Gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1): Chronic mucocutaneous candidiasis accompanied by enamel defects and delayed dental shedding

Frans, Glynis; Moens, Leen; Schaballie, Heidi; Eyck, Lien Van; Borgers, Heleen; Wuyts, Margareta; Dillaerts, Doreen; Vermeulen, Edith; Dooley, James; Grimbacher, Bodo; Cant, Andrew J.; Declerck, Dominique; Peumans, Marleen; Renard, Marleen; Boeck, K. De; Hoffman, Ilse; François, Inge; Liston, Adrian; Claessens, Frank; Bossuyt, Xavier; Meyts, Isabelle

doi:10.1016/j.jaci.2014.05.044

Cited by 45 publications

(43 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…13, 26, 27 As expected, CD4 + T cells from pt 2 displayed exaggerated STAT1-phosphorylation in response to in vitro stimulation with types I and II IFN which could also be mitigated by in vitro treatment with ruxolitinib (Fig E2 in the Online Repository). Importantly, pt 2 suffered from chronic mucocutaneous candidiasis and opportunistic infectious without any clinical evidence of autoimmunity and displayed an increase in the fraction of circulating CXCR5 + , PD1 + T FH cells (Fig 3 C).…”

Section: Resultssupporting

confidence: 62%

“…This finding was corroborated in a different patient with known STAT1 T385M GOF mutation in the DNA-binding domain who presented solely with chronic mucocutaneous candidiasis and opportunistic infections but without clinical evidence of autoimmunity. 13, 26, 27 Long-term treatment with the JAK inhibitor ruxolitinib decreased the elevated STAT1 phosphorylation, reversed the dysregulated T H 1 and T FH development, improves the previously impaired T H 17 response, and enabled effective control of the autoimmune cytopenias. This is the first report demonstrating mechanistic evidence that pharmacologic manipulation of the JAK-STAT pathway in patients with STAT1 GOF mutation leads to reversal of the immune dysregulation phenotype, and provides proof of principle that JAK-inhibitors are not only effective in treating active autoimmune disease and immunodeficiency secondary to hyper-responsiveness to STAT1 but in reversing the aberrant priming of naïve cells, thereby maintaining long-term disease control and sustained remission.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation

Weinacht

Charbonnier

Alroqi

et al. 2017

Journal of Allergy and Clinical Immunology

144

105

View full text Add to dashboard Cite

Background Gain of function (GOF) mutations in the human Signal Transducer and Activator of Transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity with impaired T helper (TH) 17 cell differentiation and exaggerated responsiveness to types I and II interferon. Allogeneic bone marrow transplantation has been attempted in severely affected patients but outcomes have been poor. Objective We sought to define the effect of increased STAT1 activity on T helper cell polarization and to investigate the therapeutic potential of ruxolitinib in treating autoimmunity secondary to STAT1 GOF mutations. Methods We used in vitro polarization assays as well as phenotypic and functional analysis of STAT1-mutated patient cells. Results We report on a child with a novel mutation in the linker domain of STAT1 who suffered from life-threatening autoimmune cytopenias and chronic mucocutaneous candidiasis. Naïve patient lymphocytes displayed increased TH1 and T follicular helper (TFH) cell as well as suppressed TH17 cell responses. The mutation augmented cytokine-induced STAT1 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase (JAK) 1/2 inhibitor ruxolitinib reduced hyper-responsiveness to types I and II interferon, normalized TH1 and TFH cell responses, improved TH17 differentiation, cured mucocutaneous candidiasis and maintained remission of immune mediated cytopenias. Conclusions Autoimmunity and infection due to STAT1 GOF mutations is caused by dysregulated T helper cell responses. JAK inhibitor therapy could represent an effective targeted treatment for long-term disease control in severely affected patients for whom hematopoietic stem cell transplantation is not available.

show abstract

Section: Resultssupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation

Weinacht

Charbonnier

Alroqi

et al. 2017

Journal of Allergy and Clinical Immunology

144

105

View full text Add to dashboard Cite

show abstract

“…Many CMC-related GOF mutations have been identified in CCD/DBD of STAT1 in previous studies. 15–23, 25–44, 48 In contrast, only two MSMD-causing LOF STAT1 mutations (E320Q and Q463H) have been identified in DBD, and no LOF mutation has been reported in CCD. 10 …”

Section: Resultsmentioning

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

“…Phospho-flow can be used in the diagnostic evaluation of PIDs associated with defects in the STAT (signal transducer and activator of transcription factor) molecules, e.g., loss-of-function (LOF) STAT1 mutations seen in patients with susceptibility to intracellular bacterial and viral infections (72,73). Similarly, gain-of-function (GOF) mutations seen in the same gene, STAT1, associated with autosomal dominant chronic mucocutaneous candidiasis (CMC) and defective Th17 immunity (74)(75)(76)(77)(78) can also be assessed by changes in phosphorylation by flow cytometry. It is important to recognize that for accurate diagnostic use of phospho-flow assays, only the appropriate cell subset after careful selection of the stimulus (typically cytokines) is evaluated.…”

Section: Functional Flow Cytometry For Disease-specific Pids and Immumentioning

confidence: 99%

Flow Cytometry, a Versatile Tool for Diagnosis and Monitoring of Primary Immunodeficiencies

Abraham

Aubert

2016

Clin Vaccine Immunol

View full text Add to dashboard Cite

bGenetic defects of the immune system are referred to as primary immunodeficiencies (PIDs). These immunodeficiencies are clinically and immunologically heterogeneous and, therefore, pose a challenge not only for the clinician but also for the diagnostic immunologist. There are several methodological tools available for evaluation and monitoring of patients with PIDs, and of these tools, flow cytometry has gained prominence, both for phenotyping and functional assays. Flow cytometry allows real-time analysis of cellular composition, cell signaling, and other relevant immunological pathways, providing an accessible tool for rapid diagnostic and prognostic assessment. This minireview provides an overview of the use of flow cytometry in disease-specific diagnosis of PIDs, in addition to other broader applications, which include immune phenotyping and cellular functional measurements.

show abstract

Gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1): Chronic mucocutaneous candidiasis accompanied by enamel defects and delayed dental shedding

Cited by 45 publications

References 13 publications

Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation

Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation

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

Flow Cytometry, a Versatile Tool for Diagnosis and Monitoring of Primary Immunodeficiencies

Contact Info

Product

Resources

About