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

Details

Serval ID
serval:BIB_07A123F31FC2
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases.
Journal
Journal of Allergy and Clinical Immunology
Author(s)
Holzinger D., Fassl S.K., de Jager W., Lohse P., Röhrig U.F., Gattorno M., Omenetti A., Chiesa S., Schena F., Austermann J., Vogl T., Kuhns D.B., Holland S.M., Rodríguez-Gallego C., López-Almaraz R., Arostegui J.I., Colino E., Roldan R., Fessatou S., Isidor B., Poignant S., Ito K., Epple H.J., Bernstein J.A., Jeng M., Frankovich J., Lionetti G., Church J.A., Ong P.Y., LaPlant M., Abinun M., Skinner R., Bigley V., Sachs U.J., Hinze C., Hoppenreijs E., Ehrchen J., Foell D., Chae J.J., Ombrello A., Aksentijevich I., Sunderkoetter C., Roth J.
ISSN
1097-6825 (Electronic)
ISSN-L
0091-6749
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
136
Number
5
Pages
1337-1345
Language
english
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.
Pubmed
Web of science
Create date
30/10/2015 9:23
Last modification date
20/08/2019 12:30
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