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      STAT1 Hyperphosphorylation and Defective IL12R/IL23R Signaling Underlie Defective Immunity in Autosomal Dominant Chronic Mucocutaneous Candidiasis

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          Abstract

          We recently reported the genetic cause of autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) as a mutation in the STAT1 gene. In the present study we show that STAT1 Arg274Trp mutations in the coiled-coil (CC) domain is the genetic cause of AD-CMC in three families of patients. Cloning and transfection experiments demonstrate that mutated STAT1 inhibits IL12R/IL-23R signaling, with hyperphosphorylation of STAT1 as the likely underlying molecular mechanism. Inhibition of signaling through the receptors for IL-12 and IL-23 leads to strongly diminished Th1/Th17 responses and hence to increased susceptibility to fungal infections. The challenge for the future is to translate this knowledge into novel strategies for the treatment of this severe immunodeficiency.

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          Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.

          Shona Kerr, I Kerr, G Stark … (1994)
          Through the study of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), a previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and direct transcription. Recognition of the molecules involved in the IFN-alpha and IFN-gamma pathway has led to discoveries that a number of STAT family members exist and that other polypeptide ligands also use the Jak-STAT molecules in signal transduction.
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            A homozygous CARD9 mutation in a family with susceptibility to fungal infections.

            Erik-Oliver Glocker, Andre Hennigs, Mohammad Nabavi … (2009)
            Chronic mucocutaneous candidiasis may be manifested as a primary immunodeficiency characterized by persistent or recurrent infections of the mucosa or the skin with candida species. Most cases are sporadic, but both autosomal dominant inheritance and autosomal recessive inheritance have been described. We performed genetic studies in 36 members of a large, consanguineous five-generation family, in which 4 members had recurrent fungal infections and an additional 3 members died during adolescence, 2 after invasive infection of the brain with candida species. All 36 family members were enrolled in the study, and 22 had blood samples taken for DNA analysis. Homozygosity mapping was used to locate the mutated gene. In the 4 affected family members (patients) and the 18 unaffected members we sequenced CARD9, the gene encoding the caspase recruitment domain-containing protein 9, carried out T-cell phenotyping, and performed functional studies, with the use of either leukocytes from the patients or a reconstituted murine model of the genetic defect. We found linkage (lod score, 3.6) to a genomic interval on chromosome 9q, including CARD9. All four patients had a homozygous point mutation in CARD9, resulting in a premature termination codon (Q295X). Healthy family members had wild-type expression of the CARD9 protein; the four patients lacked wild-type expression, which was associated with low numbers of Th17 cells (helper T cells producing interleukin-17). Functional studies based on genetic reconstitution of myeloid cells from Card9(-/-) mice showed that the Q295X mutation impairs innate signaling from the antifungal pattern-recognition receptor dectin-1. An autosomal recessive form of susceptibility to chronic mucocutaneous candidiasis is associated with homozygous mutations in CARD9. 2009 Massachusetts Medical Society
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              STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis.

              Frank van de Veerdonk, Theo Plantinga, Alexander Hoischen … (2011)
              Chronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to candida infection of skin, nails, and mucous membranes. Patients with recessive CMC and autoimmunity have mutations in the autoimmune regulator AIRE. The cause of autosomal dominant CMC is unknown. We evaluated 14 patients from five families with autosomal dominant CMC. We incubated their peripheral-blood mononuclear cells with different combinations of stimuli to test the integrity of pathways that mediate immunity, which led to the selection of 100 genes that were most likely to contain the genetic defect. We used an array-based sequence-capture assay, followed by next-generation sequencing, to identify mutations. The mononuclear cells from the affected patients were characterized by poor production of interferon-γ, interleukin-17, and interleukin-22, suggesting that the defect lay within the interleukin-12 receptor and interleukin-23 receptor signaling pathways. We identified heterozygous missense mutations in the DNA sequence encoding the coiled-coil (CC) domain of signal transducer and activator of transcription 1 (STAT1) in the patients. These mutations lead to defective responses in type 1 and type 17 helper T cells (Th1 and Th17). The interferon-γ receptor pathway was intact in these patients. Mutations in the CC domain of STAT1 underlie autosomal dominant CMC and lead to defective Th1 and Th17 responses, which may explain the increased susceptibility to fungal infection. (Funded by the Netherlands Organization for Scientific Research and others.).
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2011
                Publication date (Electronic): 14 December 2011
                Volume: 6
                Issue: 12
                Electronic Location Identifier: e29248
                Affiliations
                [1 ]Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [2 ]Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [3 ]Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [4 ]Nijmegen Institute for Infection, Inflammation, and Immunity (N4i), Nijmegen, The Netherlands
                [5 ]Royal Manchester Hospital, University of Manchester, Manchester, United Kingdom
                [6 ]Institute for Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
                University Freiburg, Germany
                Author notes

                Conceived and designed the experiments: TSP FLvdV AH JAV MGN. Performed the experiments: SPS TSP BH AH. Analyzed the data: SPS TSP FLvdV BH AH LABJ BJK JAV DL JWMvdM MGN. Contributed reagents/materials/analysis tools: PDA AG DL MGN. Wrote the paper: SPS TSP FLvdV BH AH LABJ BJK JAV DL JWMvdM MGN.

                ¶ This author also contributed equally to this work.

                Article
                Publisher ID: PONE-D-11-13775
                DOI: 10.1371/journal.pone.0029248
                PMC ID: 3237610
                PubMed ID: 22195034
                SO-VID: bf5f8054-d7b1-4c1c-b5ab-b91a756998c1
                Copyright © Smeekens et al. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
                History
                Date received : 19 July 2011
                Date accepted : 23 November 2011
                Page count
                Pages: 7
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Genetics
                Subject: Human Genetics
                Subject: Autosomal Dominant
                Subject: Genetics of Disease
                Subject: Molecular Genetics
                Subject: Immunology
                Subject: Immune System
                Subject: Cytokines
                Subject: Immunity
                Subject: Immune Deficiency
                Subject: Immunity to Infections
                Subject: Medicine
                Subject: Clinical Genetics
                Subject: Infectious Diseases
                Subject: Fungal Diseases
                Subject: Cutaneous Mycoses
                Subject: Dermatophytosis
                Subject: Mycosis Infections
                Subject: Subcutaneous Mycoses
                Subject: Superficial Mycoses

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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