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STAT3 GOF is a rare genetic disorder of the immune system. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which is encoded by the STAT3 gene in humans. Germline gain-of-function (GOF) mutations in the gene ''STAT3'' causes this early-onset autoimmune disease characterized by lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity, infections, eczema, and short stature. Investigations conducted by Sarah E Flanagan and Mark Russell from the Institute of Biomedical and Clinical Science, University of Exeter Medical School, Emma Haapaniemi from the Institute of Biomedical and Clinical Science, University of Exeter Medical Schoolby, and (Joshua Milner ) from the National Institute of Allergy and Infectious Disease, National Institutes of Health have described this condition in 19 patients. ==Genetics and function== STAT3 GOF is caused by germline gain-of-function mutations in the gene ''STAT3''. ''STAT3'' maps to human chromosome 17q21.2, has 24 exons, and encodes for the 770 amino acid protein, STAT3. STAT3 is part of a family of proteins known as the STAT protein. These proteins play an essential role in chemical signaling pathways within cells. STAT3 is a transcription factor that once activated, moves into the nucleus and binds to specific areas of DNA. By binding to regulatory regions near genes, STAT3 mediates the expression of a variety of genes and is therefore necessary for many cellular processes including cell proliferation, inflammation, differentiation, and survival. STAT3 GOF patients were found to have germline heterozygous variants. Various missense mutations have been identified in multiple domains of the protein, including the all-alpha, DNA-binding, SH2, and C-terminal transactivation domains (Milner et al, 2014). The genetic model for this disease is gain-of-function. This means that for people with STAT3 GOF disease, the gene STAT3 is hyperactive, leading to an intrinsic increase of transcriptional activity 〔〔 While the consequences of STAT3 hyperactivity are not yet fully understood, some insights into the underlying mechanisms have been identified. Researchers have identified an increase of suppressor of cytokine signaling 3 (SOCS3) in a large number of STAT GOF patients.〔 SOCS3 negatively regulates STAT3 and inhibits other STAT proteins like STAT5 and STAT1. STAT5 is important for regulatory T cell (Treg) differentiation and function, which may explain why many STAT GOF patients have low Tregs. These Treg abnormalities likely play a major role in autoimmunity, although some patients with normal Tregs also presented with autoimmunity disorders.〔 Additionally, a partial decrease of STAT1 activation likely participates in immune deficiencies. Data suggest the upregulation of STAT3 transcriptional activity may have consequences for other cytokine signaling pathways as well.〔 Notably, there has been no correlation between STAT3 hyperactivity and the severity of the phenotype, in addition to an absence of any genotype-phenotype correlation. This indicates that more research must be done to further understand the role that environmental or other genetic factors may play.〔〔〔 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「STAT3 GOF」の詳細全文を読む スポンサード リンク
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