JAK3 - SCID, autosomal recessive, T-negative/B-positive type Phenotype MIM:600802
JAK3 was first reported in relation to autosomal recessive severe combined immune deficiency (T-negative/B-positive type) in 1994 (Russell et al., PMID:7973658). At least 27 unique variants (missense, in-frame indel, nonsense, frameshift, large deletion, splice) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data.
Variants in this gene have been reported in at least 15 probands, in at least 6 publications (PMID:9354668, PMID:7659163, PMID: 7481768, PMID: 30032486, PMID: 14615376, PMID: 9753072). Probands described range in age of onset between approximately 3 and 14 months. Common phenotypes include recurrent upper and lower respiratory tract infections, decreased circulating antibody levels, recurrent diarrhea, lack of circulating T cells, and a normal number of B lymphocytes.
This gene-disease association is supported by mice models, cell culture models, expression studies, and in vitro functional assays (PMID: 28513593, PMID: 14615376, PMID: 10075926, PMID: 7481768). Protein encoded by JAK3 is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction. It is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. JAK3 mediates signaling events in both innate and adaptive immunity and plays a critical role in hematopoiesis during T-cells development (PMID: 14615376, PMID: 28513593). In the cytoplasm, JAK3 plays a crucial role in signal transduction via its association with type I receptors sharing the common gamma chain (γc) (PMID: 10075926). Following ligand binding to cell surface receptors, JAK3 phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins (PMID: 7481768). JAK3 phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then translocate to the nucleus to activate gene transcription (UniProtKB/Swiss-Prot). Mutations in this gene are associated with autosomal recessive severe combined immunodeficiency and are found throughout all 7 functional domains of the protein with different functional effects.
In summary, JAK3 is definitively associated with autosomal recessive, severe combined immunodeficiency disease (T-negative/B-positive type). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time
This classification was approved by the ClinGen SCID-CID Working Group on 12/17/20 (SOP Version 8).
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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