HGNC Approved Gene Symbol: TYK2
SNOMEDCT: 1197415001;
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38): 19:10,350,533-10,380,572 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.2 | Immunodeficiency 35 | 611521 | Autosomal recessive | 3 |
To identify novel protein tyrosine kinase genes expressed in human lymphoid cells, Krolewski et al. (1990) screened B- and T-cell cDNA libraries at low stringency using an FMS (164770) tyrosine kinase domain probe. One of 3 genes so identified, TYK2, could not clearly be assigned to any of the known tyrosine kinase subfamilies and therefore may be the prototype of a novel subfamily.
Using a fragment of the clone isolated by Krolewski et al. (1990) to screen a T-cell lymphoma cell line cDNA library, Firmbach-Kraft et al. (1990) obtained a full-length TYK2 cDNA. The deduced 1,187-amino acid protein has a calculated molecular mass of 134 kD. TYK2 contains a C-terminal protein tyrosine kinase catalytic domain with a consensus ATP-binding site. It has no N-terminal signal peptide or transmembrane domain, suggesting that TYK2 is not a receptor-type protein tyrosine kinase. Northern blot analysis detected a 4.4-kb transcript in all human cell lines examined.
Krolewski et al. (1990) assigned the TYK2 gene to human chromosome 19 by Southern analysis of somatic cell hybrid DNAs. By fluorescence in situ hybridization, Firmbach-Kraft et al. (1990) and Trask et al. (1993) assigned the TYK2 gene to 19p13.2.
Firmbach-Kraft et al. (1990) found that TYK2 expression increased 5-fold in a promyelocytic cell line following retinoic acid-induced differentiation. They found a slight increase in TYK2 expression following phorbol ester-induced differentiation of a myeloid cell line.
Lukashova et al. (2001) found that platelet-activating factor (PAF) induced rapid tyrosine phosphorylation of TYK2 in 2 human monocytic cell lines and in COS-7 cells transfected with PAF receptor (PTAFR; 173393) and TYK2 cDNAs. TYK2 coimmunoprecipitated and colocalized with PTAFR independent of ligand binding. Deletion mutation analysis indicated that the N terminus of TYK2 bound PTAFR. Activation of TYK2 was followed by a time-dependent 2- to 4-fold increase in the level of tyrosine phosphorylation of STAT1 (600555), STAT2 (600556), and STAT3 (102582), and a sustained 2.5-fold increase in STAT5 (see 601511) tyrosine phosphorylation. STAT1 and STAT3 translocated to the nucleus following PAF stimulation, and their translocation was dependent on TYK2 in transiently-transfected COS-7 cells. In the presence of TYK2, PAF induced activation of PTAFR promoter-1 in a reporter assay. TYK2 activation and signaling by PAF was independent of G proteins.
In human coronary artery vascular smooth muscle cells, UPA (PLAU; 191840) stimulates cell migration via a UPA receptor (UPAR, or PLAUR; 173391) signaling complex containing TYK2 and phosphatidylinositol 3-kinase (PI3K; see 601232). Kiian et al. (2003) showed that association of TYK2 and PI3K with active GTP-bound forms of both RHOA (ARHA; 165390) and RAC1 (602048), but not CDC42 (116952), as well as phosphorylation of myosin light chain (see 160781), are downstream events required for UPA/UPAR-directed migration.
In the type I interferon receptor, TYK2 associates with the IFNAR1 (107450) receptor subunit and positively influences ligand binding to the receptor complex. Ragimbeau et al. (2003) found that TYK2 was required for stable cell surface expression of IFNAR1 in human fibrosarcoma cells. In the absence of TYK2, IFNAR1 was exported to the plasma membrane but then accumulated in endocytic organelles. TYK2 coexpression prevented intracellular accumulation of IFNAR1 by restraining its constitutive internalization, and thus stabilized it at the cell surface.
Minegishi et al. (2006) found that IFNA (147660) stimulation of cells from a patient with TYK2 deficiency (611521) failed to induce tyrosine phosphorylation of JAK1 (147795), STAT1, STAT2, STAT3, and STAT4 (600558). Likewise, IL23 (605580) stimulation failed to result in phosphorylation of STAT4. IL6 (147620) and IL10 (124092) stimulation failed to upregulate SOCS3 (604176). Impaired Th1 differentiation and accelerated Th2 differentiation in the patient's T cells suggested that TYK2 is critical for IL12 (see 161561)-induced Th1 differentiation and represses development of Th2 helper cells. Introduction of wildtype TYK2 into the patient's T cells rescued the IL12 and IFNA signaling defects. Minegishi et al. (2006) concluded that TYK2 plays an indispensable role in controlling responses to multiple cytokines in humans, a substantial difference from Tyk2 function in mice (see ANIMAL MODEL).
Immunodeficiency 35
In a 22-year-old Japanese male with immunodeficiency-35 (IMD35; 611521), Minegishi et al. (2006) identified a homozygous deletion of GCTT at nucleotide 550 in the TYK2 gene (176941.0001), resulting in a frameshift and premature termination of the protein at amino acid 90. Immunoblot analysis detected no TYK2 protein in the patient's T cells. Both of the patient's parents, who were healthy, were heterozygous for the TYK2 mutation. Introduction of wildtype TYK2 into the patient's T cells rescued their cytokine signaling defects. The patient had characteristic features of both autosomal recessive hyper-IgE syndrome (HIES; 243700) and atypical mycobacteriosis (see 209950). Minegishi et al. (2006) concluded that TYK2 deficiency is a primary immunodeficiency displaying the phenotype of autosomal recessive HIES accompanied by susceptibility to intracellular bacterial infection.
In a Turkish male, born of consanguineous parents, with IMD35, Kilic et al. (2012) identified a homozygous truncating mutation in the TYK2 gene (176941.0002), resulting in complete loss of function. Kilic et al. (2012) suggested that lack of TYK2 resulted in defective IL12 signaling and impaired production of gamma-interferon (IFNG; 147570).
In 6 patients from 4 unrelated families with IMD35, Kreins et al. (2015) identified 4 different homozygous truncating mutations in the TYK2 gene (176941.0003-176941.0006). The mutations, which were found by whole-exome sequencing or targeted next-generation sequencing, segregated with the disorder in the families. Patient cells showed low levels of IFNAR1 (107450), IL10R2 (123889), and IL12RB1 (601604) surface expression compared to controls, consistent with a defect in the scaffolding function of TYK2. These results highlighted the essential role of TYK2 in the expression of receptors for various cytokines. Patient cells also showed TYK2 catalytic defects that affected signaling, manifest as impaired, but not abolished, gamma-interferon (IFNG; 147570) induction after stimulation with BCG plus IL12 (see, e.g., 161560). Patient B cells showed impaired response to alpha- and beta-interferon (IFNA1, 147660 and IFNB1, 147640), IL23 (see 605580), and IL10, which was associated with decreased STAT1 phosphorylation and absent STAT3 phosphorylation; these defects were restored by expression of wildtype TYK2. IL6 hyporesponsiveness was detected only in cells from the patient reported by Minegishi et al. (2006), who had an HIES phenotype, and the hyporesponsiveness was found to be independent of TYK2. Cells from the other patients (including the patient reported by Kilic et al. (2012); see 176941.0002), none of whom had an HIES phenotype, showed normal IL6 responses.
In an 8-year-old boy, born to consanguineous parents of Kurdish origin, with eczema, skin abscesses, respiratory infections, and IgE levels greater than 1000 U/mL, Fuchs et al. (2016) identified homozygosity for a single-nucleotide deletion (c.647delC; 176941.0012) in the TYK2 gene, resulting in a frameshift and premature stop codon (P216RfsX14). Studies of mRNA levels and protein expression showed reduced mRNA levels and loss of protein expression, which completely abolished the IFN-alpha-mediated antiviral response.
Using whole-exome and whole-genome sequencing in an international cohort of 112 children less than 16 years old who were hospitalized for COVID19 pneumonia, Zhang et al. (2022) identified 3 unrelated patients (P2-4), all born to consanguineous Turkish parents, with homozygosity for the P216RfsX14 mutation in TYK2 reported by Fuchs et al. (2016). No pathogenic variants in TYK2 were seen among the control population of 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia. The authors noted that recessive deficiencies of type I IFN immunity such as this might underlie approximately 10% of pediatric hospitalizations for COVID19 pneumonia.
Associations Pending Confirmation
Systemic lupus erythematosus (SLE; 152700) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Increased production of type I interferon (IFN) and expression of IFN-inducible genes are commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disorder. Sigurdsson et al. (2005) analyzed 44 SNPs in 13 genes from the type I IFN pathway of 679 Swedish, Finnish, and Icelandic patients with SLE, 798 unaffected family members, and 438 unrelated control individuals for joint linkage and association with SLE. In 2 of the genes, TYK2 and IFN regulatory factor-5 (IRF5; 607218), they identified SNPs that displayed strong signals in joint analysis of linkage and association with SLE. TYK2 binds to the type I IFN receptor complex, and IRF5 is a regulator of type I IFN gene expression. The results of Sigurdsson et al. (2005) support a disease mechanism in SLE that involves key components of the type I interferon system.
For discussion of a possible association between variation in the TYK2 gene and multiple sclerosis, see MS (126200).
Karaghiosoff et al. (2000) generated Tyk2 -/- mice. In contrast to other Janus kinase family members, where inactivation leads to complete loss of the respective cytokine receptor signal, Tyk2 -/- mice showed reduced responses to Ifna/Ifnb (147640) and Il12 and selective deficiency in Stat3 activation in these pathways. Ifng signaling was also impaired, and Tyk2 -/- macrophages failed to produce nitric oxide upon lipopolysaccharide induction. Tyk2 -/- mice failed to clear vaccinia virus infection and showed a reduced T-cell response to lymphocytic choriomeningitis virus infection. Karaghiosoff et al. (2000) concluded that Tyk2 contributes selectively to signals triggered by various biologic stimuli and cytokine receptors.
Stoiber et al. (2004) demonstrated that mice deficient in Tyk2 developed Abelson murine leukemia virus (see 189980)-induced B lymphoid leukemia/lymphoma as well as Tel (600618)/Jak2 (147796)-induced T-lymphoid leukemia with a higher incidence and shortened latency compared to wildtype controls. The high susceptibility of Tyk2 -/- mice resulted from impaired tumor surveillance, and Tyk2 -/- Abelson-induced lymphomas were easily rejected after transplantation into wildtype hosts. There was decreased in vitro cytotoxic capacity of Tyk2 -/- natural killer (NK) and NK T cells toward tumor-derived cells. Stoiber et al. (2004) concluded that TYK2 is an important regulator of lymphoid tumor surveillance.
In a 22-year-old Japanese male with primary immunodeficiency-35 (IMD35; 611521), Minegishi et al. (2006) identified a homozygous deletion of GCTT at nucleotide 550 in the TYK2 gene, resulting in a frameshift and premature termination of the protein at amino acid 90. Immunoblot analysis detected no TYK2 protein in the patient's T cells. Both of the patient's parents, who were healthy, were heterozygous for the TYK2 mutation. Introduction of wildtype TYK2 into the patient's T cells rescued their cytokine signaling defects. The patient had characteristic features of both autosomal recessive hyper-IgE syndrome (HIES; 243700) and atypical mycobacteriosis (see 209950). Minegishi et al. (2006) concluded that TYK2 deficiency is a primary immunodeficiency displaying the phenotype of the autosomal recessive HIES accompanied by susceptibility to intracellular bacterial infection.
In a Turkish male, born of consanguineous parents, with immunodeficiency-35 (IMD35; 611521), Kilic et al. (2012) identified a homozygous 9-bp deletion (c.2303_2311del) in exon 16 of the TYK2 gene, resulting in a frameshift and premature termination at codon 767. Western blot analysis of cells derived from the patient showed no detectable TYK2 protein. The patient had disseminated Bacille Calmette-Guerin (BCG) infection, neurobrucellosis, and cutaneous herpes zoster infection. Serum IgE was only mildly increased. Kilic et al. (2012) suggested that lack of TYK2 resulted in defective IL12 (see 161560) signaling and impaired production of gamma-interferon (IFNG; 147570).
Kreins et al. (2015) described the protein change brought about by this deletion as L767X.
In 2 sibs, born of consanguineous Moroccan parents, with immunodeficiency-35 (IMD35; 611521), Kreins et al. (2015) identified a homozygous 1-bp insertion (c.3318_3319insC) in exon 23 of the TYK2 gene, resulting in a frameshift and premature termination (Thr1106HisfsTer4). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, or ExAC databases or in an in-house exome database. Western blot analysis of patient cells showed no detectable TYK2 protein, consistent with a complete loss of function.
In 2 sibs, born of consanguineous Iranian parents, with immunodeficiency-35 (IMD35; 611521), Kreins et al. (2015) identified a homozygous c.462G-T transversion in exon 5 of the TYK2 gene, resulting in a glu154-to-ter (E154X) substitution. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, or ExAC databases or in an in-house exome database. Western blot analysis of patient cells showed no detectable TYK2 protein, consistent with a complete loss of function.
In a patient, born of consanguineous Iranian parents, with immunodeficiency-35 (IMD35; 611521), Kreins et al. (2015) identified a homozygous 1-bp deletion (c.149delC) in exon 3 of the TYK2 gene, resulting in a frameshift and premature termination (Ser50HisfsTer1). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, or ExAC databases or in an in-house exome database. Western blot analysis of patient cells showed no detectable TYK2 protein, consistent with a complete loss of function.
In a Chinese boy (patient 4) with IMD35, Lv et al. (2022) identified compound heterozygous mutations in the TYK2 gene: c.149delC and c.2269C-G, resulting in a leu757-to-val (L757V; 176941.0008) substitution. The mutations, which were identified by targeted next-generation sequencing and confirmed by Sanger sequencing, were identified in the carrier state in the parents. The L757V mutation was not present in the ExAC database.
In a boy, born of unrelated Argentinian parents, with immunodeficiency-35 (IMD35; 611521), Kreins et al. (2015) identified a homozygous c.1912C-T transition in exon 13 of the TYK2 gene, resulting in an arg638-to-ter (R638X) substitution. The mutation, which was found by targeted next-generation sequencing, segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, or ExAC databases or in an in-house exome database. Western blot analysis of patient cells showed no detectable TYK2 protein, consistent with a complete loss of function.
Boisson-Dupuis et al. (2018) found that homozygosity for the pro1104-to-ala (P1104A) variant of TYK2 was more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls (p = 8.37 x 10(-8); OR, 89.31; 95% CI, 14.7 to 1725). The P1104A allele is found in about 1 of 600 Europeans but is rare in East Asians. Moreover, the frequency of P1104A in Europeans has decreased over the past 4,000 years, consistent with purging of the variant by endemic tuberculosis. The authors found that the P1104A variant impaired cellular responses to IL23 (see 605580), but not to IFNA (IFNA1; 147660), IL10 (124092), or IL12 (see 161560). TYK2-P1104A docked to cytokine receptors, but it lacked catalytic activity. Thus, homozygotes for P1104A lacked the ability to induce IFNG (147570) via IL23, conferring a predisposition to severe mycobacterial diseases (IMD35; 611521), particularly primary tuberculosis.
Kerner et al. (2021) studied 1,013 ancient human genomes and determined that P1104A originated about 30,000 years ago and dropped significantly in frequency after the Bronze Age, about 2,000 years ago, due to strong negative selection. The authors estimated that the relative fitness reduction on P1104A homozygotes of about 20% is among the highest in the genome.
For discussion of the c.2269C-G transversion in the TYK2 gene, resulting in a leu757-to-val (L757V) substitution, that was identified in compound heterozygous state in a Chinese boy (patient 4) with immunodeficiency-35 (IMD35; 611521) by Lv et al. (2022), see 176941.0005.
In a Chinese boy (patient 1) with immunodeficiency-35 (IMD35; 611521), Lv et al. (2022) identified compound heterozygous mutations in the TYK2 gene: a c.3041T-C transition, resulting in a leu1014-to-pro (L1014P) substitution, and a c.1253C-A transversion, resulting in a ser418-to-ter (S418X; 176941.0008) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were present in the carrier state in the parents. The L1014P mutation was present in the ExAC database at a minor allele frequency of 0.000008. TYK2 protein and mRNA levels were reduced in patient peripheral blood mononuclear cells (PBMCs). The PBMCs also showed an impaired response to alpha- and beta-interferon stimulation but a normal response to gamma-interferon.
For discussion of the c.1253C-A transversion in the TYK2 gene, resulting in a ser418-to-ter (S418X) substitution, that was identified in compound heterozygous state in a patient with immunodeficiency-35 (IMD35; 611521) by Lv et al. (2022), see 176941.0009.
In a Chinese boy (patient 2) with immunodeficiency-35 (IMD35; 611521), Lv et al. (2022) identified a homozygous c.2395G-A transition in the TYK2, resulting in a gly799-to-arg (G799R) substitution. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was identified in the carrier state in the parents. The G799R mutation was present in the ExAC database at a minor allele frequency of 0.000008. TYK2 protein and mRNA levels were reduced in patient peripheral blood mononuclear cells (PBMCs). The PBMCs also showed an impaired response to alpha- and beta-interferon stimulation but a normal response to gamma-interferon. This patient was previously reported by Wu et al. (2020).
In an 8-year-old patient with immunodeficiency-35 (IMD35; 611521) born to consanguineous parents of Kurdish origin, Fuchs et al. (2016) used whole-exome sequencing to identify homozygosity for a single-nucleotide deletion (c.647delC) in the TYK2 gene, resulting in a frameshift and premature stop codon (Pro216ArgfsTer14, P216RfsX14). The patient presented with eczema, skin abscesses, respiratory infections and IgE levels greater than 1000 U/mL. Studies of mRNA levels and protein expression showed reduced mRNA and loss of protein expression, which completely abolished the IFN-alpha mediated antiviral response.
Using whole-exome and whole-genome sequencing in an international cohort of 112 children less than 16 years old who were hospitalized for COVID19 pneumonia, Zhang et al. (2022) identified 3 unrelated patients (P2-4), all born to consanguineous Turkish parents, with homozygosity for the P216RfsX14 mutation in TYK2. No pathogenic variants in TYK2 were seen among the control population of 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia. The authors noted that recessive deficiencies of type I IFN immunity such as this might underlie approximately 10% of pediatric hospitalizations for COVID19 pneumonia.
Boisson-Dupuis, S., Ramirez-Alejo, N., Li, Z., Patin, E., Rao, G., Kerner, G., Lim, C. K., Krementsov, D. N., Hernandez, N., Ma, C. S., Zhang, Q., Markle, J., and 55 others. Tuberculosis and impaired IL-23-dependent IFN-gamma immunity in humans homozygous for a common TYK2 missense variant. Sci. Immun. 3: eaau8714, 2018. [PubMed: 30578352] [Full Text: https://doi.org/10.1126/sciimmunol.aau8714]
Firmbach-Kraft, I., Byers, M., Shows, T., Dalla-Favera, R., Krolewski, J. J. tyk2, prototype of a novel class of non-receptor tyrosine kinase genes. Oncogene 5: 1329-1336, 1990. [PubMed: 2216457]
Fuchs, S., Kaiser-Labusch, P., Bank, J., Ammann, S., Kolb-Kokocinski, A., Edelbusch, C., Omran, H., Ehl, S. Tyrosine kinase 2 is not limiting human antiviral type III interferon responses. Europ. J. Immun. 46: 2639-2649, 2016. [PubMed: 27615517] [Full Text: https://doi.org/10.1002/eji.201646519]
Karaghiosoff, M., Neubauer, H., Lassnig, C., Kovarik, P., Schindler, H., Pircher, H., McCoy, B., Bogdan, C., Decker, T., Brem, G., Pfeffer, K., Muller, M. Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity 13: 549-560, 2000. [PubMed: 11070173] [Full Text: https://doi.org/10.1016/s1074-7613(00)00054-6]
Kerner, G., Laval, G., Patin, E., Boisson-Dupuis, S., Abel, L., Casanova, J.-L., Quintana-Murci, L. Human ancient DNA analyses reveal the high burden of tuberculosis in Europeans over the last 2,000 years. Am. J. Hum. Genet. 108: 517-524, 2021. [PubMed: 33667394] [Full Text: https://doi.org/10.1016/j.ajhg.2021.02.009]
Kiian, I., Tkachuk, N., Haller, H., Dumler, I. Urokinase-induced migration of human vascular smooth muscle cells requires coupling of the small GTPase RhoA and Rac1 to the Tyk2/PI3-K signalling pathway. Thromb. Haemost. 89: 904-914, 2003. [PubMed: 12719789]
Kilic, S. S., Hacimustafaoglu, M., Boisson-Dupuis, S., Kreins, A. Y., Grant, A. V., Abel, L., Casanova, J.-L. A patient with tyrosine kinase 2 deficiency without hyper-IgE syndrome. J. Pediat. 160: 1055-1057, 2012. Note: Erratum: J. Pediat. 161: 974 only, 2012. Erratum: J. Pediat. 162: 658 only, 2013. [PubMed: 22402565] [Full Text: https://doi.org/10.1016/j.jpeds.2012.01.056]
Kreins, A. Y., Ciancanelli, M. J., Okada, S., Kong, X.-F., Ramirez-Alejo, N., Kilic, S. S., El Baghdadi, J., Nonoyama, S., Mahdaviani, S. A., Ailal, F., Bousfiha, A., Mansouri, D., and 42 others. Human TYK2 deficiency: mycobacterial and viral infections without hyper-IgE syndrome. J. Exp. Med. 212: 1641-1662, 2015. [PubMed: 26304966] [Full Text: https://doi.org/10.1084/jem.20140280]
Krolewski, J. J., Lee, R., Eddy, R., Shows, T. B., Dalla-Favera, R. Identification and chromosomal mapping of new human tyrosine kinase genes. Oncogene 5: 277-282, 1990. [PubMed: 2156206]
Lukashova, V., Asselin, C., Krolewski, J. J., Rola-Pleszczynski, M., Stankova, J. G-protein-independent activation of Tyk2 by the platelet-activating factor receptor. J. Biol. Chem. 276: 24113-24121, 2001. [PubMed: 11309383] [Full Text: https://doi.org/10.1074/jbc.M100720200]
Lv, G., Sun, G., Wu, P., Du, X., Zeng, T., Wen, W., Zhou, L., An, Y., Tang, X., He, T., Zhao, X., Du, H. Novel mutations of TYK2 leading to divergent clinical phenotypes. Pediat. Allergy Immun. 33: e13671, 2022. [PubMed: 34569645] [Full Text: https://doi.org/10.1111/pai.13671]
Minegishi, Y., Saito, M., Morio, T., Watanabe, K., Agematsu, K., Tsuchiya, S., Takada, H., Hara, T., Kawamura, N., Ariga, T., Kaneko, H., Kondo, N., and 24 others. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25: 745-755, 2006. [PubMed: 17088085] [Full Text: https://doi.org/10.1016/j.immuni.2006.09.009]
Ragimbeau, J., Dondi, E., Alcover, A., Eid, P., Uze, G., Pellegrini, S. The tyrosine kinase Tyk2 controls IFNAR1 cell surface expression. EMBO J. 22: 537-547, 2003. [PubMed: 12554654] [Full Text: https://doi.org/10.1093/emboj/cdg038]
Sigurdsson, S., Nordmark, G., Goring, H. H. H., Lindroos, K., Wiman, A.-C., Sturfelt, G., Jonsen, A., Rantapaa-Dahlqvist, S., Moller, B., Kere, J., Koskenmies, S., Widen, E., Eloranta, M.-L., Julkunen, H., Kristjansdottir, H., Steinsson, K., Alm, G., Ronnblom, L., Syvanen, A.-C. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am. J. Hum. Genet. 76: 528-537, 2005. [PubMed: 15657875] [Full Text: https://doi.org/10.1086/428480]
Stoiber, D., Kovacic, B., Schuster, C., Schellack, C., Karaghiosoff, M., Kreibich, R., Weisz, E., Artwohl, M., Kleine, O. C., Muller, M., Baumgartner-Parzer, S., Ghysdael, J., Freissmuth, M., Sexl, V. TYK2 is a key regulator of the surveillance of B lymphoid tumors. J. Clin. Invest. 114: 1650-1658, 2004. [PubMed: 15578097] [Full Text: https://doi.org/10.1172/JCI22315]
Trask, B., Fertitta, A., Christensen, M., Youngblom, J., Bergmann, A., Copeland, A., de Jong, P., Mohrenweiser, H., Olsen, A., Carrano, A., Tynan, K. Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers. Genomics 15: 133-145, 1993. [PubMed: 8432525] [Full Text: https://doi.org/10.1006/geno.1993.1021]
Wu, P., Chen, S., Wu, B., Chen, J., Lv, G. A TYK2 gene mutation c.2395G-A leads to TYK2 deficiency: a case report and literature review. Front. Pediat. 8: 253, 2020. [PubMed: 32537443] [Full Text: https://doi.org/10.3389/fped.2020.00253]
Zhang, Q., Matuozzo, D., Le Pen, J., Lee, D., Moens, L., Asano, T., Bohlen, J., Liu, Z., Moncada-Velez, M., Kendir-Demirkol, Y., Jing, H., Bizien, L., and 35 others. Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia. J. Exp. Med. 219: e20220131, 2022. [PubMed: 35708626] [Full Text: https://doi.org/10.1084/jem.20220131]