Alt. symbols: L-JAK | JAKL | LJAK | JAK3_HUMAN | JAK-3

Approved name: Janus kinase 3
Alt. names: tyrosine-protein kinase JAK3, leukocyte Janus kinase

Location: 19p13.11: 17824780 - 17848071 (-)
Gene type: protein_coding, 11 transcripts.

Scores: LoFtool: 0.159000 | pLI: 0.99586380 | LOEUF: 0.525

HGNC: 6193

NCBI: 3718, RefSeq: NG_007273.1

Ensembl: ENSG00000105639.21

LRG_77 | Status: public

OMIM: 600173

Expression | ProteinAtlas

JAK3 encodes a Janus kinase (JAK) non-receptor tyrosine kinase that mediates essential signaling events in both innate and adaptive immunity downstream of cytokine receptors that share the common gamma subunit such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. After receptor-ligand binding, JAKs phosphorylate specific tyrosine residues on each receptor subunit’s cytoplasmic tail, creating docking sites for STAT recruitment and phosphorylation. The phosphorylated STATs then homo- or hetero-dimerize and translocate to the nucleus to activate gene transcription. For example, signaling through the IL-2 receptor complex leads to JAK1/3-dependent STAT5A/B recruitment and activation.

Biallelic null mutations in JAK3 are classically associated with autosomal recessive T-B+NK- severe combined immunodeficiency (SCID) [OMIM: 600802], with a clinical phenotype nearly identical to that of X-linked SCID due to common gamma chain mutations. Clinically, patients present with opportunistic life-threatening infections, intractable diarrhea, dermatitis, and failure to thrive in the first months of life. The lack of T cells is attributed to lack of IL-7 signaling, while the NK cell defic its are attributed to lack of IL-15 signaling and B cells are nonfunctional due to both the absence of helper T cells and the lack of IL-4 and IL-21 signaling leading to impaired class switch recombination. The majority have mutations within the catalytically inactive JH2 pseudokinase domain (Exons 11-17), leading to absent protein expression. However, hypomorphic mutations in JAK3 have been linked to other forms of immunodeficiency, from life-threatening Omenn’s syndrome to milder combined immunodeficiency or primary antibody deficiency (PMID: 22520845, 23384681, 26182690, 26545580). Even significant intrafamilial variability has been reported in the spectrum and severity of the immune phenotypes, and immune dysregulatory complications, including lymphoproliferation and autoimmunity, are also increasingly noted (PMID: 11781709). A number of patients harboring biallelic hypomorphic JAK3 mutations (largely missense, though also a significant minority of splice site changes and a few other likely truncating mutations) have been diagnosed with CVID or related antibody deficiencies (PMID:11781709, 26182690, 27577878, 31942606, 32615565, 35232000). Activating mutations (A572V, A573V or V722I) in JAK3 have also been found in NK/T-cell lymphomas (PMID: 22705984, 23689514) [Load More]