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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
immunology and microbiology
Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis
Journal of Experimental Medicine, Volume 208, No. 18, Year 2011
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Description
Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity. © 2011 Liu et al.
Authors & Co-Authors
Liu, Luyan
France, Paris
L'institut Des Maladies Génétiques Imagine
Okada, Satoshi
United States, New York
Rockefeller University
Kong, Xiao Fei
United States, New York
Rockefeller University
Kreins, Alexandra Y.
United States, New York
Rockefeller University
Cypowyj, Sophie
United States, New York
Rockefeller University
Abhyankar, Avinash
United States, New York
Rockefeller University
Toubiana, Julie
France, Paris
Hôpital Necker Enfants Malades
Itan, Yuval
United States, New York
Rockefeller University
Audry, Magali
United States, New York
Rockefeller University
Nitschké, Patrick
France, Paris
Hôpital Necker Enfants Malades
Masson, Cécile
France, Paris
Hôpital Necker Enfants Malades
Tóth, Beáta
Hungary, Debrecen
Általános Orvostudományi Kar
Flatot, Jérome
France, Paris
L'institut Des Maladies Génétiques Imagine
Migaud, Mélanie
France, Paris
L'institut Des Maladies Génétiques Imagine
Chrabieh, Maya
France, Paris
L'institut Des Maladies Génétiques Imagine
Kochetkov, Tatiana
United States, New York
Rockefeller University
Bolze, Alexandre
France, Paris
L'institut Des Maladies Génétiques Imagine
United States, New York
Rockefeller University
Borghesi, Alessandro
France, Paris
L'institut Des Maladies Génétiques Imagine
Toulon, Antoine
France, Paris
Hôpital Necker Enfants Malades
Hiller, Julia
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Eyerich, Stefanie
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Eyerich, Kilian
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Germany, Munich
Technische Universität München
Gulácsy, Vera
Hungary, Debrecen
Általános Orvostudományi Kar
Chernyshova, Ludmyla
Ukraine, Kyiv
Shupyk National Healthcare University of Ukraine
Chernyshov, Viktor
Ukraine, Kyiv
National Academy of Medical Sciences of Ukraine
Bondarenko, Anastasiia V.
Ukraine, Kyiv
Shupyk National Healthcare University of Ukraine
Grimaldo, Rosa María Cortés
Mexico, Guadalajara
Umae-he-cmno-imms
Blancas-Galicia, Lizbeth
Mexico, Mexico
Instituto Nacional de Pediatría
Beas, Ileana Maria Madrigal
Mexico, Guadalajara
Umae-he-cmno-imms
Roesler, Joachim R.
Germany, Dresden
Universitätsklinikum Carl Gustav Carus Dresden
Magdorf, Klaus
Germany, Berlin
Charité – Universitätsmedizin Berlin
Engelhard, Dan
Israel, Jerusalem
Hadassah University Medical Centre
Thumerelle, Caroline
France, Lille
Chu Lille
Burgel, Pierre Régis
France, Paris
Hopital Cochin Ap-hp
Hoernes, Miriam
Switzerland, Zurich
Kinderspital Zürich
Drexel, Barbara
Switzerland, Zurich
Kinderspital Zürich
Seger, Reinhard A.
Switzerland, Zurich
Kinderspital Zürich
Kusuma, Theresia
Germany, Munich
Klinikum Der Universität München
Jansson, Annette F.
Germany, Munich
Klinikum Der Universität München
Sawalle-Belohradsky, Julie
Germany, Munich
Klinikum Der Universität München
Belohradsky, Bernd H.
Germany, Munich
Klinikum Der Universität München
Jouanguy, Emmanuelle
France, Paris
L'institut Des Maladies Génétiques Imagine
United States, New York
Rockefeller University
Bustamante, Jacinta Cecilia
France, Paris
L'institut Des Maladies Génétiques Imagine
Bué, Mélanie
France, Brest
Centre Hospitalier Universitaire de Brest
Karin, Nathan
Israel, Haifa
Technion - Israel Institute of Technology
Wildbaum, Gizi
Israel, Haifa
Technion - Israel Institute of Technology
Bodemer, Christine
France, Paris
Hôpital Necker Enfants Malades
Lortholary, Olivier
France, Paris
Hôpital Necker Enfants Malades
Fischer, Alain M.
France, Paris
Hôpital Necker Enfants Malades
Blanche, Stéphane
France, Paris
Hôpital Necker Enfants Malades
Al-Muhsen, Saleh Zaid
Israel, Haifa
Technion - Israel Institute of Technology
Reichenbach, Janine
Switzerland, Zurich
Kinderspital Zürich
Kobayashi, Masao
Japan, Hiroshima
Hiroshima University Graduate School of Biomedical and Health Sciences
Rosales, Francisco Espinosa
Mexico, Mexico
Instituto Nacional de Pediatría
Lozano, Carlos Torres
Mexico, Guadalajara
Umae-he-cmno-imms
Kiliç, Sara Şebnem
Turkey, Bursa
Bursa Uludağ Üniversitesi
Oleastro, Matías M.
Argentina, Buenos Aires
Hospital Prof. Dr. Juan P. Garrahan
Etzioni, Amos
Israel, Haifa
Technion - Israel Institute of Technology
Traidl-Hoffman, Claudia
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Germany, Munich
Technische Universität München
Renner, Ellen D.
Germany, Munich
Klinikum Der Universität München
Abel, Laurent
France, Paris
L'institut Des Maladies Génétiques Imagine
United States, New York
Rockefeller University
Pïcard, Capucine
France, Paris
L'institut Des Maladies Génétiques Imagine
France, Paris
Hôpital Necker Enfants Malades
Máródi, László D.R.
Hungary, Debrecen
Általános Orvostudományi Kar
Boisson-Dupuis, Stéphanie
France, Paris
L'institut Des Maladies Génétiques Imagine
United States, New York
Rockefeller University
Puel, Anne
France, Paris
L'institut Des Maladies Génétiques Imagine
Casanova, Jean Laurent
France, Paris
L'institut Des Maladies Génétiques Imagine
United States, New York
Rockefeller University
France, Paris
Hôpital Necker Enfants Malades
Saudi Arabia, Riyadh
College of Medicine
Statistics
Citations: 733
Authors: 66
Affiliations: 23
Identifiers
Doi:
10.1084/jem.20110958
ISSN:
00221007
e-ISSN:
15409538
Research Areas
Cancer
Genetics And Genomics