Related Experiment Video
Updated: May 5, 2026
Adenoviral Transduction of Naive CD4 T Cells to Study Treg Differentiation
Published on: August 13, 2013
Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune
Gulbu Uzel1, Elizabeth P Sampaio, Monica G Lawrence
1Laboratory of Clinical Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1684, USA.
Background:
Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers.
Objective:
We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC.
Methods:
We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX)-like phenotype for STAT1 mutations.
Results:
We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M [2 patients]). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4(+) IL-17-producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4(+) T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2-induced STAT5 phosphorylation.
Conclusions:
Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.
Insights
Gain-of-function mutations in Signal Transducer and Activator of Transcription (STAT) 1 can lead to an IPEX-like syndrome. This study found these STAT1 mutations present in children with polyendocrinopathy, enteropathy, and dermatitis, with normal regulatory T cell function.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Mutations in Signal Transducer and Activator of Transcription (STAT) 1 are linked to various diseases, including infections, autoimmune disorders, and cancers.
- Gain-of-function mutations in STAT1 are known to cause chronic mucocutaneous candidiasis (CMC).
Purpose of the Study:
- To investigate the role of STAT1 gain-of-function mutations in clinical phenotypes beyond CMC.
- To identify STAT1 mutations in patients presenting with immune dysregulation and IPEX-like symptoms.
Main Methods:
- Screening of patients with CMC and autoimmunity for STAT1 mutations.
- Functional characterization of identified STAT1 mutations in vitro.
- Analysis of immune cell profiles, including regulatory T (Treg) cells, in affected patients.
- Exploration of large patient cohorts with IPEX-like phenotypes for STAT1 mutations.
Main Results:
- Five children with polyendocrinopathy, enteropathy, and dermatitis, resembling IPEX syndrome, were identified with uniallelic STAT1 mutations.
- Patients exhibited increased and prolonged STAT1 phosphorylation in response to specific cytokines (IFN-γ, IL-6, IL-21) and diminished CD4(+) IL-17-producing T-cell numbers.
- Regulatory T (Treg) cell percentages and function were normal in affected patients, and STAT5 phosphorylation was intact.
Conclusions:
- Gain-of-function mutations in STAT1 can manifest as an IPEX-like phenotype.
- This phenotype can occur despite normal frequency and function of regulatory T (Treg) cells.
- STAT1 mutations represent a significant genetic cause of immune dysregulation presenting as IPEX-like syndrome.
More Related Videos
11:35Screening for Functional Non-coding Genetic Variants Using Electrophoretic Mobility Shift Assay EMSA and DNA-affinity Precipitation Assay DAPA
Published on: August 21, 2016
11:19Merging Absolute and Relative Quantitative PCR Data to Quantify STAT3 Splice Variant Transcripts
Published on: October 9, 2016
Related Concept Videos
01:33Pleiotropy
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:20The JAK-STAT Signaling Pathway