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J Clin Immunol. 2016 Jan;36(1):73-84. doi: 10.1007/s10875-015-0214-9. Epub 2015 Nov 25.

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

Author information

1
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Engesser Straße 4, 79108, Freiburg, Germany.
2
Faculty of Biology, University of Freiburg, Freiburg, Germany.
3
Addenbrooke's Hospital, Cambridge, UK.
4
University of Alabama at Birmingham, Birmingham, USA.
5
Helios Kliniken, Childrens Hospital, Krefeld, Germany.
6
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
7
Medical University of Hannover, Hannover, Germany.
8
Group of Primary Immunodeficiencies, Universidad de Antioquia, Medellin, Colombia.
9
Division of Pediatric Allergy and Clinical Immunology, McGill University Health Center, Montreal, QC, Canada.
10
University of São Paulo, São Paulo, Brazil.
11
Immunology Day Centre, Royal Group of Hospitals, Belfast, UK.
12
Queen's University Belfast, Belfast, UK.
13
Child Life and Health, University of Edinburgh, Edinburgh, UK.
14
Department of Paediatric Gastroenterology, Royal Hospital for Sick Children, Glasgow, UK.
15
Department of Genetics, Aarhus University Hospital, Aarhus, Denmark.
16
Royal Free Hospital, University College London, London, UK.
17
Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
18
Department of Microbiology and Immunology, Experimental Laboratory Immunology, Katholieke Universiteit Leuven, Leuven, Belgium.
19
Center for Diagnosis and Treatment of Primary Immunodeficiencies, Department of Pediatrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovak Republic.
20
Department of Paediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
21
Immuno Deficiency Center Leipzig, Clinic St. Georg, Leipzig, Germany.
22
Translational Centre for Regenerative Medicine, University Leipzig, Leipzig, Germany.
23
Division of Rheumatology and Immunology, Children's Hospital Central California, Madera, CA, USA.
24
University of Washington and Seattle Children's Research Institute, Seattle, WA, USA.
25
Department of Pediatrics and Immunology, University of Washington, Seattle, WA, USA.
26
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Engesser Straße 4, 79108, Freiburg, Germany. bodo.grimbacher@uniklinik-freiburg.de.
27
Royal Free Hospital, University College London, London, UK. bodo.grimbacher@uniklinik-freiburg.de.
28
DZIF Center, Standort Freiburg, Germany. bodo.grimbacher@uniklinik-freiburg.de.

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:

CMC; Chronic mucocutaneous candidiasis; GOF; PID; STAT1; gain-of-function; phosphorylation; primary immunodeficiency; signal transducer and activator of transcription 1

PMID:
26604104
PMCID:
PMC4718942
DOI:
10.1007/s10875-015-0214-9
[Indexed for MEDLINE]
Free PMC Article

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