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The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1

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The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1. / Depner, Mark; Fuchs, Sebastian; Raabe, Jan; Frede, Natalie; Glocker, Cristina; Doffinger, Rainer; Gkrania-Klotsas, Effrossyni; Kumararatne, Dinakantha; Atkinson, T Prescott; Schroeder, Harry W; Niehues, Tim; Dückers, Gregor; Stray-Pedersen, Asbjørg; Baumann, Ulrich; Schmidt, Reinhold; Franco, Jose L; Orrego, Julio; Ben-Shoshan, Moshe; McCusker, Christine; Jacob, Cristina Miuki Abe; Carneiro-Sampaio, Magda; Devlin, Lisa A; Edgar, J David M; Henderson, Paul; Russell, Richard K; Skytte, Anne-Bine; Seneviratne, Suranjith L; Wanders, Jennifer; Stauss, Hans; Meyts, Isabelle; Moens, Leen; Jesenak, Milos; Kobbe, Robin; Borte, Stephan; Borte, Michael; Wright, Dowain A; Hagin, David; Torgerson, Troy R; Grimbacher, Bodo.

In: J CLIN IMMUNOL, Vol. 36, No. 1, 01.2016, p. 73-84.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Depner, M, Fuchs, S, Raabe, J, Frede, N, Glocker, C, Doffinger, R, Gkrania-Klotsas, E, Kumararatne, D, Atkinson, TP, Schroeder, HW, Niehues, T, Dückers, G, Stray-Pedersen, A, Baumann, U, Schmidt, R, Franco, JL, Orrego, J, Ben-Shoshan, M, McCusker, C, Jacob, CMA, Carneiro-Sampaio, M, Devlin, LA, Edgar, JDM, Henderson, P, Russell, RK, Skytte, A-B, Seneviratne, SL, Wanders, J, Stauss, H, Meyts, I, Moens, L, Jesenak, M, Kobbe, R, Borte, S, Borte, M, Wright, DA, Hagin, D, Torgerson, TR & Grimbacher, B 2016, 'The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1', J CLIN IMMUNOL, vol. 36, no. 1, pp. 73-84. https://doi.org/10.1007/s10875-015-0214-9

APA

Depner, M., Fuchs, S., Raabe, J., Frede, N., Glocker, C., Doffinger, R., Gkrania-Klotsas, E., Kumararatne, D., Atkinson, T. P., Schroeder, H. W., Niehues, T., Dückers, G., Stray-Pedersen, A., Baumann, U., Schmidt, R., Franco, J. L., Orrego, J., Ben-Shoshan, M., McCusker, C., ... Grimbacher, B. (2016). The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1. J CLIN IMMUNOL, 36(1), 73-84. https://doi.org/10.1007/s10875-015-0214-9

Vancouver

Depner M, Fuchs S, Raabe J, Frede N, Glocker C, Doffinger R et al. The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1. J CLIN IMMUNOL. 2016 Jan;36(1):73-84. https://doi.org/10.1007/s10875-015-0214-9

Bibtex

@article{a12d9ec0e2de4253b4fcedf9c2398df9,
title = "The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1",
abstract = "PURPOSE: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients.METHODS: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients.RESULTS: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61%). Out of 39 familial cases from 11 families, 26 patients (67%) from 9 families and out of 18 sporadic cases, 9 patients (50%) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients.CONCLUSION: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.",
keywords = "Adult, Candidiasis, Chronic Mucocutaneous, Cells, Cultured, Cytokines, DNA Mutational Analysis, Female, Humans, Immunologic Deficiency Syndromes, Leukocytes, Mononuclear, Male, Mutation, Pedigree, Phenotype, Protein Structure, Tertiary, STAT1 Transcription Factor, Journal Article, Research Support, Non-U.S. Gov't",
author = "Mark Depner and Sebastian Fuchs and Jan Raabe and Natalie Frede and Cristina Glocker and Rainer Doffinger and Effrossyni Gkrania-Klotsas and Dinakantha Kumararatne and Atkinson, {T Prescott} and Schroeder, {Harry W} and Tim Niehues and Gregor D{\"u}ckers and Asbj{\o}rg Stray-Pedersen and Ulrich Baumann and Reinhold Schmidt and Franco, {Jose L} and Julio Orrego and Moshe Ben-Shoshan and Christine McCusker and Jacob, {Cristina Miuki Abe} and Magda Carneiro-Sampaio and Devlin, {Lisa A} and Edgar, {J David M} and Paul Henderson and Russell, {Richard K} and Anne-Bine Skytte and Seneviratne, {Suranjith L} and Jennifer Wanders and Hans Stauss and Isabelle Meyts and Leen Moens and Milos Jesenak and Robin Kobbe and Stephan Borte and Michael Borte and Wright, {Dowain A} and David Hagin and Torgerson, {Troy R} and Bodo Grimbacher",
year = "2016",
month = jan,
doi = "10.1007/s10875-015-0214-9",
language = "English",
volume = "36",
pages = "73--84",
journal = "J CLIN IMMUNOL",
issn = "0271-9142",
publisher = "Springer New York",
number = "1",

}

RIS

TY - JOUR

T1 - The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1

AU - Depner, Mark

AU - Fuchs, Sebastian

AU - Raabe, Jan

AU - Frede, Natalie

AU - Glocker, Cristina

AU - Doffinger, Rainer

AU - Gkrania-Klotsas, Effrossyni

AU - Kumararatne, Dinakantha

AU - Atkinson, T Prescott

AU - Schroeder, Harry W

AU - Niehues, Tim

AU - Dückers, Gregor

AU - Stray-Pedersen, Asbjørg

AU - Baumann, Ulrich

AU - Schmidt, Reinhold

AU - Franco, Jose L

AU - Orrego, Julio

AU - Ben-Shoshan, Moshe

AU - McCusker, Christine

AU - Jacob, Cristina Miuki Abe

AU - Carneiro-Sampaio, Magda

AU - Devlin, Lisa A

AU - Edgar, J David M

AU - Henderson, Paul

AU - Russell, Richard K

AU - Skytte, Anne-Bine

AU - Seneviratne, Suranjith L

AU - Wanders, Jennifer

AU - Stauss, Hans

AU - Meyts, Isabelle

AU - Moens, Leen

AU - Jesenak, Milos

AU - Kobbe, Robin

AU - Borte, Stephan

AU - Borte, Michael

AU - Wright, Dowain A

AU - Hagin, David

AU - Torgerson, Troy R

AU - Grimbacher, Bodo

PY - 2016/1

Y1 - 2016/1

N2 - PURPOSE: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients.METHODS: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients.RESULTS: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61%). Out of 39 familial cases from 11 families, 26 patients (67%) from 9 families and out of 18 sporadic cases, 9 patients (50%) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients.CONCLUSION: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.

AB - PURPOSE: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients.METHODS: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients.RESULTS: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61%). Out of 39 familial cases from 11 families, 26 patients (67%) from 9 families and out of 18 sporadic cases, 9 patients (50%) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients.CONCLUSION: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.

KW - Adult

KW - Candidiasis, Chronic Mucocutaneous

KW - Cells, Cultured

KW - Cytokines

KW - DNA Mutational Analysis

KW - Female

KW - Humans

KW - Immunologic Deficiency Syndromes

KW - Leukocytes, Mononuclear

KW - Male

KW - Mutation

KW - Pedigree

KW - Phenotype

KW - Protein Structure, Tertiary

KW - STAT1 Transcription Factor

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1007/s10875-015-0214-9

DO - 10.1007/s10875-015-0214-9

M3 - SCORING: Journal article

C2 - 26604104

VL - 36

SP - 73

EP - 84

JO - J CLIN IMMUNOL

JF - J CLIN IMMUNOL

SN - 0271-9142

IS - 1

ER -