title: The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Engesser Straße 4, 79108, Freiburg, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Depner
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Engesser Straße 4, 79108, Freiburg, Germany.|Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fuchs
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Engesser Straße 4, 79108, Freiburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Raabe
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Engesser Straße 4, 79108, Freiburg, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Frede
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Engesser Straße 4, 79108, Freiburg, Germany.
authors.forename: Cristina
authors.initials: C
authors.lastname: Glocker
authors.affiliation: Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Rainer
authors.initials: R
authors.lastname: Doffinger
authors.affiliation: Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Effrossyni
authors.initials: E
authors.lastname: Gkrania-Klotsas
authors.affiliation: Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Dinakantha
authors.initials: D
authors.lastname: Kumararatne
authors.affiliation: University of Alabama at Birmingham, Birmingham, USA.
authors.forename: T Prescott
authors.initials: TP
authors.lastname: Atkinson
authors.affiliation: University of Alabama at Birmingham, Birmingham, USA.
authors.forename: Harry W
authors.initials: HW
authors.lastname: Schroeder
authors.affiliation: Helios Kliniken, Childrens Hospital, Krefeld, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Niehues
authors.affiliation: Helios Kliniken, Childrens Hospital, Krefeld, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Dückers
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Asbjørg
authors.initials: A
authors.lastname: Stray-Pedersen
authors.affiliation: Medical University of Hannover, Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baumann
authors.affiliation: Medical University of Hannover, Hannover, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schmidt
authors.affiliation: Group of Primary Immunodeficiencies, Universidad de Antioquia, Medellin, Colombia.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Franco
authors.affiliation: Group of Primary Immunodeficiencies, Universidad de Antioquia, Medellin, Colombia.
authors.forename: Julio
authors.initials: J
authors.lastname: Orrego
authors.affiliation: Division of Pediatric Allergy and Clinical Immunology, McGill University Health Center, Montreal, QC, Canada.
authors.forename: Moshe
authors.initials: M
authors.lastname: Ben-Shoshan
authors.affiliation: Division of Pediatric Allergy and Clinical Immunology, McGill University Health Center, Montreal, QC, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: McCusker
authors.affiliation: University of São Paulo, São Paulo, Brazil.
authors.forename: Cristina Miuki Abe
authors.initials: CM
authors.lastname: Jacob
authors.affiliation: University of São Paulo, São Paulo, Brazil.
authors.forename: Magda
authors.initials: M
authors.lastname: Carneiro-Sampaio
authors.affiliation: Immunology Day Centre, Royal Group of Hospitals, Belfast, UK.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Devlin
authors.affiliation: Immunology Day Centre, Royal Group of Hospitals, Belfast, UK.|Queen's University Belfast, Belfast, UK.
authors.forename: J David M
authors.initials: JD
authors.lastname: Edgar
authors.affiliation: Child Life and Health, University of Edinburgh, Edinburgh, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Henderson
authors.affiliation: Department of Paediatric Gastroenterology, Royal Hospital for Sick Children, Glasgow, UK.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Russell
authors.affiliation: Department of Genetics, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Anne-Bine
authors.initials: AB
authors.lastname: Skytte
authors.affiliation: Royal Free Hospital, University College London, London, UK.
authors.forename: Suranjith L
authors.initials: SL
authors.lastname: Seneviratne
authors.affiliation: Royal Free Hospital, University College London, London, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wanders
authors.affiliation: Royal Free Hospital, University College London, London, UK.
authors.forename: Hans
authors.initials: H
authors.lastname: Stauss
authors.affiliation: Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meyts
authors.affiliation: Department of Microbiology and Immunology, Experimental Laboratory Immunology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Moens
authors.affiliation: Center for Diagnosis and Treatment of Primary Immunodeficiencies, Department of Pediatrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovak Republic.
authors.forename: Milos
authors.initials: M
authors.lastname: Jesenak
authors.affiliation: Department of Paediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Robin
authors.initials: R
authors.lastname: Kobbe
authors.affiliation: Immuno Deficiency Center Leipzig, Clinic St. Georg, Leipzig, Germany.|Translational Centre for Regenerative Medicine, University Leipzig, Leipzig, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Borte
authors.affiliation: Immuno Deficiency Center Leipzig, Clinic St. Georg, Leipzig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Borte
authors.affiliation: Division of Rheumatology and Immunology, Children's Hospital Central California, Madera, CA, USA.
authors.forename: Dowain A
authors.initials: DA
authors.lastname: Wright
authors.affiliation: University of Washington and Seattle Children's Research Institute, Seattle, WA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hagin
authors.affiliation: Department of Pediatrics and Immunology, University of Washington, Seattle, WA, USA.
authors.forename: Troy R
authors.initials: TR
authors.lastname: Torgerson
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Engesser Straße 4, 79108, Freiburg, Germany. bodo.grimbacher@uniklinik-freiburg.de.|Royal Free Hospital, University College London, London, UK. bodo.grimbacher@uniklinik-freiburg.de.|DZIF Center, Standort Freiburg, Germany. bodo.grimbacher@uniklinik-freiburg.de.
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
mesh_terms: D000328:Adult; D002178:Candidiasis, Chronic Mucocutaneous / Q000175:diagnosis* / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017434:Protein Structure, Tertiary / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human
keywords: CMC; Chronic mucocutaneous candidiasis; GOF; PID; STAT1; gain-of-function; phosphorylation; primary immunodeficiency; signal transducer and activator of transcription 1