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STAT1
signal transducer and activator of transcription 1
STAT1 is located on the long (q) arm of chromosome 2, at band 2q32.2. Arm ratio per GRCh38 - banding schematic.
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Overview
STAT1 (signal transducer and activator of transcription 1) is located on chromosome 2 and produces a 750-amino-acid protein essential for coordinating immune system responses. The protein acts as a transcription factor, meaning it regulates which genes are switched on or off in immune cells. STAT1 plays a dual role in immunity: it promotes interferon-mediated defence against viruses and mycobacteria whilst simultaneously restraining inflammatory pathways that respond to fungal infections. This balancing function is critical for preventing both immunodeficiency and excessive inflammation. Pathogenic variants in STAT1 can cause either loss of immune function or inappropriate immune activation, depending on how the variant affects the protein's activity.
What the gene does
The STAT1 protein functions as a central regulator in several immune signalling cascades. When activated by interferon-alpha, interferon-beta, or interferon-gamma signals, STAT1 undergoes phosphorylation and moves into the cell nucleus, where it binds to DNA and activates genes required for antiviral and antibacterial responses. The interferon-gamma pathway, in particular, is essential for controlling mycobacterial infections including tuberculosis. Conversely, STAT1 inhibits the interleukin-17 pathway, which generates inflammation and antimicrobial peptides in response to Candida fungus. By suppressing IL-17 signalling, STAT1 prevents excessive tissue damage from prolonged inflammation. This regulatory function requires precise control: the protein must be activated when interferons are present but remain inactive otherwise. The protein's ability to recognise specific DNA sequences and recruit other transcription factors determines which immune genes are expressed in response to different pathogens.
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Chromosome location
STAT1 is located at chromosomal band 2q32.2 on the long arm of chromosome 2. This genomic region contains the complete coding sequence for the 750-amino-acid protein, spanning multiple exons that are transcribed and spliced together to form the mature messenger RNA.
Protein structure
The STAT1 protein is organised into distinct functional regions that enable its role as a transcription factor. A coiled coil domain extends from amino acids 136 to 317, facilitating protein-protein interactions essential for STAT1 to form dimers with other transcription factors. The C-terminal region contains an SH2 domain spanning amino acids 573 to 670, which recognises and binds to phosphorylated tyrosine residues on receptor proteins, allowing STAT1 to respond to interferon signals. These structural elements work together to control when and how the protein activates gene transcription.
Key variants
Variants in STAT1 produce distinct clinical effects depending on whether they enhance or reduce protein function. Gain-of-function variants typically impair the protein's ability to be switched off after activation, resulting in excessive suppression of the IL-17 pathway and increased susceptibility to Candida infections. Loss-of-function variants reduce or eliminate the protein's normal activity, weakening interferon-mediated immunity and causing vulnerability to viral and mycobacterial infections. The variant landscape reflects both autosomal dominant and autosomal recessive inheritance patterns.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Pathogenic STAT1 variants are associated with several immune disorders affecting infection susceptibility. Mendelian susceptibility to mycobacterial disease can result from loss-of-function variants that impair interferon-gamma signalling, reducing the body's ability to control mycobacterial infections. STAT1 gain-of-function (chronic mucocutaneous candidiasis) arises from variants that cause prolonged protein activation, suppressing IL-17 responses and leading to recurrent Candida infections of the skin, nails, and mucous membranes. The clinical severity and specific infection pattern depend on how the variant affects protein activity and which immune pathways are most disrupted.
- Mendelian susceptibility to mycobacterial disease
- STAT1 gain-of-function (CMC) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic STAT1 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
STAT1 is included on several NHS England PanelApp gene panels used for diagnosing immune disorders. It holds green (high-evidence) classification on the COVID-19 research panel, the Infantile enterocolitis and monogenic inflammatory bowel disease panel, and the Primary immunodeficiency or monogenic inflammatory bowel disease panel. These classifications reflect the gene's established role in immune regulation and its relevance to clinical genomic testing pathways within the NHS Genomic Medicine Service.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the difference between STAT1 gain-of-function and loss-of-function variants?
Gain-of-function variants cause the STAT1 protein to remain active for too long, suppressing IL-17 immunity and leading to Candida infections. Loss-of-function variants reduce or eliminate protein activity, weakening interferon responses and causing susceptibility to viral and mycobacterial infections.
How is STAT1 inherited?
STAT1-related conditions can follow either autosomal dominant or autosomal recessive inheritance patterns depending on the specific variant. Gain-of-function variants typically cause dominant conditions, whilst some loss-of-function variants follow recessive inheritance.
Why does STAT1 affect susceptibility to specific infections rather than all pathogens?
STAT1 regulates particular immune pathways rather than general immunity. It promotes interferon responses effective against viruses and mycobacteria whilst restraining IL-17 inflammation that controls fungal infections, so variants affect only the specific pathways where STAT1 normally functions.
References
- Depner M, Fuchs S, Raabe J. The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1. Journal of clinical immunology. 2016. PMID: 26604104
- Toubiana J, Okada S, Hiller J. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood. 2016. PMID: 27114460
- Mizoguchi Y, Tsumura M, Okada S. Simple diagnosis of STAT1 gain-of-function alleles in patients with chronic mucocutaneous candidiasis. Journal of leukocyte biology. 2014. PMID: 24343863
- Yamazaki Y, Yamada M, Kawai T. Two novel gain-of-function mutations of STAT1 responsible for chronic mucocutaneous candidiasis disease: impaired production of IL-17A and IL-22, and the presence of anti-IL-17F autoantibody. Journal of immunology (Baltimore, Md. : 1950). 2014. PMID: 25288569
- Smeekens SP, van de Veerdonk FL, Kullberg BJ. Genetic susceptibility to Candida infections. EMBO molecular medicine. 2013. PMID: 23629947
- Soltész B, Tóth B, Shabashova N. New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe. Journal of medical genetics. 2013. PMID: 23709754
- Boisson-Dupuis S, Kong XF, Okada S. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Current opinion in immunology. 2012. PMID: 22651901
- Liu L, Okada S, Kong XF. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. The Journal of experimental medicine. 2011. PMID: 21727188