Advertisement

Pediatric Rheumatology

, 11:A158 | Cite as

PW02-018 - Impact of PSTPIP1 mutaions on clinical phenotype

  • D Holzinger
  • P Lohse
  • S Faßl
  • J Austermann
  • T Vogl
  • W de Jager
  • S Holland
  • M Gattorno
  • C Rodriguez-Gallego
  • J Arostegui
  • S Fessatou
  • B Isidor
  • K Ito
  • H-J Epple
  • J Bernstein
  • M Jeng
  • G Lionetti
  • P Ong
  • C Hinze
  • B Sampson
  • C Sunderkoetter
  • D Foell
  • J Chae
  • A Ombrello
  • J Brady
  • I Aksentijevich
  • J Roth
Open Access
Meeting abstract

Keywords

Glutamic Acid Clinical Phenotype Cytokine Profile Heterozygous Carrier E275K Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Introduction

Hyperzincaemia and hypercalprotectinaemia (Hz/Hc), a rare condition within the spectrum of autoinflammatory diseases, is associated with hepatosplenomegaly, arthritis, anemia, cutaneous inflammation, and failure to thrive. So far, no genetic cause has been identified. While the clinical appearance is heterogeneous, all affected individuals present with extremely elevated MRP8/MRP14 (calprotectin) serum concentrations (0.9-12.0 g/l (normal range < 0.001 g/l)).

Objectives

The clinical phenotype of 12 patients was characterized and compared to 11 patients with classical PAPA syndrome. Screening of candidate genes was performed to identify disease-causing mutations.

Methods

Serum concentrations of MRP8/14 complex were analyzed in 12 patients with Hz/Hc and compared to 11 PAPA patients. Candidate exons of these patients were sequenced. Cytokine profile of 12 patients with PSTPIP1 mutations was analyzed by mulitplex ELISA. MRP8/14 secretion from patient´s PBMCs was measured and activity of patient`s sera on monocytes evaluated. The clinical phenotype of all enrolled patients was characterized and compared.

Results

Ten of twelve patients were heterozygous carriers of a glutamic acid 250 (GAG)→lysine (AAG)/p.Glu250Lys/E250K substitution and 1 patient of a glutamic acid 257 (GAG)→lysine (AAG)/p.Glu250Lys/E257K substitution in exon 11 of the PSTPIP1 gene. MRP8/MRP14 concentrations were extremely elevated in these patients (0.9-12 g/l) compared to eleven patients presenting with classical PAPA symptoms (0.02-0.35 g/l), whose levels again were significantly higher compared to normal controls. Cytokine profiling confirmed the heterogeneity of PSTPIP1 mutations with a distinct profile for the Hz/Hc phenotype. MRP8/14 hypersecretion was found in PBMCs of patients with PSTPIP1 mutations and the serum of patients with active disease showed co-stimulatory properties on monocytes activated with TLR-1 ligands.

Conclusion

The novel PSTPIP1 E250K and E275K mutations cause an autoinflammatory disorder known as hyperzincaemia and hypercalprotectinaemia. The disease causes a heterogeneous spectrum of symptoms that only partially overlaps with the presentation of the classical PAPA syndrome. Elevated MRP8/14 levels are a common hallmark and biomarker of disorders caused by mutations in the PSTPIP1 gene.

Disclosure of interest

None declared.

Copyright information

© Holzinger et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Authors and Affiliations

  • D Holzinger
    • 1
    • 2
  • P Lohse
    • 3
  • S Faßl
    • 1
  • J Austermann
    • 1
  • T Vogl
    • 1
  • W de Jager
    • 4
  • S Holland
    • 5
  • M Gattorno
    • 6
  • C Rodriguez-Gallego
    • 7
  • J Arostegui
    • 8
  • S Fessatou
    • 9
  • B Isidor
    • 10
  • K Ito
    • 11
  • H-J Epple
    • 12
  • J Bernstein
    • 13
  • M Jeng
    • 13
  • G Lionetti
    • 13
  • P Ong
    • 14
  • C Hinze
    • 15
  • B Sampson
    • 16
  • C Sunderkoetter
    • 17
  • D Foell
    • 2
  • J Chae
    • 18
  • A Ombrello
    • 18
  • J Brady
    • 18
  • I Aksentijevich
    • 18
  • J Roth
    • 1
  1. 1.Institute of ImmunologyUniversity Hospital MuensterGermany
  2. 2.Department of Paediatric Rheumatology and ImmunologyUniversity Children´s Hospital MuensterMuensterGermany
  3. 3.Department of Clinical Chemistry GroßhadernUniversity MunichMunichGermany
  4. 4.Department of Pediatric ImmunologyUniversity Medical Centre UtrechtUtrechtThe Netherlands
  5. 5.National Institute of Allergy and Infectious DiseasesNational Institute of HealthBethesdaUSA
  6. 6.2nd Division of Pediatrics"G. Gaslini" Scientific InstituteGenovaItaly
  7. 7.Department of ImmunologyDr. Negrín University Hospital, Las Palmas de Gran CanariaSpain
  8. 8.Immunology Department-CDB/IDIBAPSHospital ClinicBarcelonaSpain
  9. 9.3rd Department of PediatricsAthens University Medical FacultyAthensGreece
  10. 10.Service de Génétique MédicaleCentre Hospitalo-UniversitaireNantesFrance
  11. 11.Department of Pediatrics and NeonatologyNagoya City UniversityNagoyaJapan
  12. 12.Department of Gastroenterology, Infectious Diseases and RheumatologyCharité University Hospital BerlinBerlinGermany
  13. 13.Department of PediatricsStanford University Medical CenterStanfordUSA
  14. 14.Division of Clinical Immunology and AllergyChildren's Hospital Los AngelesLAUSA
  15. 15.Deutsches Zentrum für Kinder- und Jugendrheumatologie, Garmisch-PatenkirchenGermany
  16. 16.Department of Clinical ChemistryCharing Cross HospitalLondonUK
  17. 17.Department of DermatologyUniversity Hospital MuensterMuensterGermany
  18. 18.National Institute of Arthritis and Musculoskeletal and Skin DiseasesNational Institute of HealthBethesdaUSA

Personalised recommendations