Alternative titles; symbols
HGNC Approved Gene Symbol: JAK3
Cytogenetic location: 19p13.11 Genomic coordinates (GRCh38): 19:17,824,782-17,847,982 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.11 | SCID, autosomal recessive, T-negative/B-positive type | 600802 | Autosomal recessive | 3 |
JAK3 is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction (see also JAK1, 147795; JAK2, 147796; TYK2, 176941).
Kawamura et al. (1994) identified and cloned a leukocyte protein-tyrosine kinase (PTK) from natural killer (NK) cell mRNA. The cDNA encodes a deduced 1,124-amino acid protein with a molecular mass of 125 kD. The protein lacked SH2 and SH3 domains typical of the SRC family kinases, but had tandem nonidentical catalytic domains similar to members of the Janus family of PTKs. Kawamura et al. (1994) termed the protein L-JAK for leukocyte Janus kinase; the protein was subsequently designated JAK3 (Rane and Reddy, 1994; Johnston et al., 1994). In contrast to JAK1, JAK2, and TYK2, which are ubiquitously expressed, expression of L-JAK was limited to NK cells and an NK-like cell line, and was not found in resting T cells or in other tissues. Stimulated and transformed T cells did express the gene, suggesting a role in lymphoid activation.
Rane and Reddy (1994) isolated and identified the JAK3 gene. A 4.3-kb JAK3 mRNA transcript encodes a protein with the double catalytic domain characteristic of the JAK family. However, unlike other members of the JAK family, it contains 2 stretches of additional amino acid sequences of 147 and 28 residues, spanning amino acid positions 322 to 469 and 632 to 660, respectively. Expression studies found very low levels of JAK3 expression in immature hematopoietic cells, which was dramatically upregulated during terminal differentiation of these cells. Rane and Reddy (1994) concluded that JAK3 plays an important role in the differentiation of hematopoietic cells.
Riedy et al. (1996) reported that the human JAK3 gene contains 19 exons and spans 13,600 bp. Dissimilarity between the exon structures of the catalytic (JH1) and pseudokinase (JH2) domains argued against the suggestion that JH2 (exons 9-15) arose from a duplication of JH1 (exons 16-19). In a revised analysis, Brooimans et al. (1999) found that the JAK3 gene contains 23 exons and shows strong homology with the organization of the murine JAK3 locus.
By fluorescence in situ hybridization, Riedy et al. (1996) localized the JAK3 gene to chromosome 19p13.1, near the TYK2 gene.
Kono et al. (1996) mapped the Jak3 gene to mouse chromosome 8 by interspecific backcross matings.
The Epstein-Barr virus latent membrane protein-1 (LMP1) contains a 200-amino acid cytoplasmic domain involved in the induction of signaling cascades leading to nuclear factor kappa-B (NFKB; see 164011) and activator protein-1 (AP1; see 165160) activation. Using sequence, electrophoretic mobility shift, and immunoprecipitation analyses, Gires et al. (1999) showed that in addition to 2 C-terminal activating regions (CTAR1 and CTAR2), LMP1 possesses a proline-rich sequence within its 33-bp repeat region that interacts with JAK3. This interaction led to rapid enhanced tyrosine phosphorylation of JAK3 and the activation of STAT1 (600555). Gires et al. (1999) suggested that binding and activation of JAK3 by LMP1 upregulated the same cellular genes as CD40 (109535) when activated by its specific ligand.
By analysis of mutations in the JAK3 gene (600173.0001; 600173.0006; 600173.0007), Zhou et al. (2001) determined that the JAK3 FERM domain has 2 critical functions: receptor interaction and maintenance of kinase integrity. The mutations inhibited receptor binding and abrogated kinase activity, suggesting interactions between the FERM and kinase domains. The domains were found to associate physically, and coexpression of the FERM domain enhanced activity of the isolated kinase domain. Conversely, staurosporine, which alters kinase domain structure, disrupted receptor binding, even though the catalytic activity of JAK3 was dispensable for receptor binding.
Interleukin-2 (IL2; 147680) signaling requires the dimerization of IL2 receptor-beta (IL2RB; 146710) with the common gamma chain (gamma-c; IL2RG; 308380). Mutations in the IL2RG gene cause X-linked severe combined immunodeficiency (300400). IL2, IL4, IL7, IL9, and IL15, whose receptors are known to contain the common gamma chain, induce the tyrosine phosphorylation and activation of JAK1 and JAK3. Russell et al. (1994) found that truncations of gamma-c and a point mutation of gamma-c, causing moderate X-linked combined immunodeficiency, decreased the association between the common gamma chain and JAK3. Since mutations in the IL2RG gene in at least some XSCID and XCID patients prevent normal JAK3 activation, the authors suggested that mutations in JAK3 may result in an XSCID-like phenotype.
Cacalano and Johnston (1999) reviewed IL2 signaling in relation to inherited immunodeficiency. They noted that identification of SCID patients lacking either IL2RG or JAK3 was formal genetic proof that the IL2R components are critical for T-cell development.
In 2 unrelated patients with T-, B+, NK- severe combined immunodeficiency (600802), Macchi et al. (1995) identified 2 different homozygous mutations in the JAK3 gene (600173.0001 and 600173.0002, respectively). The findings confirmed that in humans the gamma-c chain/JAK/STAT signaling pathway is critical to early T-cell, but not B-cell, development. The authors noted that lack of NK cells also occurs in X-linked SCID, and that nonrandom patterns of X-chromosome inactivation in NK cells, as well as in T and B lymphocytes, indicates that the gamma-c product of the IL2RG gene is essential for proliferation/differentiation of all these lymphoid lines.
In a patient with T-, B+, NK- SCID, Russell et al. (1995) identified compound heterozygosity for 2 mutations in the JAK3 gene (600173.0003; 600173.0004).
Candotti et al. (1997) reported mutation analysis of 4 unrelated patients with JAK3-deficient SCID. The genetic defects were heterogeneous and included a large intragenic deletion as well as different point mutations leading to missense substitutions, early stop codons, or splicing defects. The functional consequences of several mutations were described.
Schumacher et al. (2000) developed a molecular screening test that enabled them to diagnose JAK3 deficiency in 14 patients from 12 unrelated families with T-, B+, NK- SCID (600802). Within this cohort of patients, they identified 15 independent JAK3 gene mutations, including 7 novel mutations (see, e.g., 600173.0005).
Notarangelo et al. (2001) presented molecular information on the first 27 unique mutations identified in the JAK3 gene, including clinical data on all 23 affected patients reported to that time. Mutations scattered throughout all 7 functional domains of the protein, with different functional effects, had been identified.
Sakaguchi et al. (2013) performed whole-exome sequencing for paired tumor-normal DNA from 13 individuals with juvenile myelomonocytic leukemia (JMML; 607785) (cases), followed by deep sequencing of 8 target genes in 92 tumor samples. JMML was characterized by a paucity of gene mutations (0.85 nonsilent mutations per sample) with somatic or germline RAS pathway involvement in 82 cases (89%). The SETBP1 (611060) and JAK3 mutations were among common targets for secondary mutations. Mutations in JAK3 were often subclonal, and Sakaguchi et al. (2013) hypothesized that they may be involved in the progression rather than the initiation of leukemia; these mutations associated with poor clinical outcomes.
Thomis et al. (1995) found that mice lacking Jak3 showed a severe block in B-cell development at the pre-B stage in bone marrow. In contrast, although the thymi of these mice were small, T-cell maturation progressed relatively normally. In response to mitogenic signals, peripheral T cells in Jak3-deficient mice did not proliferate and secreted low amounts of Il2. The findings demonstrated that Jak3 was critical for the progression of B-cell development in the bone marrow and for the functional competence of mature T cells. Nosaka et al. (1995) also found that mice with disruption of the Jak3 gene had profound reductions in thymocytes and severe B-cell and T-cell lymphopenia similar to that of SCID; furthermore, the residual T cells and B cells were functionally deficient.
Mice deficient in either Jak3 or Ctla4 (123890) have similar predominantly CD4 (186940)-positive peripheral T-cell phenotypes, but die from SCID and lymphoproliferative disorder, respectively. Using CDR3 spectratyping analysis of T-cell receptor repertoires of Jak3- and Ctla4-deficient mice, Gozalo-Sanmillan et al. (2001) found that Ctla4 -/- mice had the same diverse repertoire as control unimmunized mice, whereas Jak3 -/- peripheral but not thymic T cells had a limited number of expanded T-cell clones, suggesting an antigen-dependent activation in the Jak3-deficient mice as opposed to a universal activation in the Ctla4-deficient mice. The authors concluded that the 2 similar phenotypes of T-cell expansion are derived by distinct mechanisms.
Because of its requirement for signaling by multiple cytokines, JAK3 is an excellent target for clinical immunosuppression. Changelian et al. (2003) reported the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. Changelian et al. (2003) suggested that JAK3 blockade by CP-690,550 may have potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.
In a patient with T-, B+, NK- SCID (600802), Macchi et al. (1995) identified a homozygous 394A-G transition in the JAK3 gene, resulting in a tyr100-to-cys (Y100C) substitution. The parents were consanguineous. The patient had increased numbers of nonfunctional B cells and was severely hypogammaglobulinemic.
Zhou et al. (2001) identified the Y100C mutation in a SCID patient. This mutation occurs in a residue predicted to be at the beginning of an important linker region between JAK3 subdomains A and B. The Y100 residue is conserved in murine, avian, and piscine Jak3, other Jaks, and FERM-domain proteins.
In a patient with T-, B+, NK- SCID (600802), Macchi et al. (1995) identified a homozygous 151-bp deletion (del2294-2444) in the kinase-like domain of the JAK3 gene, predicting a truncated gene product. The parents were consanguineous. The patient had increased numbers of nonfunctional B cells and was severely hypogammaglobulinemic.
In a girl with T-, B+, NK- SCID (600802) whose immunologic features were indistinguishable from those of X-linked SCID (300400), Russell et al. (1995) identified compound heterozygosity for 2 mutations in the JAK3 gene: a 1-bp insertion (1172insG) in the JH4 domain, resulting in a premature stop at codon 408, and a 1695C-A transversion in the JH2 domain, resulting in a nonsense mutation (C565X; 600173.0004). An Epstein-Barr virus (EBV)-transformed cell line derived from her lymphocytes lacked JAK3 protein and had greatly diminished levels of JAK3 mRNA. The lack of JAK3 expression correlated with impaired B-cell signaling, as demonstrated by the inability of IL4 to activate STAT6 in the EBV-transformed cell line from the patient.
For discussion of the cys565-to-ter (C565X) mutation in the JAK3 gene that was found in compound heterozygous state in a patient with T-, B+, NK- SCID (600802) by Russell et al. (1995), see 600173.0003.
In affected members of 2 related families with autosomal recessive T-, B+, NK- SCID (600802), Schumacher et al. (2000) identified a homozygous 1428C-T transition in exon 9 of the JAK3 gene, resulting in an arg445-to-ter (R445X) amino acid substitution. Schumacher et al. (2000) identified the R445X mutation in heterozygous state in a third, unrelated family.
In a patient with T-, B+, NK- SCID (600802), Zhou et al. (2001) identified compound heterozygosity for 2 mutations in the JAK3 gene: an asp169-to-glu (D169E) substitution and a deletion of ala58 (600173.0007).
For discussion of the ala58 (A58) deletion in the JAK3 gene that was found in compound heterozygous state in a patient with T-, B+, NK- SCID (600802) by Zhou et al. (2001), see 600173.0006.
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Zhou, Y.-J., Chen, M., Cusack, N. A., Kimmel, L. H., Magnuson, K. S., Boyd, J. G., Lin, W., Roberts, J. L., Lengi, A., Buckley, R. H., Geahlen, R. L., Candotti, F., Gadina, M., Changelian, P. S., O'Shea, J. J. Unexpected effects of FERM domain mutations on catalytic activity of Jak3: structural implication for Janus kinases. Molec. Cell 8: 959-969, 2001. [PubMed: 11741532] [Full Text: https://doi.org/10.1016/s1097-2765(01)00398-7]