<unk>  domain structures. Various missense mutations have been identified in multiple domains of the protein. Black lines indicate the position of the mutations.<unk>  is caused by germline gain-of-function mutations in the gene<unk> .<unk>  maps to human chromosome 17q21.2, has 24 exons, and encodes for the 770 amino acid protein,<unk> .<unk>  is part of a family of proteins known as the<unk> protein. These proteins play an essential role in chemical signaling pathways within cells.<unk>  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,<unk>  mediates the expression of a variety of genes and is therefore necessary for many cellular processes including cell proliferation, inflammation, differentiation, and survival.<unk>  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<unk>  disease, the gene<unk>  is hyperactive, leading to an intrinsic increase of transcriptional activity While the consequences of<unk>  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<unk>  patients. SOCS3 negatively regulates<unk>  and inhibits other<unk> proteins like<unk>  and<unk> .<unk>  is important for regulatory T cell (Treg) differentiation and function, which may explain why many<unk>  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<unk>  activation likely participates in immune deficiencies. Data suggest the upregulation of<unk>  transcriptional activity may have consequences for other cytokine signaling pathways as well. Notably, there has been no correlation between<unk>  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.
STAT3 GOF
HL23V
Philadelphia chromosome
Tbx18 transduction
T790M
ABL 
Fusion gene
GcMAF