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

详细信息    查看全文

• 作者：Dirk Holzinger ; MD^a ; ^b ; ^c ; Selina Kathleen Fassl ; MSc^a ; Wilco de Jager ; PhD^d ; Peter Lohse ; MD^e ; Ute F. Rö ; hrig ; 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 ; MDⁱ ; Carlos Rodrí ; guez-Gallego ; PhD^j ; Ricardo Ló ; pez-Almaraz ; MD^k ; Juan I. Arostegui ; MD ; PhD^l ; Elena Colino ; MD^m ; Rosa Roldan ; MD ; PhDⁿ ; 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 ; ^{rothj@uni-muenster.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：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
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：136
• 期：5
• 页码：1337-1345
• 全文大小：1879 K

文摘

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.