The Goldilocks Principle of JAKs and STATs: Gain-of function mutations, loss-of-function mutations, and their clinical consequences

Abstract The JAK-STAT signalling pathway plays a key role in cytokine signalling and is involved in development, immunity, and tumorigenesis for nearly any cell. At first glance, the JAK-STAT signalling pathway appears to be straight forward. However, on closer examination, there are many different factors influencing the JAK and the STAT proteins, which even so cannot sufficiently explain the wide variety of the cell's responses to the large number of cytokines. The JAK-STAT signalling pathway has been, and still is, subject of basic research and offers an enormous potential for the development of new methods of personalised medicine and thus the translation of basic molecular research into clinical practice beyond the use of JAK inhibitors. Gain-of-function and loss-of-function mutations in the two immunologically particularly relevant signal transducers STAT1 and STAT3 present themselves through individual phenotypic clinical pictures. This review is intended to provide an overview of these specific syndromes and to summarise current findings on pathomechanism, symptoms, immunological features and therapeutic options of STAT1, STAT3, JAK1 and JAK3 loss-of-function and gain-of-function diseases.