STAT1 was first reported in relation to Mendelian Susceptibility to Mycobacterial Disease (MSMD), autosomal dominant, in 2001 (Dupuis et al., PMID: 11452125). STAT1 is primarily activated by IFN in the response of the antimicrobial immune system. IFN-γ stimulation leads to STAT1 phosphorylation, inducing its homodimerization to form γ-activating factor (GAF), which is translocated to the nucleus, and binds to γ-activating sequences to induce transcription of target genes (PMID: 35456913).
MSMD is a primary immunodeficiency disease characterized by predisposition to clinical disease caused by weakly virulent mycobacteria such as non-tuberculous mycobacteria, Bacillus Calmette Guerin (BCG) and environmental mycobacteria, caused by a single gene mutation (PMID: 25453225). Genetic etiologies of MSMD are involved in the production or response to interferon-γ (IFN-γ).
6 missense variants that have been reported in 7 probands in 4 publications are included in this curation (PMIDs: 11452125, 16934001, 22573496, 36339330). Functional experiments demonstrated impaired phosphorylation, nuclear accumulation and GAF DNA binding activity of the mutant STAT1. Variants reported showed a dominant-negative effect on the gamma interferon activated sequence (GAS) activation, but not on the interferon-stimulated response element (ISRE) activation (PMID: 22573496).
Experimental evidence also supports this gene-disease relationship. Expression of STAT1 is widely enhanced in EBV transformed lymphocytes (PMID: 23715323). Defective GAF response which results in impaired mycobacterial immunity could be demonstrated in a mouse fibroblast cell line. Mutant cells showed defective STAT1 phosphorylation and nuclear accumulation upon stimulation by IFN-γ (PMID: 11452125).
In summary, STAT1 is definitively associated with Mendelian Susciptibility to Mycobacterial Disease (MSMD). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.