Alternative titles; symbols
HGNC Approved Gene Symbol: POU2AF1
Cytogenetic location: 11q23.1 Genomic coordinates (GRCh38): 11:111,352,255-111,379,275 (from NCBI)
B-lymphocyte-restricted transcription of immunoglobulin (Ig) genes is controlled by cooperative interactions between promoter and enhancer elements that are B-cell-specific in their activity. One of these elements, the octamer motif ATGCAAAT, is conserved in promoters of all Ig genes and in most of the Ig enhancers. In vivo studies established the critical importance of this motif (Staudt and Lenardo, 1991). In B lymphocytes, 2 nuclear transcription factors bind to the octamer motif: the ubiquitously expressed OCT1 (164175) and the largely B-cell-restricted OCT2 (164176). Strubin et al. (1995) cloned a human B-cell-specific transcriptional coactivator that specifically associates with either OCT1 or OCT2 and was designated OBF1 by them (for Oct-binding factor-1). (Others had isolated the same cDNA and designated it either OCA-B (Luo and Roeder, 1995) or Bob1 (Gstaiger et al., 1995).)
POU domain proteins contain a bipartite DNA-binding domain divided by a flexible linker that enables them to adopt various monomer configurations on DNA. The versatility of POU protein operation is additionally conferred at the dimerization level. Tomilin et al. (2000) found that the POU dimer from the OCT1 gene formed on the palindromic OCT factor recognition element, or PORE (ATTTGAAATGCAAAT), could recruit the transcriptional coactivator OBF1, whereas POU dimers formed on the consensus MORE (more PORE) (ATGCATATGCAT) or on MOREs from Ig heavy chain promoters (AT[G/A][C/A]ATATGCAA) failed to interact. An interaction with OBF1 was precluded since the same OCT1 residues that form the MORE dimerization interface are also used for OBF1/OCT1 interactions on the PORE. These findings provided a paradigm of how specific POU dimer assemblies can differentially recruit a coregulatory activity with distinct transcriptional readouts.
Casellas et al. (2002) reported that OCAB is essential for V(D)J recombination of a subset of Ig-kappa genes. They showed that OCAB modulates recombination by directly enhancing Ig-kappa gene transcription in vivo.
Lins et al. (2003) showed that osteopontin (SPP1; 166490), which contains a PORE sequence in its enhancer region, depended on the presence of OBF1 in B cells for its expression. OBF1 alleviated the DNA sequence requirements on the OCT1 dimer on PORE-related sequences in vitro. OBF1 stabilized POU dimer-DNA interactions and overrode OCT1 interface mutations, which abolished PORE-mediated dimerization without OBF1. Lins et al. (2003) concluded that the PORE-type OCT1 or OCT2 dimer, rather than the monomer, is the primary target of the OBF1 cofactor.
Junker et al. (1996) assigned the OBF1 gene to chromosome 11 by Southern blot analysis of human/rodent somatic cell hybrid cells. By fluorescence in situ hybridization, they refined the localization to 11q23.1 in a region involved in leukemias. The authors noted that the MLL gene (159555) is involved in most of the translocations with breakpoints within 11q23; whether there are others that involve the OBF1 gene leading to leukemia remained to be determined.
Associations Pending Confirmation
For discussion of a possible association between autosomal recessive agammaglobulinemia (see AGM1, 601495) and variation in the POU2AF1 gene, see 601206.0001.
Schubart et al. (2001) noted that Oct2-deficient mice die at birth but have normal B-cell development and transcription of Ig genes. Obf1-deficient mice are viable with unaffected B-cell development in bone marrow and normal serum IgM but have reduced B-cell numbers in spleen and low serum IgG. By creating double knockout mice, Schubart et al. (2001) confirmed that B-cell development and Ig gene transcription can proceed normally without these B-cell specific factors. However, in these animals the mature B-cell pool was strongly reduced, suggesting that these factors play an important role in controlling the expansion and/or maintenance of mature B cells.
Marginal zone (MZ) B cells are a first line of defense against particulate blood-borne antigens and, together with B1 cells, are responsible for the early response against type II T cell-independent antigens. Using flow cytometry and histologic analysis, Samardzic et al. (2002) found that Obf1 -/- mice lacked MZ B cells. The lack of MZ B cells in Obf1 -/- mice was due to an intrinsic B-cell defect, and MZ B-cell development required Obf1 expression in spleen. Western blot and immunohistochemical analysis showed that Obf1 was expressed in MZ B cells. B cells lacking Obf1 displayed altered migration properties and had reduced Baffr (TNFRSF13C; 606269) expression and B-cell receptor signaling. However, development of and B-cell receptor signaling in B1 B cells was unaffected by loss of Obf1.
Sun et al. (2003) found that Aiolos (ZNFN1A3; 606221) -/- mice spontaneously developed symptoms of systemic lupus erythematosus (SLE; 152700), but Aiolos -/- Obf1 -/- mice did not. Flow cytometric analysis showed that B-cell development at the immature B-cell stage was severely impaired in bone marrow of Aiolos -/- Obf1 -/- mice.
OBF1 expression is largely restricted to B cells, but it can be induced in T lymphocytes by costimulation with phorbol esters and calcium mobilization. Bartholdy et al. (2006) developed transgenic mice expressing Obf1 specifically in T cells and found that expression of Spib (606802), which is essential for germinal center formation and maintenance, was proportional to Obf1 levels in mouse thymocytes. Obf1 bound the octamer-containing promoter 2 (P2) of Spib in vivo and controlled transcription of Spib from P2. Obf1 was essential for Spib transcription in both T cells and B cells, and Obf1-null mice failed to form germinal centers following challenge with a T-cell dependent antigen.
Using flow cytometric, Western blot, and RT-PCR analyses, Siegel et al. (2006) showed that mice lacking Ocab had an altered distribution of bone marrow B cells and compromised pre-B cell receptor differentiation and signaling. Quantitative PCR and immunoblot analysis revealed reduced Syk (600085) expression in Ocab -/- cells. Immunofluorescence and immunoprecipitation analysis showed that Syk and Ocab colocalized in cytoplasm and interacted directly. Siegel et al. (2006) suggested that, together with dysregulation of other OCAB target genes, altered regulation of SYK may help explain the magnitude of defects observed in B-cell development, including the pre-B1-to-pre-B2 transition, and immune responses in Ocab -/- mice.
This variant is classified as a variant of unknown significance because its contribution to autosomal recessive agammaglobulinemia (see AGM1, 601495) has not been confirmed.
In a 3-year-old boy (P-FR1), born of consanguineous Caucasian parents, with agammaglobulinemia, Kury et al. (2021) identified a homozygous 1-bp deletion (c.233delC, NM_006235.3) in the POU2AF1 gene, resulting in a frameshift and premature termination (Thr78LysfsTer63). The variant, which was found by exome sequencing, segregated with the disorder in the family and was not present in the gnomAD database. Patient cells and HEK293 cells transfected with the variant had no detectable POU2AF1 protein expression, indicating instability of the aberrant protein. The patient had normal B-cell numbers, but his B cells showed disturbed differentiation with decreased class-switched memory cells and a relative increase in atypical memory cells. Patient B cells had abnormal expression of surface molecules, impaired responses to B-cell receptor (BCR) and CD40 stimulation, defective class switching, and defective marginal zone formation. Cultured patient B cells showed absence of plasmablasts and secreted immunoglobulins. Expression of wildtype POU2AF1 restored these defects. There was also a reduction in helper T cells. Overall, the findings were consistent with a severe B cell-intrinsic defect mainly affecting the later stages of development. The patient presented at 18 months of age with recurrent respiratory infections associated with agammaglobulinemia; he received intravenous Ig treatment. He also demonstrated progressive central nervous system disease with spastic tetraparesis, loss of ability to walk at age 2 years, language delay, and seizures, in the absence of an identified central nervous system infection. Brain imaging showed enlarged outer cerebral spinal fluid spaces and hypomyelination. It was unclear whether the neurodegenerative features were due to the immunologic defect or another genetic disorder.
Bartholdy, B., Du Roure, C., Bordon, A., Emslie, D., Corcoran, L. M., Matthias, P. The Ets factor Spi-B is a direct critical target of the coactivator OBF-1. Proc. Nat. Acad. Sci. 103: 11665-11670, 2006. [PubMed: 16861304] [Full Text: https://doi.org/10.1073/pnas.0509430103]
Casellas, R., Jankovic, M., Meyer, G., Gazumyan, A., Luo, Y., Roeder, R. G., Nussenzweig, M. C. OcaB is required for normal transcription and V(D)J recombination of a subset of immunoglobulin kappa genes. Cell 110: 575-585, 2002. [PubMed: 12230975] [Full Text: https://doi.org/10.1016/s0092-8674(02)00911-x]
Gstaiger, M., Knoepfel, L., Georgiev, O., Schaffner, W., Hovens, C. M. A B-cell coactivator of octamer-binding transcription factors. Nature 373: 360-362, 1995. [PubMed: 7779176] [Full Text: https://doi.org/10.1038/373360a0]
Junker, S., Brondum-Nielsen, K., Newell, J. W., Matthias, P., Tommerup, N. Assignment of the human gene for Oct-binding factor-1 (OBF1), a B-cell-specific coactivator of octamer-binding transcription factors 1 and 2, to 11q23.1 by somatic cell hybridization and in situ hybridization. Genomics 33: 143-145, 1996. [PubMed: 8617501] [Full Text: https://doi.org/10.1006/geno.1996.0173]
Kury, P., Staniek, J., Wegehaupt, O., Janowska, I., Eckenweiler, M., Korinthenberg, R., Japaridze, N., Pendziwiat, M., Helbig, I., Verhoeyen, E., Jung, J., Garcia de Oteyza, A. C., Proietti, M., Phirtskhalaishvili, T., Rtskhiladze, I., Nielsen, P. J., Ehl, S., Speckmann, C., Rizzi, M. Agammaglobulinemia with normal B-cell numbers in a patient lacking Bob1. J. Allergy Clin. Immun. 147: 1977-1980, 2021. [PubMed: 33571536] [Full Text: https://doi.org/10.1016/j.jaci.2021.01.027]
Lins, K., Remenyi, A., Tomilin, A., Massa, S., Wilmanns, M., Matthias, P., Scholer, H. R. OBF1 enhances transcriptional potential of Oct1. EMBO J. 22: 2188-2198, 2003. [PubMed: 12727885] [Full Text: https://doi.org/10.1093/emboj/cdg199]
Luo, Y., Roeder, R. G. Cloning, functional characterization, and mechanism of action of the B-cell-specific transcriptional activator OCA-B. Molec. Cell. Biol. 15: 4115-4124, 1995. [PubMed: 7623806] [Full Text: https://doi.org/10.1128/MCB.15.8.4115]
Samardzic, T., Marinkovic, D., Nielsen, P. J., Nitschke, L., Wirth, T. BOB.1/OBF.1 deficiency affects marginal-zone B-cell compartment. Molec. Cell. Biol. 22: 8320-8331, 2002. [PubMed: 12417733] [Full Text: https://doi.org/10.1128/MCB.22.23.8320-8331.2002]
Schubart, K., Massa, S., Schubart, D., Corcoran, L. M., Rolink, A. G., Matthias, P. B cell development and immunoglobulin gene transcription in the absence of Oct-2 and OBF-1. Nature Immun. 2: 69-74, 2001. Note: Erratum: Nature Immun. 7: 1004 only, 2006. [PubMed: 11135581] [Full Text: https://doi.org/10.1038/83190]
Siegel, R., Kim, U., Patke, A., Yu, X., Ren, X., Tarakhovsky, A., Roeder, R. G. Nontranscriptional regulation of SYK by the coactivator OCA-B is required at multiple stages of B cell development. Cell 125: 761-774, 2006. [PubMed: 16713566] [Full Text: https://doi.org/10.1016/j.cell.2006.03.036]
Staudt, L. M., Lenardo, M. J. Immunoglobulin gene transcription. Annu. Rev. Immun. 9: 373-398, 1991. [PubMed: 1910683] [Full Text: https://doi.org/10.1146/annurev.iy.09.040191.002105]
Strubin, M., Newell, J. W., Matthias, P. OBF-1, a novel B cell-specific coactivator that stimulates immunoglobulin promoter activity through association with octamer-binding proteins. Cell 80: 497-506, 1995. [PubMed: 7859290] [Full Text: https://doi.org/10.1016/0092-8674(95)90500-6]
Sun, J., Matthias, G., Mihatsch, M. J., Georgopoulos, K., Matthias, P. Lack of transcriptional coactivator OBF-1 prevents the development of systemic lupus erythematosus-like phenotypes in Aiolos mutant mice. J. Immun. 170: 1699-1706, 2003. [PubMed: 12574333] [Full Text: https://doi.org/10.4049/jimmunol.170.4.1699]
Tomilin, A., Remenyi, A., Lins, K., Bak, H., Leidel, S., Vriend, G., Wilmanns, M., Scholer, H. R. Synergism with the coactivator OBF-1 (OCA-B, BOB-1) is mediated by a specific POU dimer configuration. Cell 103: 853-864, 2000. [PubMed: 11136971] [Full Text: https://doi.org/10.1016/s0092-8674(00)00189-6]