Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases.
Abstract | BACKGROUND: OBJECTIVE: We sought to characterize the genetic cause and clinical spectrum of Hz/Hc. METHODS: 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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Authors | Dirk Holzinger, Selina Kathleen Fassl, Wilco de Jager, Peter Lohse, Ute F Röhrig, Marco Gattorno, Alessia Omenetti, Sabrina Chiesa, Francesca Schena, Judith Austermann, Thomas Vogl, Douglas B Kuhns, Steven M Holland, Carlos Rodríguez-Gallego, Ricardo López-Almaraz, Juan I Arostegui, Elena Colino, Rosa Roldan, Smaragdi Fessatou, Bertrand Isidor, Sylvaine Poignant, Koichi Ito, Hans-Joerg Epple, Jonathan A Bernstein, Michael Jeng, Jennifer Frankovich, Geraldina Lionetti, Joseph A Church, Peck Y Ong, Mona LaPlant, Mario Abinun, Rod Skinner, Venetia Bigley, Ulrich J Sachs, Claas Hinze, Esther Hoppenreijs, Jan Ehrchen, Dirk Foell, Jae Jin Chae, Amanda Ombrello, Ivona Aksentijevich, Cord Sunderkoetter, Johannes Roth |
Journal | The Journal of allergy and clinical immunology
(J Allergy Clin Immunol)
Vol. 136
Issue 5
Pg. 1337-45
(Nov 2015)
ISSN: 1097-6825 [Electronic] United States |
PMID | 26025129
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2015 American Academy of Allergy, Asthma & Immunology. All rights reserved. |
Chemical References |
- Adaptor Proteins, Signal Transducing
- Alarmins
- Calgranulin A
- Cytokines
- Cytoskeletal Proteins
- Leukocyte L1 Antigen Complex
- MEFV protein, human
- PSTPIP1 protein, human
- Pyrin
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Topics |
- Adaptor Proteins, Signal Transducing
(genetics, metabolism)
- Adolescent
- Alarmins
(genetics, metabolism)
- Calgranulin A
(genetics, metabolism)
- Child
- Cytokines
(metabolism)
- Cytoskeletal Proteins
(genetics, metabolism)
- Female
- Genotype
- Humans
- Leukocyte L1 Antigen Complex
(genetics, metabolism)
- Male
- Metal Metabolism, Inborn Errors
(genetics, immunology)
- Mutation, Missense
(genetics)
- Phenotype
- Phosphorylation
- Protein Binding
(genetics)
- Protein Interaction Maps
(genetics)
- Protein Multimerization
- Pyrin
- Young Adult
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