HGNC Approved Gene Symbol:TNFRSF21
Cytogenetic location:6p12.3 Genomic coordinates(GRCh38) :6:47,231,532-47,309,905 (from NCBI)
Within the tumor necrosis factor receptor (TNFR; see TNFR1 (191190)) superfamily there is a subgroup termed death receptors, which contain a cytoplasmic death domain. Activation of these receptors leads to the engagement of components of the cell death pathway, including the adaptor molecule TRADD (603500) and subsequently the FADD (602457)-caspase-8 (CASP8;601763) pathway, which in turn activates the nuclear factor kappa-B (NFKB; see164011) pathway. TNFRSF21 belongs to the death receptor subfamily of TNFRs (summary byPan et al., 1998).
By EST database searching with the extracellular binding domain of TNFR2 (191191) as the probe,Pan et al. (1998) identified a cDNA encoding DR6. The deduced 655-amino acid protein has an N-terminal signal sequence followed by 4 TNFR-like cysteine-rich motifs, and a transmembrane domain followed by a cytoplasmic portion containing a 135-amino acid death domain and a 150-residue tail. The death domain of DR6 is 27% identical to that of TNFR1. Northern blot analysis revealed wide expression of a 4.0-kb transcript in normal tissues and in cervical, lung, and colorectal carcinomas and melanomas; expression was not detected in hemopoietic tumor lines.
Zhao et al. (2001) cloned mouse Tnfrsf21 and determined that the protein sequence is 88% identical to the human protein. Expression analysis revealed that Dr6 levels were 2-fold higher in Th2 than Th1 cells.
Mi et al. (2011) found that rat Dr6 was expressed in the oligodendrocyte lineage. Real-time PCR and Western blot analysis of rat brain detected highest Dr6 mRNA and protein expression between postnatal days 7 and 14, with lower expression in rat embryos and adults. In situ hybridization detected Dr6 in premyelinating oligodendrocytes in the corpus collosum of adult rat brain.
By immunofluorescent staining in a 3-week-old mouse eye,Pan et al. (2019) demonstrated strong expression of Tnfrsf21 in all layers of the ocular globe as well as in the optic nerve.
Gross (2019) mapped the TNFRSF21 gene to chromosome 6p12.3 based on an alignment of the TNFRSF21 sequence (GenBankBC010241) with the genomic sequence (GRCh38).
Pan et al. (1998) found that overexpression of DR6 induced death in cervical carcinoma cell lines, but not in breast carcinoma cell lines. DR6-induced death was dependent on the presence of the death domain. Coimmunoprecipitation analysis indicated that DR6 interacted with TRADD, but not with RAIDD (603454), RIP (603453), or FADD. Luciferase reporter and immunoprecipitation analyses showed activation of the NFKB and JNK (601158) pathways by DR6.Pan et al. (1998) suggested that DR6 is likely to be involved in inflammation and immune regulation.
Mi et al. (2011) found that overexpression of Dr6 in rat oligodendrocyte progenitor cells induced Casp3-dependent cell death. Oligodendrocyte cell death did not involve App, suggesting that different pathways lead to Casp3 activation in neurons and oligodendrocytes. Immunohistochemical analysis showed 4-fold elevated numbers of DR6-expressing cells in multiple sclerosis (see126200) white matter compared with normal human white matter. Based on these findings and studies in rodents (see ANIMAL MODEL),Mi et al. (2011) concluded that DR6 negatively regulates oligodendrocyte survival, maturation, and myelination.
Strilic et al. (2016) showed that human and murine tumor cells induce programmed necrosis (necroptosis) of endothelial cells, which promotes tumor cell extravasation and metastasis. Treatment of mice with the receptor-interacting serine/threonine-protein kinase-1 (RIPK1;603453) inhibitor necrostatin-1 or endothelial cell-specific deletion of RIPK3 (605817) reduced tumor cell-induced endothelial necroptosis, tumor cell extravasation, and metastasis. In contrast, pharmacologic caspase inhibition or endothelial cell-specific loss of CASP8 (601763) promoted these processes.Strilic et al. (2016) showed in vitro and in vivo that tumor cell-induced endothelial necroptosis leading to extravasation and metastasis requires APP expressed by tumor cells and its receptor, DR6, on endothelial cells as the primary mediators of these effects.Strilic et al. (2016) concluded that their data identified a novel mechanism underlying tumor cell extravasation and metastasis, and suggested endothelial DR6-mediated necroptotic signaling pathways as targets for antimetastatic therapies.
By homologous recombination,Zhao et al. (2001) generated mice that did not express the extracellular and transmembrane domains of Dr6. These Dr6-deficient mice had expanded T-cell populations in thymus and peripheral blood, but there were no differences in other lymphoid and myeloid cells. The T-cell proliferation and secretion of IL2 (147680) and IL4 (147780) increased in response to mitogens and to specific antigen after immunization. Immunized Dr6-deficient mice also had increased levels of serum immunoglobulins associated with polarization toward a Th2 response. The regulation of T-cell differentiation was not attributable to activation-induced cell death but was associated with a reduction of JNK activity.Zhao et al. (2001) concluded that DR6 is involved in T-helper cell activation and differentiation, and they proposed that DR6 ligand may be secreted in an autocrine manner by activated T cells.
Mi et al. (2011) stated that Dr6 -/- mice are viable and fertile, with no obvious tissue pathology. However,Mi et al. (2011) observed precocious myelination in Dr6 -/- mice. Blocking Dr6 via a neutralizing antibody or genetic deletion promoted oligodendrocyte survival and remyelination in rodent models of demyelinating diseases, and these effects were independent of an antiinflammatory response.
In a 3-generation Chinese family segregating autosomal dominant nonsyndromic high myopia (see160700),Pan et al. (2019) identified heterozygosity for a missense mutation in the TNFRSF21 gene (P146A;605732.0001) that segregated fully with disease and was not found in public variant databases. Analysis of the TNFRSF21 gene in 220 unrelated Chinese patients with high myopia identified a nonsense mutation and 2 missense variants in 3 patients; the missense variant (P202L) in 1 of the patients (SHM185) was also present in her affected mother (SHM221).
The article byNikolaev et al. (2009) regarding beta-amyloid precursor protein and DR6 was retracted.
This variant is classified as a variant of unknown significance because its contribution to high myopia has not been confirmed.
In 9 affected members of a 3-generation Chinese family segregating autosomal dominant nonsyndromic high myopia (see160700),Pan et al. (2019) identified heterozygosity for a c.436C-G transversion (c.436C-G, ENST00000296861) in the TNFRSF21 gene, resulting in a pro146-to-ala (P146A) substitution at a highly conserved residue within the third cysteine-rich domain of the tumor necrosis factor receptor region. The mutation segregated fully with disease in the family and was not found in the 1000 Genomes Project, GO-ESP, ExAC, or gnomAD databases. Functional analysis in transfected ARPE-19 cells demonstrated significantly increased apoptosis with the P146A mutant compared to wildtype. Axial lengths, measured in the proband and her affected father, were increased. Funduscopy in the proband's father showed typical features of high myopia, including tigroid appearance of the retina, peripapillary atrophy, and macular thinning and depigmentation. Optical coherence tomography revealed foveal flattening and choroidal thinning.
Gross, M. B.Personal Communication. Baltimore, Md. 12/2/2019.
Mi, S., Lee, X., Hu, Y., Ji, B., Shao, Z., Yang, W., Huang, G., Walus, L., Rhodes, K., Gong, B. J., Miller, R. H., Pepinsky, R. B.Death receptor 6 negatively regulates oligodendrocyte survival, maturation and myelination. Nature Med. 17: 816-821, 2011. [PubMed:21725297,related citations] [Full Text]
Nikolaev, A., McLaughlin, T., O'Leary, D. D. M., Tessier-Lavigne, M.APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457: 981-989, 2009. Note: Retraction: Nature 625: 204 only, 2024. [PubMed:19225519,images,related citations] [Full Text]
Pan, G., Bauer, J. H., Haridas, V., Wang, S., Liu, D., Yu, G., Vincenz, C., Aggarwal, B. B., Ni, J., Dixit, V. M.Identification and functional characterization of DR6, a novel death domain-containing TNF receptor. FEBS Lett. 431: 351-356, 1998. [PubMed:9714541,related citations] [Full Text]
Pan, H., Wu, S., Wang, J., Zhu, T., Li, T., Wan, B., Liu, B., Luo, Y., Ma, X., Sui, R., Wang, B.TNFRSF21 mutations cause high myopia. J. Med. Genet. 56: 671-677, 2019. [PubMed:31189563,related citations] [Full Text]
Strilic, B., Yang, L., Albarran-Juarez, J., Wachsmuth, L., Han, K., Muller, U. C., Pasparakis, M., Offermanns, S.Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. Nature 536: 215-218, 2016. [PubMed:27487218,related citations] [Full Text]
Zhao, H., Yan, M., Wang, H., Erickson, S., Grewal, I. S., Dixit, V. M.Impaired c-Jun amino terminal kinase activity and T cell differentiation in death receptor 6-deficient mice. J. Exp. Med. 194: 1441-1448, 2001. [PubMed:11714751,images,related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: TNFRSF21
Cytogenetic location: 6p12.3 Genomic coordinates(GRCh38) : 6:47,231,532-47,309,905(from NCBI)
Within the tumor necrosis factor receptor (TNFR; see TNFR1 (191190)) superfamily there is a subgroup termed death receptors, which contain a cytoplasmic death domain. Activation of these receptors leads to the engagement of components of the cell death pathway, including the adaptor molecule TRADD (603500) and subsequently the FADD (602457)-caspase-8 (CASP8; 601763) pathway, which in turn activates the nuclear factor kappa-B (NFKB; see 164011) pathway. TNFRSF21 belongs to the death receptor subfamily of TNFRs (summary by Pan et al., 1998).
By EST database searching with the extracellular binding domain of TNFR2 (191191) as the probe, Pan et al. (1998) identified a cDNA encoding DR6. The deduced 655-amino acid protein has an N-terminal signal sequence followed by 4 TNFR-like cysteine-rich motifs, and a transmembrane domain followed by a cytoplasmic portion containing a 135-amino acid death domain and a 150-residue tail. The death domain of DR6 is 27% identical to that of TNFR1. Northern blot analysis revealed wide expression of a 4.0-kb transcript in normal tissues and in cervical, lung, and colorectal carcinomas and melanomas; expression was not detected in hemopoietic tumor lines.
Zhao et al. (2001) cloned mouse Tnfrsf21 and determined that the protein sequence is 88% identical to the human protein. Expression analysis revealed that Dr6 levels were 2-fold higher in Th2 than Th1 cells.
Mi et al. (2011) found that rat Dr6 was expressed in the oligodendrocyte lineage. Real-time PCR and Western blot analysis of rat brain detected highest Dr6 mRNA and protein expression between postnatal days 7 and 14, with lower expression in rat embryos and adults. In situ hybridization detected Dr6 in premyelinating oligodendrocytes in the corpus collosum of adult rat brain.
By immunofluorescent staining in a 3-week-old mouse eye, Pan et al. (2019) demonstrated strong expression of Tnfrsf21 in all layers of the ocular globe as well as in the optic nerve.
Gross (2019) mapped the TNFRSF21 gene to chromosome 6p12.3 based on an alignment of the TNFRSF21 sequence (GenBank BC010241) with the genomic sequence (GRCh38).
Pan et al. (1998) found that overexpression of DR6 induced death in cervical carcinoma cell lines, but not in breast carcinoma cell lines. DR6-induced death was dependent on the presence of the death domain. Coimmunoprecipitation analysis indicated that DR6 interacted with TRADD, but not with RAIDD (603454), RIP (603453), or FADD. Luciferase reporter and immunoprecipitation analyses showed activation of the NFKB and JNK (601158) pathways by DR6. Pan et al. (1998) suggested that DR6 is likely to be involved in inflammation and immune regulation.
Mi et al. (2011) found that overexpression of Dr6 in rat oligodendrocyte progenitor cells induced Casp3-dependent cell death. Oligodendrocyte cell death did not involve App, suggesting that different pathways lead to Casp3 activation in neurons and oligodendrocytes. Immunohistochemical analysis showed 4-fold elevated numbers of DR6-expressing cells in multiple sclerosis (see 126200) white matter compared with normal human white matter. Based on these findings and studies in rodents (see ANIMAL MODEL), Mi et al. (2011) concluded that DR6 negatively regulates oligodendrocyte survival, maturation, and myelination.
Strilic et al. (2016) showed that human and murine tumor cells induce programmed necrosis (necroptosis) of endothelial cells, which promotes tumor cell extravasation and metastasis. Treatment of mice with the receptor-interacting serine/threonine-protein kinase-1 (RIPK1; 603453) inhibitor necrostatin-1 or endothelial cell-specific deletion of RIPK3 (605817) reduced tumor cell-induced endothelial necroptosis, tumor cell extravasation, and metastasis. In contrast, pharmacologic caspase inhibition or endothelial cell-specific loss of CASP8 (601763) promoted these processes. Strilic et al. (2016) showed in vitro and in vivo that tumor cell-induced endothelial necroptosis leading to extravasation and metastasis requires APP expressed by tumor cells and its receptor, DR6, on endothelial cells as the primary mediators of these effects. Strilic et al. (2016) concluded that their data identified a novel mechanism underlying tumor cell extravasation and metastasis, and suggested endothelial DR6-mediated necroptotic signaling pathways as targets for antimetastatic therapies.
By homologous recombination, Zhao et al. (2001) generated mice that did not express the extracellular and transmembrane domains of Dr6. These Dr6-deficient mice had expanded T-cell populations in thymus and peripheral blood, but there were no differences in other lymphoid and myeloid cells. The T-cell proliferation and secretion of IL2 (147680) and IL4 (147780) increased in response to mitogens and to specific antigen after immunization. Immunized Dr6-deficient mice also had increased levels of serum immunoglobulins associated with polarization toward a Th2 response. The regulation of T-cell differentiation was not attributable to activation-induced cell death but was associated with a reduction of JNK activity. Zhao et al. (2001) concluded that DR6 is involved in T-helper cell activation and differentiation, and they proposed that DR6 ligand may be secreted in an autocrine manner by activated T cells.
Mi et al. (2011) stated that Dr6 -/- mice are viable and fertile, with no obvious tissue pathology. However, Mi et al. (2011) observed precocious myelination in Dr6 -/- mice. Blocking Dr6 via a neutralizing antibody or genetic deletion promoted oligodendrocyte survival and remyelination in rodent models of demyelinating diseases, and these effects were independent of an antiinflammatory response.
In a 3-generation Chinese family segregating autosomal dominant nonsyndromic high myopia (see 160700), Pan et al. (2019) identified heterozygosity for a missense mutation in the TNFRSF21 gene (P146A; 605732.0001) that segregated fully with disease and was not found in public variant databases. Analysis of the TNFRSF21 gene in 220 unrelated Chinese patients with high myopia identified a nonsense mutation and 2 missense variants in 3 patients; the missense variant (P202L) in 1 of the patients (SHM185) was also present in her affected mother (SHM221).
The article by Nikolaev et al. (2009) regarding beta-amyloid precursor protein and DR6 was retracted.
This variant is classified as a variant of unknown significance because its contribution to high myopia has not been confirmed.
In 9 affected members of a 3-generation Chinese family segregating autosomal dominant nonsyndromic high myopia (see 160700), Pan et al. (2019) identified heterozygosity for a c.436C-G transversion (c.436C-G, ENST00000296861) in the TNFRSF21 gene, resulting in a pro146-to-ala (P146A) substitution at a highly conserved residue within the third cysteine-rich domain of the tumor necrosis factor receptor region. The mutation segregated fully with disease in the family and was not found in the 1000 Genomes Project, GO-ESP, ExAC, or gnomAD databases. Functional analysis in transfected ARPE-19 cells demonstrated significantly increased apoptosis with the P146A mutant compared to wildtype. Axial lengths, measured in the proband and her affected father, were increased. Funduscopy in the proband's father showed typical features of high myopia, including tigroid appearance of the retina, peripapillary atrophy, and macular thinning and depigmentation. Optical coherence tomography revealed foveal flattening and choroidal thinning.
Gross, M. B.Personal Communication. Baltimore, Md. 12/2/2019.
Mi, S., Lee, X., Hu, Y., Ji, B., Shao, Z., Yang, W., Huang, G., Walus, L., Rhodes, K., Gong, B. J., Miller, R. H., Pepinsky, R. B.Death receptor 6 negatively regulates oligodendrocyte survival, maturation and myelination. Nature Med. 17: 816-821, 2011. [PubMed: 21725297] [Full Text: https://doi.org/10.1038/nm.2373]
Nikolaev, A., McLaughlin, T., O'Leary, D. D. M., Tessier-Lavigne, M.APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457: 981-989, 2009. Note: Retraction: Nature 625: 204 only, 2024. [PubMed: 19225519] [Full Text: https://doi.org/10.1038/nature07767]
Pan, G., Bauer, J. H., Haridas, V., Wang, S., Liu, D., Yu, G., Vincenz, C., Aggarwal, B. B., Ni, J., Dixit, V. M.Identification and functional characterization of DR6, a novel death domain-containing TNF receptor. FEBS Lett. 431: 351-356, 1998. [PubMed: 9714541] [Full Text: https://doi.org/10.1016/s0014-5793(98)00791-1]
Pan, H., Wu, S., Wang, J., Zhu, T., Li, T., Wan, B., Liu, B., Luo, Y., Ma, X., Sui, R., Wang, B.TNFRSF21 mutations cause high myopia. J. Med. Genet. 56: 671-677, 2019. [PubMed: 31189563] [Full Text: https://doi.org/10.1136/jmedgenet-2018-105684]
Strilic, B., Yang, L., Albarran-Juarez, J., Wachsmuth, L., Han, K., Muller, U. C., Pasparakis, M., Offermanns, S.Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. Nature 536: 215-218, 2016. [PubMed: 27487218] [Full Text: https://doi.org/10.1038/nature19076]
Zhao, H., Yan, M., Wang, H., Erickson, S., Grewal, I. S., Dixit, V. M.Impaired c-Jun amino terminal kinase activity and T cell differentiation in death receptor 6-deficient mice. J. Exp. Med. 194: 1441-1448, 2001. [PubMed: 11714751] [Full Text: https://doi.org/10.1084/jem.194.10.1441]
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