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, Jahrgang 36, Nr. 1, 01.2016, S. 73-84.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -