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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-60930

Liu, L; Okada, S; Kong, X F; Kreins, A Y; Cypowyj, S; Abhyankar, A; Toubiana, J; Itan, Y; Audry, M; Nitschke, P; Masson, C; Toth, B; Flatot, J; Migaud, M; Chrabieh, M; Kochetkov, T; Bolze, A; Borghesi, A; Toulon, A; Hiller, J; Eyerich, S; Eyerich, K; Gulácsy, V; Chernyshova, L; Chernyshov, V; Bondarenko, A; Grimaldo, R M C; Blancas-Galicia, L; Beas, I M M; Roesler, J; Magdorf, K; Engelhard, D; Thumerelle, C; Burgel, P R; Hoernes, M; Drexel, B; Seger, R; Kusuma, T; Jansson, A F; Sawalle-Belohradsky, J; Belohradsky, B; Jouanguy, E; Bustamante, J; Bué, M; Karin, N; Wildbaum, G; Bodemer, C; Lortholary, O; Fischer, A; Blanche, S; Al-Muhsen, S; Reichenbach, J; Kobayashi, M; Rosales, F E; Lozano, C T; Kilic, S S; Oleastro, M; Etzioni, A; Traidl-Hoffmann, C; Renner, E D; Abel, L; Picard, C; Maródi, L; Boisson-Dupuis, S; Puel, A; Casanova, J L (2011). Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. Journal of Experimental Medicine, 208(8):1635-1648.

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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.


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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Deposited On:11 Mar 2012 07:57
Last Modified:05 Apr 2016 15:43
Publisher:Rockefeller University Press
Publisher DOI:10.1084/jem.20110958
PubMed ID:21727188

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