title: Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases.
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.
  
  
  CONCLUSIONS
  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.affiliation: 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.
authors.forename: Dirk
authors.initials: D
authors.lastname: Holzinger
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany.
authors.forename: Selina Kathleen
authors.initials: SK
authors.lastname: Fassl
authors.affiliation: Laboratory for Translational Immunology, Department of Paediatric Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Wilco
authors.initials: W
authors.lastname: de Jager
authors.affiliation: Department of Clinical Chemistry Großhadern, University of Munich, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lohse
authors.affiliation: Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, Switzerland.
authors.forename: Ute F
authors.initials: UF
authors.lastname: Röhrig
authors.affiliation: 2nd Division of Pediatrics "G. Gaslini" Scientific Institute, Genoa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
authors.affiliation: 2nd Division of Pediatrics "G. Gaslini" Scientific Institute, Genoa, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Omenetti
authors.affiliation: 2nd Division of Pediatrics "G. Gaslini" Scientific Institute, Genoa, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Chiesa
authors.affiliation: 2nd Division of Pediatrics "G. Gaslini" Scientific Institute, Genoa, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Schena
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany; Interdisciplinary Centre for Clinical Research IZKF, University Hospital Muenster, University of Muenster, Muenster, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Austermann
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany; Interdisciplinary Centre for Clinical Research IZKF, University Hospital Muenster, University of Muenster, Muenster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.affiliation: Leidos Biomedical Research, Frederick, Md.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kuhns
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: Department of Immunology, Hospital Universitario Son Espases, Palma de Mallorca, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodríguez-Gallego
authors.affiliation: Department of Pediatrics, Hospital Universitario de Canarias, La Laguna, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: López-Almaraz
authors.affiliation: Department of Immunology-CDB, Hospital Clinic-IDIBAPS, Barcelona, Spain.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Arostegui
authors.affiliation: Department of Paediatrics, Complejo Hospitalario Universitario Insular Materno Infantil, Las Palmas de Gran Canaria, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Colino
authors.affiliation: Department of Pediatric Rheumatology Hospital Universitario Reina Sofia, Cordoba, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Roldan
authors.affiliation: 3rd Department of Pediatrics, Athens University Medical School, "ATTIKON" Hospital, Athens, Greece.
authors.forename: Smaragdi
authors.initials: S
authors.lastname: Fessatou
authors.affiliation: Service de Génétique Médicale, Centre Hospitalo-Universitaire, Nantes, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.affiliation: Service de Pédiatrie, CH Cholet, Cholet, France.
authors.forename: Sylvaine
authors.initials: S
authors.lastname: Poignant
authors.affiliation: Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ito
authors.affiliation: Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Hans-Joerg
authors.initials: HJ
authors.lastname: Epple
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Bernstein
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Michael
authors.initials: M
authors.lastname: Jeng
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Frankovich
authors.affiliation: Department of Pediatrics, University of California, San Francisco, Calif.
authors.forename: Geraldina
authors.initials: G
authors.lastname: Lionetti
authors.affiliation: 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.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Church
authors.affiliation: 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.
authors.forename: Peck Y
authors.initials: PY
authors.lastname: Ong
authors.affiliation: Children's Hospital and Clinics of Minnesota, Saint Paul, Minn.
authors.forename: Mona
authors.initials: M
authors.lastname: LaPlant
authors.affiliation: 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.
authors.forename: Mario
authors.initials: M
authors.lastname: Abinun
authors.affiliation: 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.
authors.forename: Rod
authors.initials: R
authors.lastname: Skinner
authors.affiliation: Human Dendritic Cell Laboratory, Newcastle University Medical School, Newcastle upon Tyne, United Kingdom.
authors.forename: Venetia
authors.initials: V
authors.lastname: Bigley
authors.affiliation: Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, Giessen, Germany.
authors.forename: Ulrich J
authors.initials: UJ
authors.lastname: Sachs
authors.affiliation: Interdisciplinary Centre for Clinical Research IZKF, University Hospital Muenster, University of Muenster, Muenster, Germany; Deutsches Zentrum für Kinder-und Jugendrheumatologie, Garmisch-Partenkirchen, Germany.
authors.forename: Claas
authors.initials: C
authors.lastname: Hinze
authors.affiliation: Department of Paediatrics/Paediatric Rheumatology, St Maartenskliniek and Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Hoppenreijs
authors.affiliation: 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.
authors.forename: Jan
authors.initials: J
authors.lastname: Ehrchen
authors.affiliation: 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.
authors.forename: Dirk
authors.initials: D
authors.lastname: Foell
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Md.
authors.forename: Jae Jin
authors.initials: JJ
authors.lastname: Chae
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Md.
authors.forename: Amanda
authors.initials: A
authors.lastname: Ombrello
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Md.
authors.forename: Ivona
authors.initials: I
authors.lastname: Aksentijevich
authors.affiliation: 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.
authors.forename: Cord
authors.initials: C
authors.lastname: Sunderkoetter
authors.affiliation: 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.
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000067531:Alarmins / Q000235:genetics / Q000378:metabolism; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism; D002648:Child; D016207:Cytokines / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D039841:Leukocyte L1 Antigen Complex / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008664:Metal Metabolism, Inborn Errors / Q000235:genetics / Q000276:immunology*; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics; D060066:Protein Interaction Maps / Q000235:genetics; D055503:Protein Multimerization; D000071198:Pyrin; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000067531:Alarmins; D040501:Calgranulin A; D016207:Cytokines; D003598:Cytoskeletal Proteins; D039841:Leukocyte L1 Antigen Complex; C000604192:MEFV protein, human; C486382:PSTPIP1 protein, human; D000071198:Pyrin
keywords: Hyperzincemia and hypercalprotectinemia; S100 proteins; autoinflammation; calprotectin; genotype; myeloid-related protein 8/14; phenotype; proline-serine-threonine phosphatase-interacting protein 1; pyogenic arthritis, pyoderma gangrenosum, and acne syndrome; zinc