HGNC Approved Gene Symbol: JAK1
Cytogenetic location: 1p31.3 Genomic coordinates (GRCh38): 1:64,833,229-65,067,746 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p31.3 | Autoinflammation, immune dysregulation, and eosinophilia | 618999 | Autosomal dominant | 3 |
The protein-tyrosine kinases (PTKs) are a large family of proteins, each of which bears a conserved domain of 250 to 300 amino acids capable of phosphorylating substrate proteins on tyrosine residues. Wilks (1989) exploited the existence of 2 highly conserved sequence elements within the catalytic domain to generate PTK-specific degenerate oligonucleotide primers. Wilks et al. (1991) described the primary sequence of new PTKs identified by application of PCR. One, called Janus kinase 1 (JAK1), is a member of a new class of PTKs characterized by the presence of a second phosphotransferase-related domain immediately N-terminal to the PTK domain--hence the name Janus. The second phosphotransferase domain bore all the hallmarks of a protein kinase, although its structure differed significantly from that of the PTK and threonine/serine kinase family members. JAK1 is a large, widely expressed membrane-associated phosphoprotein of approximately 130,000 Da. The PTK activity is located in the C-terminal PTK-like domain; the role of the second kinase-like domain was unknown. A second member of the family, JAK2 (147796), was partially characterized and exhibited a similar array of kinase-related domains.
By in situ hybridization and Southern blot analysis of a panel of mouse/human hybrid cell lines, Pritchard et al. (1992) demonstrated that the JAK1 gene maps to 1p31.3. By in situ hybridization, they mapped the JAK2 gene to 9p24. Howard et al. (1992) mapped JAK1 to chromosome 1 using somatic cell hybrids and linkage studies based on the CEPH families. Modi et al. (1995) used in situ hybridization to map JAK1 to 1p32.3-p31.3; they referred to the gene as JAK1A.
Gough et al. (1995) mapped the mouse Jak1 gene to chromosome 4 in a region of homology of synteny to human 1p33-p31.
By mutagenesis and selection for resistance to interferon, Muller et al. (1993) produced a cell line that lacks JAK1 and is completely defective in interferon response. Complementation of this mutant with JAK1 restored the response, establishing the requirement for JAK1 in both the interferon-alpha/beta and -gamma signal transduction pathways. The reciprocal interdependence between JAK1 and TYK2 (176941) activities in the interferon-alpha pathway, and between JAK1 and JAK2 in the interferon-gamma pathway, may reflect a requirement for these kinases in the correct assembly of interferon receptor complexes.
Ihle (1995) reviewed cytokine receptor signaling. Numerous aspects of lymphoid and myeloid cell function are controlled by a group of ligands termed cytokines, all of which signal through a related set of receptors. All such receptors are associated with one or more members of the JAK family. These kinases couple ligand binding to tyrosine phosphorylation of various known signaling proteins and of a unique family of transcription factors termed the signal transducers and activators of transcription, or STATs (e.g., 600555). The cytokine receptors included those for IL3 (308385; 138981) and IL6 (147880).
The JAK-STAT signaling pathway is a major relay between cell surface receptors and cytokine responses (Schindler et al., 2007). Levy and Loomis (2007) reviewed the mutant phenotypes in mice and humans associated with mutations in 4 JAK family members-- --JAK1, JAK2 (147796), JAK3 (600173), and tyrosine kinase-2 (TYK2; 176941)--and 7 STAT proteins.
In a mother and her 2 sons with autoinflammation, immune dysregulation, and eosinophilia (AIIDE; 618999), Del Bel et al. (2017) identified a heterozygous missense mutation in the JAK1 gene (A634D; 147795.0001). The mutation, which was found by a combination of whole-exome and targeted Sanger sequencing, segregated with the disorder in the family. In vitro studies of patient B and T cells showed enhanced STAT1 (600555)/STAT3 (102582) phosphorylation and activation in response to stimulation, consistent with a gain-of-function effect. Treatment with ruxolitinib, a JAK1/2 inhibitor, significantly reduced this hyperresponsivity and resulted in clinical improvement.
In an 18-year-old woman with AIIDE, Gruber et al. (2020) identified a de novo heterozygous missense mutation in the JAK1 gene (S703I; 147795.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in any public databases. In vitro functional studies showed that the mutation caused increased basal phosphorylation of STAT proteins and active target gene transcription in the absence of cytokine stimulation, as well as hyperresponsiveness to cytokine stimulation compared to controls, consistent with a gain-of-function effect. Treatment with tofacitinib, a pan-JAK inhibitor, resulted in nearly complete resolution of clinical symptoms and laboratory abnormalities. This pharmacologic rescue of JAK hyperactivity was confirmed in in vitro studies of patient cells, which showed a decrease in STAT phosphorylation after treatment.
In a 22-year-old Japanese woman with AIIDE, Takeichi et al. (2021) identified a heterozygous missense mutation in the JAK1 gene (H596D; 147795.0003) affecting a conserved residue in the pseudokinase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Immunohistochemical analysis of patient-derived keratinocytes showed strong nucleocytoplasmic staining for JAK1, in contrast to mostly cytoplasmic localization of JAK1 in normal skin. Patient skin cells also showed nuclear strong expression of phosphorylated STAT proteins. In vitro studies in HEK293T cells transfected with the mutation showed increased phosphorylation of JAK1 and certain members of the STAT family of proteins compared to controls, consistent with a gain-of-function effect.
Associations Pending Confirmation
For discussion of a possible association between variation in the JAK1 gene and susceptibility or protection from dengue hemorrhagic fever, see 614371.
For discussion of a possible association between variation in the JAK1 gene and a primary immunodeficiency with susceptibility to atypical mycobacterial infections, see 147795.0004.
Rodig et al. (1998) reported the generation of mice lacking the ubiquitously expressed JAK1 kinase. Jak1 -/- mice were runted at birth, failed to nurse, and died perinatally. Although Jak1 -/- cells were responsive to many cytokines, they failed to manifest biologic responses to cytokines that bind to 3 distinct families of cytokine receptors. These include all class II cytokine receptors, cytokine receptors that utilize the gamma(c) subunit for signaling, and the family of cytokine receptors that depend on the gp130 subunit for signaling. These results demonstrated that JAK1 plays an essential and nonredundant role in promoting biologic responses induced by a select subset of cytokine receptors, including those in which JAK utilization was thought to be nonspecific.
Takeichi et al. (2021) found that mutant mice with a heterozygous H595D mutation (see H596D; 147795.0003) in the Jak1 gene had smaller body size, lower weight, and decreased survival compared to wildtype. Mutant mice also developed hyperkeratosis and scales on the ears, feet, and tail, as well as lymphocytic infiltration in the liver, recapitulating the human phenotype. Similar to patient skin, keratinocytes and liver tissue from the mutant mice showed strong nucleocytoplasmic localization of phosphorylated JAK1 and members of the STAT family. Gene expression studies of tissue from mutant mice indicated hyperactivation of tyrosine kinases and upregulation of NFKB (see 164011) signaling compared to controls.
In a mother and her 2 sons with autoinflammation, immune dysregulation, and eosinophilia (AIIDE; 618999), Del Bel et al. (2017) identified a heterozygous c.1901C-A transversion in the JAK1 gene, resulting in an ala634-to-asp (A634D) substitution at a highly conserved residue in the inhibitory pseudokinase domain. The mutation, which was found by a combination of whole-exome and targeted Sanger sequencing, segregated with the disorder in the family. It occurred de novo in the affected mother. The mutation was not present in the ExAC database. The mutation did not affect JAK1 mRNA or protein levels. In vitro studies of patient B and T cells showed enhanced STAT1 phosphorylation in response to stimulation, consistent with a gain-of-function effect. Treatment with ruxolitinib, a JAK1/2 inhibitor, significantly reduced this hyperresponsivity.
In an 18-year-old woman with autoinflammation, immune dysregulation, and eosinophilia (AIIDE; 618999), Gruber et al. (2020) identified a de novo heterozygous c.2108G-T transversion in the JAK1 gene, resulting in a ser703-to-ile (S703I) substitution at a highly conserved residue in the pseudokinase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in any public databases. PCR analysis of patient tissues showed that it was a somatic mutation that occurred very early in development, estimated at the first 12 cell divisions between fertilization and gastrulation. In vitro functional studies in patient-derived B cells and transduced cells showed that the mutation caused increased basal phosphorylation of STAT proteins and active target gene transcription in the absence of cytokine stimulation, as well as hyperresponsiveness to cytokine stimulation compared to controls, consistent with a gain-of-function effect. The mutant JAK1 protein was itself hyperphosphorylated compared to controls; in addition, there was hyperphosphorylation of other signaling partners, including JAK2 (147796), TYK2 (176941), and JAK3 (600173), and activation of several noncanonical STAT signaling pathways. Treatment with tofacitinib, a pan-JAK inhibitor, resulted in nearly complete resolution of clinical symptoms and laboratory abnormalities. This pharmacologic rescue of JAK hyperactivity was confirmed in in vitro studies of patient cells, which showed a decrease in STAT phosphorylation after treatment.
In a 22-year-old Japanese woman with autoinflammation, immune dysregulation, and eosinophilia (AIIDE; 618999), Takeichi et al. (2021) identified a heterozygous c.1786C-G transversion in the JAK1 gene, resulting in a his596-to-asp (H596D) substitution at a conserved residue in the pseudokinase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The variant allele frequency of the H596D mutation in patient peripheral blood cells was 0.421053, which could indicate either a germline or somatic mutation. Immunohistochemical analysis of patient-derived keratinocytes showed strong nucleocytoplasmic staining for JAK1, in contrast to mostly cytoplasmic localization of JAK1 in normal skin. Patient skin cells also showed nuclear strong expression of phosphorylated STAT proteins. In vitro studies in HEK293T cells transfected with the mutation showed increased phosphorylation of JAK1 and certain members of the STAT family of proteins compared to controls, consistent with a gain-of-function effect. Mutant mice with a heterozygous H595D mutation in the Jak1 gene recapitulated the human phenotype (see ANIMAL MODEL). In addition to atopic dermatitis and eosinophilia, the patient had liver failure requiring liver transplant, poor overall growth, moderate motor impairment, learning disabilities, and autism.
This variant is classified as a variant of unknown significance because its contribution to a primary immunodeficiency syndrome has not been confirmed.
In a 23-year-old man, born of consanguineous Pakistani parents, with a primary immune disorder manifest as recurrent infections with atypical mycobacteria, Eletto et al. (2016) identified 2 homozygous missense variants in the JAK1 gene in cis: a c.2198C-T transition, resulting in a pro733-to-leu (P733L) substitution, and a c.2494C-T transition, resulting in a pro832-to-ser (P832S) substitution. The variants, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Heterozygous carriers in the family were unaffected. The P733L variant was not present in the ExAC database, whereas P832S was detected in 4 heterozygous individuals (frequency of 3.3 x 10(-5)). Both variants occurred in the pseudokinase domain. The patient presented at 3 years of age with global developmental delay and recurrent infections since the first year of life. He received BCG vaccine at birth. He later developed a systemic atypical mycobacterial infection with lytic bone lesions, lymphadenopathy, failure to thrive, and elevated erythrocyte sedimentation rate. Immunologic workup showed variable abnormalities that changed over time, including reduced numbers of naive CD4+ and CD8+ T cells, increased IgG and IgA, and T-cell lymphopenia with impaired proliferative responses. At age 16, he presented with cardiomyopathy, and at 21, he was found to have anemia associated with metastatic bladder cancer; he died at age 23. Patient lymphocytes showed deficits in multiple JAK1-mediated signaling pathways involving STAT family genes, suggesting a functional JAK1 deficiency. There was evidence of immune dysregulation, with low IFNG (147570) and IL10 (124092) production by T cells after stimulation. These abnormalities were associated with decreased phosphorylation of JAK1 and some members of the STAT signaling family. In vitro studies indicated that the P733L variant had a more detrimental effect on the JAK1 signaling pathway compared to the P832S variant. Eletto et al. (2016) postulated that the variants were hypomorphic and resulted in functional JAK1 deficiency.
Del Bel, K. L., Ragotte, R. J., Saferali, A., Lee, S., Vercauteren, S. M., Mostafavi, S. A., Schreiber, R. A., Prendiville, J. S., Phang, M. S., Halparin J., Au, N., Dean, J. M., Priatel, J. J., Jewels, E., Junker, A. K., Rogers, P. C., Seear, M., McKinnon, M. L., Turvey, S. E. JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome. (Letter) J. Allergy Clin. Immun. 139: 2016-2020, 2017. [PubMed: 28111307] [Full Text: https://doi.org/10.1016/j.jaci.2016.12.957]
Eletto, D., Burns, S. O., Angulo, I., Plagnol, V., Gilmour, K. C., Henriquez, F., Curtis, J., Gaspar, M., Nowak, K., Daza-Cajigal, V., Kumararatne, D., Doffinger, R., Thrasher, A. J., Nejentsev, S. Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection. Nature Commun. 7: 13992, 2016. [PubMed: 28008925] [Full Text: https://doi.org/10.1038/ncomms13992]
Gough, N. M., Rakar, S., Harpur, A., Wilks, A. F. Localization of genes for two members of the JAK family of protein tyrosine kinases to murine chromosomes 4 and 19. Mammalian Genome 6: 247-248, 1995. [PubMed: 7613027] [Full Text: https://doi.org/10.1007/BF00352409]
Gruber, C. N., Calis, J. J. A., Buta, S., Evrony, G., Martin, J. C., Uhl, S. A., Caron, R., Jarchin, L., Dunkin D., Phelps, R., Webb, B. D., Saland, J. M., Merad, M., Orange, J. S., Mace, E. M., Rosenberg, B. R., Gelb, B. D., Bogunovic, D. Complex autoinflammatory syndrome unveils fundamental principles of JAK1 kinase transcriptional and biochemical function. Immunity 53: 672-684, 2020. [PubMed: 32750333] [Full Text: https://doi.org/10.1016/j.immuni.2020.07.006]
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Muller, M., Briscoe, J., Laxton, C., Guschin, D., Ziemiecki, A., Silvennoinen, O., Harpur, A. G., Barbieri, G., Witthuhn, B. A., Schindler, C., Pellegrini, S., Wilks, A. F., Ihle, J. N., Stark, G. R., Kerr, I. M. The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature 366: 129-135, 1993. [PubMed: 8232552] [Full Text: https://doi.org/10.1038/366129a0]
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Rodig, S. J., Meraz, M. A., White, J. M., Lampe, P. A., Riley, J. K., Arthur, C. D., King, K. L., Sheehan, K. C. F., Yin, L., Pennica, D., Johnson, E. M., Jr., Schreiber, R. D. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell 93: 373-383, 1998. [PubMed: 9590172] [Full Text: https://doi.org/10.1016/s0092-8674(00)81166-6]
Schindler, C., Levy, D. E., Decker, T. JAK-STAT signaling: from interferons to cytokines. J. Biol. Chem. 282: 20059-20063, 2007. [PubMed: 17502367] [Full Text: https://doi.org/10.1074/jbc.R700016200]
Takeichi, T., Lee, J. Y. W., Okuno, Y., Miyasaka, Y., Murase, Y., Yoshikawa, T., Tanahashi, K., Nishida, E., Okamoto, T., Ito, K., Muro, Y., Sugiura, K., Ohno, T., McGrath, J. A., Akiyama, M. Autoinflammatory keratinization disease with hepatitis and autism reveals roles for JAK1 kinase hyperactivity in autoinflammation. Front. Immun. 12: 737747, 2021. [PubMed: 35046931] [Full Text: https://doi.org/10.3389/fimmu.2021.737747]
Wilks, A. F., Harpur, A. G., Kurban, R. R., Ralph, S. J., Zurcher, G., Ziemiecki, A. Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Molec. Cell. Biol. 11: 2057-2065, 1991. [PubMed: 1848670] [Full Text: https://doi.org/10.1128/mcb.11.4.2057-2065.1991]
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