# Consequences of a Stat1 gain-of-function mutation in gene expression and viral response

> **NIH NIH FI2** · NATIONAL INST ARTH/MUSCLOSKEL/SKIN DIS · 2020 · —

## Abstract

Project Summary/Abstract
Stat proteins are major drivers of gene expression and genetic variations are linked to many immune
pathologies, indicating the importance of Stat proteins in regulating gene expression in health and disease. In
addition, Stat proteins themselves must be regulated. Indeed, cytokine signaling can be tuned by the relative
abundance and activation of Stat proteins. One disease example of altered tuning of Stat signaling is the
heterozygous autosomal dominant gain-of-function (GOF) Stat1 disorder. Stat1-GOF mutations are located in
its coil-coil domain or DNA binding domain and result in heightened Stat1 activation/phosphorylation after
cytokine stimulation. Consequently, Stat1-activating cytokines induce elevated gene expression in samples
from Stat1-GOF patients. This disorder was first described in patients with chronic mucosal candidiasis (CMC)
and later attributed to a broad clinical phenotype, including chronic infections associated with primary
immunodeficiencies (fungal, bacterial, viral), autoimmunity, and cancer. A simple view of this disorder is that
enhanced type 1 immunity/IFN-gamma production inhibits type 3/Th17 responses and may thus explain fungal
disease, however many patients also develop chronic viral infections which typically requires type 1 immunity
for viral clearance. This paradox emphasizes that there is still a critical need to understand the basic principles
of cytokine signaling, specifically how a Stat1-GOF mutation alters the cytokine output. Using a new mouse
model with mutated Stat1, we will determine in Aim 1 how a Stat1-GOF mutation alters the transcriptome,
chromatin landscape, and Stat1/Stat4 binding in IL-12-stimulated NK cells, and in Aim 2 examine how Stat1-
GOF mice respond to MCMV infection. These results will provide critical new insights into basic principles of
canonical cell signaling pathway and mechanisms of transcriptional regulation.

## Key facts

- **NIH application ID:** 10026895
- **Project number:** 1FI2GM137942-01
- **Recipient organization:** NATIONAL INST ARTH/MUSCLOSKEL/SKIN DIS
- **Principal Investigator:** Rachael Laura Philips
- **Activity code:** FI2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026895

## Citation

> US National Institutes of Health, RePORTER application 10026895, Consequences of a Stat1 gain-of-function mutation in gene expression and viral response (1FI2GM137942-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10026895. Licensed CC0.

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