The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1

Depner, Mark; Fuchs, Sebastian; Raabe, Jan; Frede, Natalie; Glocker, Cristina; Döffinger, Rainer; Gkrania‐Klotsas, Effrossyni; Kumararatne, Dinakantha; Atkinson, T. Prescott; Schroeder, Harry W.; Niehues, Tim; Dückers, Gregor; Stray-Pedersen, Asbjørg; Baumann, Ulrich; Schmidt, Reinhold; Franco, José Luis; Orrego, Julio César; Ben‐Shoshan, Moshe; McCusker, Christine; Jacob, Cristina Miuki Abe; Carneiro‐Sampaio, Magda; Devlin, Lisa; Edgar, J. D. M.; Henderson, Paul; Russell, Richard K.; Skytte, Anne‐Bine; Seneviratne, Suranjith L.; Wanders, J; Stauss, Hans J.; Meyts, Isabelle; Moens, Leen; Jeseňák, Miloš; Kobbe, Robin; Borte, Stephan; Borte, Michael; Wright, Dowain A.; Hagin, David; Torgerson, Troy R.; Grimbacher, Bodo

doi:10.1007/s10875-015-0214-9

Cited by 122 publications

(148 citation statements)

References 45 publications

Supporting

Mentioning

142

Contrasting

Unclassified

Order By: Relevance

“…P2 and P4 were also treated for suspected pulmonary tuberculosis and tuberculous meningitis, respectively, without microbiological confirmation. None of the other clinical manifestations previously reported in patients with GOF STAT1 mutations, such as autoimmune endocrinopathy, aneurysms, or mucosal carcinomas, were detected (16,17,23,37,51). Detailed phenotyping of lymphocyte subsets was performed for patients from kindreds D, E, and H and revealed no abnormality (Fig.…”

Section: Resultsmentioning

confidence: 94%

“…In patients with STAT1 GOF mutations, CMC results, at least partly, from impairment of the development and/or survival of IL-17A/F-producing T cells, the underlying mechanisms of which remain unknown (28,52). Patients with these mutations, who had long been known to be prone to thyroid autoimmunity, were recently found to display other infectious and autoimmune phenotypes (16,17,23,37,51). Another genetic etiology of syndromic CMCD has recently been described, with AR retinoic acid-related orphan receptors γ (ROR-γ/γT) deficiency in three kindreds with CMC and severe mycobacterial disease (53).…”

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Lévy

Okada

Béziat

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

150

127

View full text Add to dashboard Cite

Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensalCandidaspecies. The first genetic etiology of isolated CMC—autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency—was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity toCandidaandStaphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.

show abstract

Section: Resultsmentioning

confidence: 94%

Section: Significancementioning

confidence: 99%

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Lévy

Okada

Béziat

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

150

127

View full text Add to dashboard Cite

show abstract

“…This is consistent with previous clinical observations that most reported disease-causing mutations in CCD/DBD are GOF and are associated with CMC. 4, 15, 16, 22, 36 In contrast, only two AD MSMD-related LOF mutations, E320Q and Q463H, both in DBD, have yet been reported in those domains. 10 The alanine-scanning assay revealed that four of 176 alanine substituents (E157A, T224A, G250A, and Q311A) in CCD were LOF.…”

Section: Discussionmentioning

confidence: 99%

Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants

Kagawa

Fujiki

Tsumura

et al. 2017

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

Background Germline heterozygous mutations in human STAT1 can cause loss of function (LOF), as in patients with Mendelian susceptibility to mycobacterial diseases (MSMD), or gain of function (GOF), as in patients with chronic mucocutaneous candidiasis (CMC). LOF and GOF mutations are equally rare and can affect the same domains of STAT1, especially the coiled-coil and DNA-binding domains (CCD/DBD). Moreover, 6% of CMC patients with a GOF STAT1 mutation develop mycobacterial disease, obscuring the functional significance of the identified STAT1 mutations. Current computational approaches, such as combined annotation-dependent depletion, do not distinguish LOF and GOF variants Objective Estimate variations in CCD/DBD of STAT1 Method Mutagenized 342 individual wild-type amino acids in CCD/DBD (45.6% of full-length STAT1) to alanine and tested the mutants for STAT1 transcriptional activity. Results Of these 342 mutants, 201 were neutral, 30 LOF, and 111 GOF in a luciferase assay. This assay system correctly estimated all previously reported LOF mutations (100%) and slightly fewer GOF mutations (78.1%) in CCD/DBD of STAT1. We found that GOF alanine mutants occurred at the interface of the antiparallel STAT1 dimer, suggesting that they destabilize this dimer. This assay also precisely predicted the impact of two hypomorphic and dominant-negative mutations, E157K and G250E, in CCD of STAT1 that we found in two unrelated MSMD patients. Conclusion Systematic alanine-scanning assay is a useful tool to estimate the GOF or LOF status and impact of heterozygous missense mutations in STAT1 identified in patients with severe infectious diseases, including mycobacterial and fungal diseases.

show abstract

“…Chronic mucocutaneous candidiasis is a clinical syndrome characterized by recurrent infections of mucus membranes and skin with Candida species. A majority of these patients have been shown to have gain-of-function mutations in STAT1, which promote type 1 immune responses and repress type 17 responses, predisposing individuals to infection with fungal diseases (54–58). Additionally, loss-of-function mutations in STAT1 have also been identified that confer significant susceptibility to viral and mycobacterial infections (59).…”

Section: Discussionmentioning

confidence: 99%

STAT1 Represses Cytokine-Producing Group 2 and Group 3 Innate Lymphoid Cells during Viral Infection

Stier

Goleniewska

Cephus

et al. 2017

The Journal of Immunology

View full text Add to dashboard Cite

The appropriate orchestration of different arms of the immune response is critical during viral infection to promote efficient viral clearance while limiting immunopathology. However, the signals and mechanisms that guide this coordination are not fully understood. Interferons are produced at high levels during viral infection and have convergent signaling through signal transducer and activator of transcription 1 (STAT1). We hypothesized that STAT1 signaling during viral infection would regulate the balance of innate lymphoid cells (ILC), a diverse class of lymphocytes that are poised to respond to environmental insults including viral infections with the potential for both anti-viral or immunopathologic functions. During infection with respiratory syncytial virus (RSV), STAT1-deficient mice had reduced numbers of anti-viral IFNγ+ ILC1 and increased numbers of immunopathologic IL-5+ and IL-13+ ILC2 and IL-17A+ ILC3 compared to RSV-infected WT mice. Using bone marrow chimeric mice, we found that both ILC-intrinsic and ILC-extrinsic factors were responsible for this ILC dysregulation during viral infection in STAT1-deficient mice. Regarding ILC-extrinsic mechanisms, we found that STAT1-deficient mice had significantly increased expression of IL-33 and IL-23, cytokines that promote ILC2 and ILC3 respectively, compared to WT mice during RSV infection. Moreover, disruption of IL-33 or IL-23 signaling attenuated cytokine-producing ILC2 and ILC3 responses in STAT1-deficient mice during RSV-infection. Collectively, these data demonstrate that STAT1 is a key orchestrator of cytokine-producing ILC responses during viral infection via ILC-extrinsic regulation of IL-33 and IL-23.

show abstract

The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1

Cited by 122 publications

References 45 publications

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants

STAT1 Represses Cytokine-Producing Group 2 and Group 3 Innate Lymphoid Cells during Viral Infection

Contact Info

Product

Resources

About