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STAT1 Mutations in Autosomal Dominant Chronic Mucocutaneous Candidiasis Frank L

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STAT1 Mutations in Autosomal Dominant Chronic Mucocutaneous Candidiasis Frank L T h e new england journal o f medicine original article STAT1 Mutations in Autosomal Dominant Chronic Mucocutaneous Candidiasis Frank L. van de Veerdonk, M.D., Ph.D., Theo S. Plantinga, Ph.D., Alexander Hoischen, Ph.D., Sanne P. Smeekens, M.Sc., Leo A.B. Joosten, Ph.D., Christian Gilissen, Ph.D., Peer Arts, Ph.D., Diana C. Rosentul, M.Sc., Andrew J. Carmichael, M.D., Chantal A.A. Smits-van der Graaf, M.D., Ph.D., Bart Jan Kullberg, M.D., Ph.D., Jos W.M. van der Meer, M.D., Ph.D., Desa Lilic, M.D., Ph.D., Joris A. Veltman, Ph.D., and Mihai G. Netea, M.D., Ph.D. Abstr act Background Chronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to can- From the Departments of Medicine (F.L.V., dida infection of skin, nails, and mucous membranes. Patients with recessive CMC T.S.P., S.P.S., L.A.B.J., D.C.R., C.A.A.S.G., B.J.K., J.W.M.M., M.G.N.), Human Genet- and autoimmunity have mutations in the autoimmune regulator AIRE. The cause of ics (A.H., C.G., P.A., J.A.V.), and Pulmonary autosomal dominant CMC is unknown. Diseases (C.A.A.S.G.), Radboud University Nijmegen Medical Center, and the Nijme- Methods gen Institute for Infection, Inflammation, and Immunity (F.L.V., T.S.P., S.P.S., L.A.B.J., We evaluated 14 patients from five families with autosomal dominant CMC. We D.C.R., C.A.A.S.G., B.J.K., J.W.M.M., M.G.N.) incubated their peripheral-blood mononuclear cells with different combinations of — both in Nijmegen, the Netherlands; and the Department of Dermatology, James stimuli to test the integrity of pathways that mediate immunity, which led to the Cook University Hospital, Middlesbrough selection of 100 genes that were most likely to contain the genetic defect. We used an (A.J.C.), and the Institute for Cellular Medi- array-based sequence-capture assay, followed by next-generation sequencing, to iden- cine, Newcastle University, Newcastle upon Tyne (D.L.) — both in the United Kingdom. tify mutations. Address reprint requests to Dr. van der Meer at the Department of Medicine, Radboud Results University Nijmegen Medical Center, P.O. Box 9101, 6500 HB Nijmegen, the Nether- The mononuclear cells from the affected patients were characterized by poor pro- lands, or at [email protected]. duction of interferon-γ, interleukin-17, and interleukin-22, suggesting that the defect lay within the interleukin-12 receptor and interleukin-23 receptor signaling pathways. The following two groups of authors con- tributed equally to this article: Drs. van de We identified heterozygous missense mutations in the DNA sequence encoding the Veerdonk, Plantinga, and Hoischen; and coiled-coil (CC) domain of signal transducer and activator of transcription 1 (STAT1) Drs. Lilic, Veltman, and Netea. in the patients. These mutations lead to defective responses in type 1 and type 17 This article (10.1056/NEJMoa1100102) was helper T cells (Th1 and Th17). The interferon-γ receptor pathway was intact in these published on June 29, 2011, at NEJM.org. patients. N Engl J Med 2011. Conclusions Copyright © 2011 Massachusetts Medical Society. 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.) 10.1056/nejmoa1100102 nejm.org 1 The New England Journal of Medicine Downloaded from nejm.org on June 30, 2011. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. T h e new england journal o f medicine hronic mucocutaneous candidiasis autoimmune hepatitis, and the daughter has auto- (CMC) is a primary immunodeficiency dis- immune hemolysis and pernicious anemia, along Corder that is characterized by susceptibility with antiphospholipid antibodies. The daughter to infection of the skin, nails, and mucous mem- has had pulmonary embolism and Pneumocystis branes by candida species and dermatophytes.1 jirovecii pneumonia with symptomatic cytomega- There are several CMC subtypes: autosomal reces- lovirus infection. The son has extensive dermato- sive autoimmune polyendocrinopathy candidiasis phytosis (Trichophyton rubrum) of the feet but no with ectodermal dystrophy (APECED), autosomal autoimmune phenomena. We characterized the im- dominant CMC with or without thyroid disease, mune responses of peripheral-blood mononuclear and autosomal recessive, isolated CMC. cells (PBMCs) from the three affected family mem- The defect in APECED resides in the autoim- bers, the unaffected mother, and three healthy con- mune regulator AIRE, which has a key role in im- trol subjects. The father has nine unaffected sib- munotolerance.2 The susceptibility to candida in lings (Fig. 1A). We carried out genetic analyses of patients with APECED is attributed to autoantibod- all affected and unaffected family members. ies to interleukin-17 and interleukin-22,3 since type 17 helper T cells (Th17) are crucial for mucosal Families 2, 3, and 4 antifungal immunity.4 Little is known about the We performed immunologic and genetic analyses defects underlying susceptibility to candida in pa- of samples from nine members of three unrelat- tients with autosomal dominant CMC. In a pre- ed families of European descent from the United vious study, we found that Th1–interferon-γ re- Kingdom (Families 2, 3, and 4). All nine patients sponses were defective in patients with autosomal have autosomal dominant CMC with hypothyroid- dominant CMC.5 In a more recent study, investiga- ism. Their characteristics have been reported previ- tors found defective Th17 responses in patients ously9,10 (Table S1 in the Supplementary Appendix). with this disorder.6 Defective recognition of can- One patient in Family 2 has oral squamous-cell dida because of mutations in the dectin-1–CARD9 carcinoma; the father in Family 4 died of esopha- pathway leads to increased susceptibility to fun- geal cancer.9 All patients were screened for AIRE gi,7,8 but the clinical picture is less severe than mutations to rule out the APECED syndrome.11 We in autosomal dominant CMC. We sought the ge- also analyzed samples from unaffected members netic cause of susceptibility to mucocutaneous of Family 4. fungal infection in families with autosomal dom- inant CMC. Family 5 We analyzed two members with CMC and three Methods unaffected members of a Dutch family (Family 5). Both Patient 1 and her mother had esophageal can- Study Design cer (Table S1 in the Supplementary Appendix). The study was approved by the ethics committee at Radboud University Nijmegen Medical Center and Unaffected Subjects the Newcastle and North Tyneside research ethics We assessed 301 unrelated healthy Dutch control committee. Written informed consent was obtained subjects and 56 healthy British control subjects of from all family members and healthy control sub- European ancestry for the genetic mutations of jects who were evaluated. CMC. We also analyzed an in-house Nijmegen da- tabase of 100 exome data sets that were derived Family 1 from healthy subjects of European ancestry with- Family 1 was a nonconsanguineous family of Dutch out signs of CMC. A questionnaire concerning descent in which the father, daughter, and son have the ethnic origin of parents and grandparents of had severe CMC since early childhood (Fig. 1A, and the healthy subjects confirmed their ancestry in the Tables S1 and S2 in the Supplementary Appendix, Netherlands and the United Kingdom. available with the full text of this article at NEJM .org). The patients have severe oropharyngeal Immunologic Studies chronic candidiasis and severe dermatophytosis We incubated PBMCs (5×106 per milliliter), ob- and candidiasis of the feet (Fig. 1B). The father has tained by density centrifugation, at 37°C in 96-well 2 10.1056/nejmoa1100102 nejm.org The New England Journal of Medicine Downloaded from nejm.org on June 30, 2011. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. STAT1 Mutations in Chronic Mucocutaneous Candidiasis plates (Greiner),12 with or without heat-killed Can- A Family 1 dida albicans (1×106 microorganisms per milliliter [strain UC820]), Escherichia coli lipopolysaccharide (1 ng per milliliter) (Sigma-Aldrich), interleukin-1β (10 ng per milliliter), interleukin-12 (10 ng per mil- liliter), interleukin-18 (50 ng per milliliter), inter- leukin-23 (10 ng per milliliter) (R&D Systems), or interferon-γ (1 μg per milliliter) (Boehringer). We used an enzyme-linked immunosorbent assay to P1 measure levels of interleukin-1β, tumor necrosis factor α (TNF-α), interleukin-17, interleukin-22 (R&D Systems), interferon-γ, and interleukin-6 (PeliKine) after 24 and 48 hours of incubation (in the absence of serum) and after 5 days of incuba- P2 P3 tion (in the presence of 10% serum). All experi- ments were performed at least three times. B Clinical Manifestations Patient 1 Patient 2 Sequence Capture and DNA Sequencing We applied array-based sequence capture followed by next-generation sequencing (454 Life Sciences) to analyze 100 genes from known immunologic pathways (Table S3 in the Supplementary Appen- dix). Details regarding coverage statistics are also provided in Table S4 in the Supplementary Patient 1 Patient 3 Appendix. Validation of Mutations and Haplotype Analysis To validate the presence of mutations in signal transducer and activator of transcription 1 (STAT1) in affected patients, we amplified their DNA, using a polymerase-chain-reaction (PCR) assay, and se- Figure 1. Pedigree of Family 1 with Autosomal Dominant Chronic Mucocu- quenced the amplified DNA fragments by Sanger’s taneous Candidiasis (CMC) and Clinical Signs in Affected Family Members. method. All coding exons of the coiled-coil (CC) Panel A shows the pedigree of a Dutch family in which three members of domain of STAT1, including exon 10, were ampli- two generations have clinical symptoms characteristic of CMC (black sym- fied and analyzed.
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