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Open Access 01-01-2016 | Original Research

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

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

Published in: Journal of Clinical Immunology | Issue 1/2016

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.

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Title: The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1
Authors: Mark Depner
Sebastian Fuchs
Jan Raabe
Natalie Frede
Cristina Glocker
Rainer Doffinger
Effrossyni Gkrania-Klotsas
Dinakantha Kumararatne
T. Prescott Atkinson
Harry W. Schroeder Jr.
Tim Niehues
Gregor Dückers
Asbjørg Stray-Pedersen
Ulrich Baumann
Reinhold Schmidt
Jose L. Franco
Julio Orrego
Moshe Ben-Shoshan
Christine McCusker
Cristina Miuki Abe Jacob
Magda Carneiro-Sampaio
Lisa A. Devlin
J. David M. Edgar
Paul Henderson
Richard K. Russell
Anne-Bine Skytte
Suranjith L. Seneviratne
Jennifer Wanders
Hans Stauss
Isabelle Meyts
Leen Moens
Milos Jesenak
Robin Kobbe
Stephan Borte
Michael Borte
Dowain A. Wright
David Hagin
Troy R. Torgerson
Bodo Grimbacher
Publication date: 01-01-2016
Publisher: Springer US
Published in: Journal of Clinical Immunology / Issue 1/2016
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-015-0214-9

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

Abstract

Purpose

Methods

Results

Conclusion

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Abstract

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Conclusion

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