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

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

doi:10.1016/j.jaci.2015.04.016

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

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 IsidorSylvaine 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

Child Health

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1337-1345
Number of pages	9
Journal	Journal of Allergy and Clinical Immunology
Volume	136
Issue number	5
DOIs	https://doi.org/10.1016/j.jaci.2015.04.016
Publication status	Published - Nov 2015

Keywords

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

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10.1016/j.jaci.2015.04.016

Cite this

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., ... Roth, J. (2015). Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases. Journal of Allergy and Clinical Immunology, 136(5), 1337-1345. https://doi.org/10.1016/j.jaci.2015.04.016

@article{3b19e45d5f144c5abae097157fc230ab,

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.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.",

keywords = "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",

author = "Dirk Holzinger and Fassl, {Selina Kathleen} and {de Jager}, Wilco and Peter Lohse and R{\"o}hrig, {Ute F} and Marco Gattorno and Alessia Omenetti and Sabrina Chiesa and Francesca Schena and Judith Austermann and Thomas Vogl and Kuhns, {Douglas B} and Holland, {Steven M} and Carlos Rodr{\'i}guez-Gallego and Ricardo L{\'o}pez-Almaraz and Arostegui, {Juan I} and Elena Colino and Rosa Roldan and Smaragdi Fessatou and Bertrand Isidor and Sylvaine Poignant and Koichi Ito and Hans-Joerg Epple and Bernstein, {Jonathan A} and Michael Jeng and Jennifer Frankovich and Geraldina Lionetti and Church, {Joseph A} and Ong, {Peck Y} and Mona LaPlant and Mario Abinun and Rod Skinner and Venetia Bigley and Sachs, {Ulrich J} and Claas Hinze and Esther Hoppenreijs and Jan Ehrchen and Dirk Foell and Chae, {Jae Jin} and Amanda Ombrello and Ivona Aksentijevich and Cord Sunderkoetter and Johannes Roth",

year = "2015",

month = nov,

doi = "10.1016/j.jaci.2015.04.016",

language = "English",

volume = "136",

pages = "1337--1345",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "5",

}

Holzinger, D, Fassl, SK, de Jager, W, Lohse, P, Röhrig, UF, Gattorno, M, Omenetti, A, Chiesa, S, Schena, F, Austermann, J, Vogl, T, Kuhns, DB, Holland, SM, Rodríguez-Gallego, C, López-Almaraz, R, Arostegui, JI, Colino, E, Roldan, R, Fessatou, S, Isidor, B, Poignant, S, Ito, K, Epple, H-J, Bernstein, JA, Jeng, M, Frankovich, J, Lionetti, G, Church, JA, Ong, PY, LaPlant, M, Abinun, M, Skinner, R, Bigley, V, Sachs, UJ, Hinze, C, Hoppenreijs, E, Ehrchen, J, Foell, D, Chae, JJ, Ombrello, A, Aksentijevich, I, Sunderkoetter, C & Roth, J 2015, 'Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases', Journal of Allergy and Clinical Immunology, vol. 136, no. 5, pp. 1337-1345. https://doi.org/10.1016/j.jaci.2015.04.016

Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases. / Holzinger, Dirk; Fassl, Selina Kathleen; de Jager, Wilco et al.
In: Journal of Allergy and Clinical Immunology, Vol. 136, No. 5, 11.2015, p. 1337-1345.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases

AU - Holzinger, Dirk

AU - Fassl, Selina Kathleen

AU - de Jager, Wilco

AU - Lohse, Peter

AU - Röhrig, Ute F

AU - Gattorno, Marco

AU - Omenetti, Alessia

AU - Chiesa, Sabrina

AU - Schena, Francesca

AU - Austermann, Judith

AU - Vogl, Thomas

AU - Kuhns, Douglas B

AU - Holland, Steven M

AU - Rodríguez-Gallego, Carlos

AU - López-Almaraz, Ricardo

AU - Arostegui, Juan I

AU - Colino, Elena

AU - Roldan, Rosa

AU - Fessatou, Smaragdi

AU - Isidor, Bertrand

AU - Poignant, Sylvaine

AU - Ito, Koichi

AU - Epple, Hans-Joerg

AU - Bernstein, Jonathan A

AU - Jeng, Michael

AU - Frankovich, Jennifer

AU - Lionetti, Geraldina

AU - Church, Joseph A

AU - Ong, Peck Y

AU - LaPlant, Mona

AU - Abinun, Mario

AU - Skinner, Rod

AU - Bigley, Venetia

AU - Sachs, Ulrich J

AU - Hinze, Claas

AU - Hoppenreijs, Esther

AU - Ehrchen, Jan

AU - Foell, Dirk

AU - Chae, Jae Jin

AU - Ombrello, Amanda

AU - Aksentijevich, Ivona

AU - Sunderkoetter, Cord

AU - Roth, Johannes

PY - 2015/11

Y1 - 2015/11

N2 - 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.

AB - 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.

KW - Hyperzincemia and hypercalprotectinemia

KW - myeloid-related protein 8/14

KW - calprotectin

KW - S100 proteins

KW - zinc

KW - proline-serine-threonine phosphatase-interacting protein 1

KW - pyogenic arthritis

KW - pyoderma gangrenosum, and acne syndrome

KW - genotype

KW - phenotype

KW - autoinflammation

U2 - 10.1016/j.jaci.2015.04.016

DO - 10.1016/j.jaci.2015.04.016

M3 - Article

C2 - 26025129

SN - 0091-6749

VL - 136

SP - 1337

EP - 1345

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 5

ER -

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

Abstract

Keywords

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