Autosomal dominant JAK1-related immune dysregulation was first reported in2017 (Del Bel KL, et al., 2017, PMID: 28111307). JAK1 is activated by a broad range of cytokines and can phosphorylate any STAT. The JAK/STAT pathway plays an integral role in extracellular cytokine and growth factor signaling, as well as in controlling hematopoiesis and immune function. JAK1 gain-of-function variants result in a systemic immune dysregulatory condition, with clinical features including autoimmunity with skin inflammation, eosinophilia, impairment of growth, and liver abnormalities. Ten missense variants have been reported in 10 probands and one case-control study in 6 publications (PMIDs: 28111307, 30940614, 32750333, 35046931, 37343845, 38563820). This gene-disease relationship is further supported by experimental evidence including its biochemical function (PMID: 8232552), which is hyperactive in patients (PMIDs: 28111307, 32750333, 37343845, and PMID:38563820), and multiple model organisms that recapitulate aspects of the disease (PMIDs: 36546480, 35046931, 23791841). In summary, there is Definitive evidence to support the relationship between JAK1 and autosomal dominant immune dysregulation. 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).
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