Alternative titles; symbols
HGNC Approved Gene Symbol: RELB
Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38): 19:45,001,464-45,038,192 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.32 | ?Immunodeficiency 53 | 617585 | Autosomal recessive | 3 |
The RELB gene encodes a member of the nuclear factor kappa-B (NFKB) family of transcription factors. RELB works in the alternative, as opposed to the classical, pathway of NFKB activation (summary by Merico et al., 2015).
For background information on the NFKB complex, see NFKB1 (164011).
By screening a Jurkat T-cell cDNA library with a probe obtained by use of degenerate PCR primers for RELA (164014), Ruben et al. (1992) obtained a cDNA encoding RELB. The deduced protein, which the authors termed I-Rel, has 579 amino acids. Northern blot analysis revealed expression of a 2.3-kb transcript induced by T-cell mitogens.
Gross (2017) mapped the RELB gene to chromosome 19q13.32 based on an alignment of the RELB sequence (GenBank BC028013) with the genomic sequence (GRCh38).
Using electrophoretic mobility shift analysis, Bours et al. (1994) demonstrated that human RELB, when generated in mammalian cells, formed kappa-B-binding heterodimeric complexes with p50 (NFKB1) or p52 (NFKB2; 164012). Homodimeric complexes of RELB did not show DNA-binding activity.
By RT-PCR and immunocytochemical analyses, Clark et al. (1999) showed that RELB expression correlated with dendritic cell activation.
NF-kappa-B-inducing kinase (NIK, or MAP3K14; 604655) is required for osteoclastogenesis in response to pathologic stimuli. Vaira et al. (2008) found that overexpression of Relb, but not Rela, rescued differentiation of mouse Nik -/- osteoclast precursors, indicating that blockade of the alternative NF-kappa-B pathway, rather than the classical NF-kappa-B pathway, is responsible for the osteoclastogenic defect in the absence of Nik. Using Relb -/- mice, they showed that Relb itself was required for Rankl-induced osteoclastogenesis in vitro and for TNF (191160)-induced bone resorption in vivo. Both Relb -/- and Nik -/- mice were resistant to tumor-mediated osteolysis. Vaira et al. (2008) concluded that the alternative NF-kappa-B pathway, via RELB, plays an essential and unique role in RANKL signaling toward osteoclast development.
In 3 male patients from a consanguineous family of Irish descent with immunodeficiency-53 (IMD53; 617585), Merico et al. (2015) identified a homozygous truncating mutation in the RELB gene (Y397X; 604758.0001). The mutation, which was found by a combination of linkage analysis and whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient lymphocytes showed no detectable RELB protein, consistent with a complete loss of function. Immunologic workup showed normal to increased numbers of circulating lymphocytes, with an increased CD4+:CD8+ ratio compared to controls. In vitro studies showed impaired T-cell proliferative responses to multiple antigens, as well as impaired ability to produce specific immunoglobulins, indicating an effect on humoral immunity as well. The findings were consistent with a primary T-cell defect. Total serum immunoglobulin levels were normal, and patients did not show susceptibility to atypical mycobacterial infections. However, the disorder was severe enough to warrant treatment with hematopoietic stem cell transplantation. Sharfe et al. (2015) found that a thymus biopsy from 1 of the patients showed decreased levels of new emigrant T cells from the thymus and decreased T-cell receptor excision circles (TREC), consistent with deficient new T-cell production. Circulating cells from all patients showed low numbers of naive T cells and increased numbers of central memory T cells.
Weih et al. (1995) found that Relb -/- mice exhibited a dramatic reduction of constitutive kappa-B-binding activity in thymus and spleen. RelB -/- mice displayed multifocal, mixed inflammatory cell infiltration in multiple organs and had myeloid hyperplasia, splenomegaly due to extramedullary hemopoiesis, and a reduced population of thymic dendritic cells. Contact sensitivity experiments showed that Relb -/- mice had impaired cellular immunity. Weih et al. (1995) concluded that RELB has a decisive role in the hemopoietic system.
Independently, Burkly et al. (1995) showed that Relb expression correlated with dendritic cell differentiation in autoimmune infiltrates in mice. Disruption of the Relb gene in mice resulted in impaired antigen-presenting cell function and a syndrome of excess granulocyte and macrophage production. Relb -/- mice also lacked thymic Uea1-positive medullary epithelial cells, which resembled dendritic cells in wildtype mice. Burkly et al. (1995) concluded that RELB is critical for the coordinated activation of genes necessary for differentiation of both dendritic cells and thymic Uea1-positive medullary epithelial cells.
In 3 male patients from a consanguineous family of Irish descent with immunodeficiency-53 (IMD53; 617585), Merico et al. (2015) identified a homozygous c.1191C-A transversion in the RELB gene, resulting in a tyr397-to-ter (Y397X) substitution. The mutation, which was found by a combination of linkage analysis and whole-genome sequencing, was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family and was not found in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Patient cells showed no detectable RELB protein, consistent with a complete loss of function.
Sharfe et al. (2015) studied lymphocyte function and development in the 3 patients with the Y397X mutation in RELB reported by Merico et al. (2015). They found that T-cell responses to mitogens (e.g., phytohemagglutinin) were diminished and that responses to specific antigens were abrogated in all 3 patients. Production of IFNG (147570) could be restored by exogenous IL2 (147680) or IL12 (161561). Western blot analysis showed reduced expression of TBET (TBX21; 604895) and STAT1 (600555) in patient T cells. In contrast, stimulation of the patient cells with anti-CD3 (see 186790)/CD28 (186760) resulted in hyperactivation, possibly due to reduced RELA (164014) heterodimer formation and activation. Responses to B-cell mitogens, but not specific antibody production after stimulation with T cell-dependent antigens, were normal. Levels of CD27 (TNFRSF7; 186711)-positive activated memory B cells were markedly reduced in patients, and expression of BAFFR (TNFRSF13C; 606269) was reduced on patient B-lymphocytes. Responses by monocytes and granulocytes to endotoxin were normal. Sharfe et al. (2015) concluded that RELB deficiency results in intrinsic defects in T- and B-lymphocyte maturation and function, leading to combined immunodeficiency and autoimmunity.
Bours, V., Azarenko, V., Dejardin, E., Siebenlist, U. Human RelB (I-Rel) functions as a kappa-B site-dependent transactivating member of the family of Rel-related proteins. Oncogene 9: 1699-1702, 1994. [PubMed: 8183565]
Burkly, L., Hession, C., Ogata, L., Reilly, C., Marconi, L. A., Olson, D., Tizard, R., Cate, R., Lo, D. Expression of relB is required for the development of thymic medulla and dendritic cells. Nature 373: 531-536, 1995. [PubMed: 7845467] [Full Text: https://doi.org/10.1038/373531a0]
Clark, G. J., Gunningham, S., Troy, A., Vuckovic, S., Hart, D. N. Expression of the RelB transcription factor correlates with the activation of human dendritic cells. Immunology 98: 189-196, 1999. [PubMed: 10540217] [Full Text: https://doi.org/10.1046/j.1365-2567.1999.00829.x]
Gross, M. B. Personal Communication. Baltimore, Md. 8/8/2017.
Merico, D., Sharfe, N., Hu, P., Herbrick, J.-A., Roifman, C. M. RelB deficiency causes combined immunodeficiency. LymphoSign J. 2: 147-155, 2015.
Ruben, S. M., Klement, J. F., Coleman, T. A., Maher, M., Chen, C.-H., Rosen, C. A. I-Rel: a novel rel-related protein that inhibits NF-kappa-B transcriptional activity. Genes Dev. 6: 745-760, 1992. [PubMed: 1577270] [Full Text: https://doi.org/10.1101/gad.6.5.745]
Sharfe, N., Merico, D., Karanxha, A., Macdonald, C., Dadi, H., Ngan, B., Herbrick, J.-A., Roifman, C. M. The effects of RelB deficiency on lymphocyte development and function. J. Autoimmun. 65: 90-100, 2015. [PubMed: 26385063] [Full Text: https://doi.org/10.1016/j.jaut.2015.09.001]
Vaira, S., Johnson, T., Hirbe, A. C., Alhawagri, M., Anwisye, I., Sammut, B., O'Neal, J., Zou, W., Weilbaecher, K. N., Faccio, R., Novack, D. V. RelB is the NF-kappa-B subunit downstream of NIK responsible for osteoclast differentiation. Proc. Nat. Acad. Sci. 105: 3897-3902, 2008. [PubMed: 18322009] [Full Text: https://doi.org/10.1073/pnas.0708576105]
Weih, R., Carrasco, D., Durham, S. K., Barton, D. S., Rizzo, C. A., Ryseck, R.-P., Lira, S. A., Bravo, R. Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa-B/Rel family. Cell 80: 331-340, 1995. [PubMed: 7834753] [Full Text: https://doi.org/10.1016/0092-8674(95)90416-6]