Alternative titles; symbols
HGNC Approved Gene Symbol: TYROBP
Cytogenetic location: 19q13.12 Genomic coordinates (GRCh38) : 19:35,904,403-35,908,295 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.12 | Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 | 221770 | Autosomal recessive | 3 |
Natural killer (NK) cells express cell surface receptors that recognize major histocompatibility complex class I peptides (e.g., 142800) and inhibit NK cell-mediated cytotoxicity. NK cell receptors belong to 2 distinct groups: the immunoglobulin superfamily for the killer cell inhibitory receptors (KIRs; e.g., 602992), and the C-type lectin superfamily for the NKG2 receptors (e.g., 161555). These inhibitory receptors possess 'immunoreceptor tyrosine-based inhibitory motifs' (ITIMs) in their cytoplasmic domains that recruit SH2 domain-containing protein-tyrosine phosphatases, resulting in inactivation of NK cells. Certain isoforms of NK cell receptors lack ITIM sequences, and these non-inhibitory receptors activate, rather than inhibit, NK cells. Cell surface immunoglobulin receptors, T-cell antigen receptors (e.g., 186880), and certain Fc receptors noncovalently associate with small transmembrane proteins, such as CD3-delta (CD3D; 186790), -gamma (CD3G; 186740), -epsilon (CD3E; 186830), -zeta (CD3Z; 186780), CD79-alpha (112205), -beta (147245), and FCER1G (147139), that contain an 'immunoreceptor tyrosine-based activation motif' (ITAM) sequence and are required for signal transduction by these receptor complexes. Lanier et al. (1998) hypothesized that non-inhibitory NK cell receptors might require an associated protein with similar properties to mediate positive signal transduction. By searching an EST database with the protein sequences of CD3D, CD3G, CD3E, CD3Z, and FCER1G, they isolated a human CD1+ dendritic cell EST encoding an ITAM-containing protein, which they named DAP12. The predicted 113-amino acid DAP12 protein is composed of a signal peptide, a 14-amino acid extracellular domain, a transmembrane segment, and a 48-amino acid cytoplasmic domain. Although DAP12 shares less than 25% similarity with the human CD3D, CD3G, CD3E, CD3Z, and FCER1G proteins, its cytoplasmic domain contains a sequence that precisely corresponds to the prototype ITAM consensus. Potential sites for phosphorylation are also present in the DAP12 cytoplasmic region. The transmembrane domain of DAP12 contains the charged amino acid aspartic acid, which is conserved in the transmembrane domain of the CD3 subunits.
Tomasello et al. (1998) cloned the full-length coding sequence of mouse Tyrobp, which they called Karap for 'killer cell-activating receptor-associated protein.' The deduced human and mouse TYROBP proteins are 73% identical and are more similar to CD3Z and FCER1G than to other known ITAM-bearing molecules. RT-PCR analysis of a variety of hematopoietic and nonhematopoietic mouse cell lines revealed almost ubiquitous expression of Tyrobp.
Lanier et al. (1998) demonstrated that the DAP12 protein is expressed on the cell surface as a disulfide-bonded homodimer. DAP12 noncovalently associated with KIR2DS2, a KIR family member that lacks an ITIM. Crosslinking of KIR2DS2/DAP12 complexes, but not of KIR2DS2 alone, resulted in cellular activation, as indicated by tyrosine phosphorylation of cellular proteins and upregulation of early-activation antigens. In addition, crosslinking of KIR2DS2/DAP12 complexes induced tyrosine phosphorylation of DAP12 and resulted in the association of phosphorylated DAP12 with the protein-tyrosine kinase SYK (600085). Peptides corresponding to the cytoplasmic domain of DAP12 formed complexes with the protein-tyrosine kinases SYK and ZAP70 (176947) only if the tyrosine residues in the ITAM of DAP12 were phosphorylated. Northern blot analysis detected an abundant 0.7-kb DAP12 transcript in human peripheral blood leukocytes and spleen but not in thymus or the other tissues examined. The authors found DAP12 expression in human NK cell lines but not in a T leukemia cell line or a B lymphoblastoid cell line. Lanier et al. (1998) suggested that DAP12 associates with the non-inhibitory isoforms of the KIR molecules in NK cells and permits cellular activation through these receptors, in a way similar to the function of the CD3 subunits in the T-cell receptor complex and the CD79 subunits in the B-cell receptor complex.
DAP12 associates with the cell surface receptor TREM2 (605086), and the DAP12-TREM2 complex is involved in dendritic cell maturation. Paloneva et al. (2003) analyzed differentiation of peripheral blood mononuclear cells from DAP12- and TREM2-deficient Finnish or German polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; 221770) patients into osteoclasts. They found that homozygous loss-of-function mutations in DAP12 or TREM2 resulted in inefficient, aberrant, and delayed differentiation into osteoclasts and significantly diminished bone resorption capability in vitro. RT-PCR analysis detected no differences between patient and control cells in the expression of several genes, but expression of DAP12 and TREM2 increased in control cells during osteoclastic differentiation. Paloneva et al. (2003) concluded that the DAP12-TREM2 signaling complex is important in the differentiation and function of osteoclasts.
Lanier et al. (1998) stated that the human TYROBP genomic sequence is contained within a cosmid (GenBank AD000833) that maps to 19q13.1. By FISH, Tomasello et al. (1998) mapped the mouse Tyrobp gene to 7B. They noted that human 19q13 shows homology of synteny with mouse chromosome 7.
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL1; 221770), also known as Nasu-Hakola disease, is a recessively inherited disorder characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. Identification of a shared 153-kb ancestor haplotype in all Finnish disease alleles on 19q13.1 was the first step in characterizing the molecular defect. The TYROBP gene was one of those located in the critical DNA region for PLOSL. Paloneva et al. (2000) failed to obtain products by PCR amplification of the coding region of TYROBP in the genomic DNA of Finnish PLOSL patients with primers flanking exons 1-4, whereas exon 5 was amplified normally. This indicated that the patients carried a homozygous deletion encompassing exons 1-4 of TYROBP (604142.0001). They located the 5-prime deletion breakpoint 2,900 bp upstream of the initiation methionine, and the 3-prime breakpoint in the last intron of TYROBP, 1,300 bp upstream of the termination codon. Sequence analysis of the 342-bp coding region of TYROBP from the genomic DNA of a Japanese PLOSL patient demonstrated homozygosity for a 1-bp deletion in exon 3 (604142.0002). This mutation created a frameshift in the open reading frame, predicting premature termination of the polypeptide chain after 52 amino acids. The mutation also changed the aspartic acid residue in the transmembrane domain that is essential in mediating the interaction between the TYROBP homodimer and the associated ligand-binding receptors on the surface of natural killer (NK) cells. On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class III molecules. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP. In 1 Norwegian and 1 Swedish patient with the typical clinical features of PLOSL, linkage to 19q13.1 was excluded, and no sign of mutation of TYROBP was found in them or their families.
In 5 of 6 Japanese patients with PLOSL, Kondo et al. (2002) identified homozygous mutations in the DAP12 gene (604142.0002-604142.0003).
Kaifu et al. (2003) noted that DAP12 is expressed in the monocyte-macrophage lineage, and that osteoclasts and microglial cells share a myeloid origin, providing a link between lesions in the brain and bone in patients with presenile dementia with bone cysts due to mutation in the DAP12 gene. In Dap12 -/- mice, Kaifu et al. (2003) found progressive osteopetrosis beginning at about 6 weeks of age. Bone marrow cells of Dap12 -/- mice failed to yield mature or functional osteoclasts in vitro. Brain sections from mutant mice showed hypomyelinosis, synaptic degeneration, and immature oligodendrocytes in the region of the thalamus. The Dap12 -/- mice showed a reduced startle reflex in response to acoustic stimuli and reduced prepulse inhibition, suggesting an impairment of sensorimotor gating. Northern blot analysis of brain tissue from wildtype mice detected Dap12 mRNA in oligodendrocytes and microglial cells, but not in astrocytes or neurons.
Koga et al. (2004) showed that mice lacking immunoreceptor tyrosine-based activation motif (ITAM)-harboring adaptors Fc receptor common gamma subunit (147139) and DAP12 exhibit severe osteopetrosis owing to impaired osteoclast differentiation. In osteoclast precursor cells, Fc receptor-gamma and DAP12 associated with multiple immunoreceptors and activated calcium signaling through phospholipase C-gamma (see 172420). Thus, ITAM-dependent costimulatory signals activated by multiple immunoreceptors are essential for the maintenance of bone homeostasis. Koga et al. (2004) concluded that RANKL (602642) and macrophage colony-stimulating factor (120420) are not sufficient to activate the signals required for osteoclastogenesis.
Hamerman et al. (2005) found that macrophages from Dap12-deficient mice produced more Tnf (191160), Il6 (147620), and Il12b (161561) after stimulation of Toll-like receptors (TLRs; see 603030) with various pathogen products than did macrophages from wildtype mice. Inflammatory cytokine production returned to wildtype levels after Dap12 reconstitution, but not after reconstitution with Dap12 lacking the ITAM. Macrophages lacking Syk, which signals downstream of Dap12, showed a phenotype identical to that of Dap12-deficient macrophages. Dap12-deficient mice produced Tnf at the same rate as wildtype mice but at higher levels in response to treatment with lipopolysaccharide combined with the Tnf-sensitizing agent D-galactosamine, and none survived endotoxic shock. Three days after infection with Listeria monocytogenes, Dap12-deficient mice had substantially fewer bacteria in spleen and liver compared with wildtype mice. Hamerman et al. (2005) proposed that 1 or more DAP12-pairing receptors negatively regulate signaling through TLRs. They noted that Nasu-Hakola patients are not immunodeficient and, based on their findings, suggested that these patients may have enhanced resistance to certain pathogens.
In contrast to the findings of Hamerman et al. (2005), Turnbull et al. (2005) found that Dap12 -/- mice were less susceptible to septic shock induced by simple endotoxemia or cecal ligation and puncture than wildtype mice. They concluded that, during sepsis, DAP12 signaling augments the response to microbial products, amplifying inflammation and contributing to mortality.
Turnbull et al. (2006) found that mice lacking Trem2 were unable to inhibit cytokine production in response to microbial products. There was no difference in cytokine production by macrophages from Trem2-deficient mice and Dap12-deficient mice, leading Turnbull et al. (2006) to conclude that Trem2 is the receptor operative in the increased macrophage cytokine production observed in Dap12-deficient cells.
In all 26 Finnish patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL1; 221770) as well as in 2 Swedish patients with known ancestors in Finland, Paloneva et al. (2000) found homozygosity for a genomic deletion of 5,265 bp, including 343 bp (exons 1-4 and 5-prime untranslated region) of the 604-bp transcribed region of the TYROBP gene.
In a sequence analysis of the 342-bp coding region of the TYROBP gene from the genomic DNA of a Japanese patient with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL1; 221770), Paloneva et al. (2000) found a homozygous 1-bp deletion in exon 3. The mutation created a frameshift in the open reading frame, predicting premature termination of the polypeptide chain after 52 amino acids.
In 3 unrelated Japanese patients (patients NHD1, 5, and 6) with PLOSL1, Kondo et al. (2002) identified homozygosity for the 1-bp deletion in exon 3 of the DAP12 gene.
In 2 unrelated Japanese patients (patients NHD3,4) with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL1; 221770), both born to consanguineous parents, Kondo et al. (2002) found a T-to-C transition in the second nucleotide of the DAP12 gene, changing the start codon from ATG (met) to ACG (thr). The patients had developed neuropsychiatric signs at age 30 to 35 years and both had x-ray signs of bone cysts.
Hamerman, J. A., Tchao, N. K., Lowell, C. A., Lanier, L. L. Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. Nature Immun. 6: 579-586, 2005. Note: Erratum: Nature Immun. 10: 223 only, 2009. [PubMed: 15895090] [Full Text: https://doi.org/10.1038/ni1204]
Kaifu, T., Nakahara, J., Inui, M., Mishima, K., Momiyama, T., Kaji, M., Sugahara, A., Koito, H., Ujike-Asai, A., Nakamura, A., Kanazawa, K., Tan-Takeuchi, K., Iwasaki, K., Yokoyama, W. M., Kudo, A., Fujiwara, M., Asou, H., Takai, T. Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J. Clin. Invest. 111: 323-332, 2003. [PubMed: 12569157] [Full Text: https://doi.org/10.1172/JCI16923]
Koga, T., Inui, M., Inoue, K., Kim, S., Suematsu, A., Kobayashi, E., Iwata, T., Ohnishi, H., Matozaki, T., Kodama, T., Taniguchi, T., Takayanagi, H., Takai, T. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428: 758-763, 2004. [PubMed: 15085135] [Full Text: https://doi.org/10.1038/nature02444]
Kondo, T., Takahashi, K., Kohara, N., Takahashi, Y., Hayashi, S., Takahashi, H., Matsuo, H., Yamazaki, M., Inoue, K., Miyamoto, K., Yamamura, T. Heterogeneity of presenile dementia with bone cysts (Nasu-Hakola disease): three genetic forms. Neurology 59: 1105-1107, 2002. [PubMed: 12370476] [Full Text: https://doi.org/10.1212/wnl.59.7.1105]
Lanier, L. L., Corliss, B. C., Wu, J., Leong, C., Phillips, J. H. Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 391: 703-707, 1998. [PubMed: 9490415] [Full Text: https://doi.org/10.1038/35642]
Paloneva, J., Kestila, M., Wu, J., Salminen, A., Bohling, T., Ruotsalainen, V., Hakola, P., Bakker, A. B. H., Phillips, J. H., Pekkarinen, P., Lanier, L. L., Timonen, T., Peltonen, L. Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nature Genet. 25: 357-361, 2000. [PubMed: 10888890] [Full Text: https://doi.org/10.1038/77153]
Paloneva, J., Mandelin, J., Kiialainen, A., Bohling, T., Prudlo, J., Hakola, P., Haltia, M., Konttinen, Y. T., Peltonen, L. DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. J. Exp. Med. 198: 669-675, 2003. [PubMed: 12925681] [Full Text: https://doi.org/10.1084/jem.20030027]
Tomasello, E., Olcese, L., Vely, F., Geourgeon, C., Blery, M., Moqrich, A., Gautheret, D., Djabali, M., Mattei, M.-G., Vivier, E. Gene structure, expression pattern, and biological activity of mouse killer cell activating receptor-associated protein (KARAP)/DAP-12. J. Biol. Chem. 273: 34115-34119, 1998. [PubMed: 9852069] [Full Text: https://doi.org/10.1074/jbc.273.51.34115]
Turnbull, I. R., Gilfillan, S., Cella, M., Aoshi, T., Miller, M., Piccio, L., Hernandez, M., Colonna, M. Cutting edge: TREM-2 attenuates macrophage activation. J. Immun. 177: 3520-3524, 2006. [PubMed: 16951310] [Full Text: https://doi.org/10.4049/jimmunol.177.6.3520]
Turnbull, I. R., McDunn, J. E., Takai, T., Townsend, R. R., Cobb, J. P., Colonna, M. DAP12 (KARAP) amplifies inflammation and increases mortality from endotoxemia and septic peritonitis. J. Exp. Med. 202: 363-369, 2005. [PubMed: 16061725] [Full Text: https://doi.org/10.1084/jem.20050986]