Mario Abinun, MD ^x,^y, Rod Skinner, MD ^z,^aa, Venetia Bigley, MD ^bb, Ulrich J. Sachs, MD, PhD ^cc, Claas Hinze, MD ^b,^dd, Esther Hoppenreijs, MD ^ee, Jan Ehrchen, MD, PhD ^b,^ff,^hh, Dirk Foell, MD ^b,^c, Jae Jin Chae, PhD ^gg, Amanda Ombrello, MD ^gg, Ivona Aksentijevich, MD, PhD ^gg, Cord Sunderkoetter, MD ^b,^ff,^hh, Johannes Roth, MD ^a,^b,^⁎
^a Institute of Immunology, University of Muenster, Muenster, Germany
^b Interdisciplinary Centre for Clinical Research IZKF, University Hospital Muenster, University of Muenster, Muenster, Germany
^c Department of Paediatric Rheumatology and Immunology, University Children's Hospital Muenster, University of Muenster, Muenster, Germany
^d Laboratory for Translational Immunology, Department of Paediatric Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
^e Department of Clinical Chemistry Großhadern, University of Munich, Munich, Germany
^f Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, Switzerland
^g 2nd Division of Pediatrics “G. Gaslini” Scientific Institute, Genoa, Italy
^h Leidos Biomedical Research, Frederick, Md
ⁱ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
^j Department of Immunology, Hospital Universitario Son Espases, Palma de Mallorca, Spain
^k Department of Pediatrics, Hospital Universitario de Canarias, La Laguna, Spain
^l Department of Immunology-CDB, Hospital Clinic-IDIBAPS, Barcelona, Spain
^m Department of Paediatrics, Complejo Hospitalario Universitario Insular Materno Infantil, Las Palmas de Gran Canaria, Spain
ⁿ Department of Pediatric Rheumatology Hospital Universitario Reina Sofia, Cordoba, Spain
^o 3rd Department of Pediatrics, Athens University Medical School, “ATTIKON” Hospital, Athens, Greece
^p Service de Génétique Médicale, Centre Hospitalo-Universitaire, Nantes, France
^q Service de Pédiatrie, CH Cholet, Cholet, France
^r Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
^s Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
^t Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif
^u Department of Pediatrics, University of California, San Francisco, Calif
^v 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
^w Children's Hospital and Clinics of Minnesota, Saint Paul, Minn
^x Department of Paediatric Immunology and Children's BMT Unit, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
^y Institute of Clinical Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
^z 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
^aa Northern Institute of Cancer Research, University of Newcastle, Newcastle upon Tyne, United Kingdom
^bb Human Dendritic Cell Laboratory, Newcastle University Medical School, Newcastle upon Tyne, United Kingdom
^cc Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, Giessen, Germany
^dd Deutsches Zentrum für Kinder–und Jugendrheumatologie, Garmisch-Partenkirchen, Germany
^ee Department of Paediatrics/Paediatric Rheumatology, St Maartenskliniek and Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
^ff Department of Dermatology, University Hospital Muenster, Muenster, Germany
^gg National Human Genome Research Institute, National Institutes of Health, Bethesda, Md
^hh Department for Translational Dermatoinfectiology, University Hospital Muenster, Muenster, Germany

^∗Corresponding author: Johannes Roth, MD, Institute of Immunology, University of Muenster, 48149 Muenster, Germany.

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.

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Key words : 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

Abbreviations used : AIN, FMF, Hz/Hc, MIF, MRP, PAPA, PSTPIP1, SJIA, TLR, WT

Plan

Methods

Patients and samples

Patients with PAPA syndrome, SJIA, and FMF

Analysis of MRP8/MRP14 in serum and skin and zinc serum levels

Analysis of anti-neutrophil antibodies

Genotype analysis

Structural model and sequence alignment

Immunoprecipitation and phosphorylation of PSTPIP1

Extracellular cytokine measurement

Statistical analysis

Results

Characterization of clinical phenotype in patients with Hz/Hc

Genetic studies

Alteration of electrostatic potential of PSTPIP1

Binding of pyrin and phosphorylation of PSTPIP1

Serum concentration of MRP8/14 and zinc in patients with PSTPIP1 mutations

Serum cytokine profile of Hz/Hc and PAPA syndrome

Response to treatment

Discussion

Supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Instituters of Health, Department of Health and Haman Services (to S.M.H.) and in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Also supported by “Fondo de Investigaciones Sanitarias,” Ministerio de Economía y Competitividad (PI06/1031, PI10/01718), with the funding of European Regional Development Fund European Social Fund FEDER-FSE, the Interdisciplinary Centre for Clinical Research University of Münster, the German Research Foundation (SFB1009), and the Bundesministerium für Bildung und Forschung (AID-NET, project 01GM08100).

Disclosure of potential conflict of interest: M. Gattorno has received consultancy fees, research support, and lecture fees from Novartis and SOBI. C. Rodríguez-Gallego and C. Hinze have received lecture fees from Novartis. J. A. Bernstein has received consultancy fees from McKesson, research support from the National Institutes of Health (NIH) and CIRM, and lecture fees from the University of Minnesota. J. A. Church has received research support from Pfizer and BioProducts Laboratory. R. Skinner has provided expert testimony for the Medical Defence Union and the NHS Health Service and has received research support from Newcastle upon Tyne Hospitals NHS Foundation Trust, Malawi-Royal Victoria Infirmary, the Children's Cancer Fund, and Children with Cancer UK. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 136 - N° 5

P. 1337-1345 - novembre 2015 Retour au numéro

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Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)–associated inflammatory diseases - 06/11/15

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