Alternative titles; symbols
HGNC Approved Gene Symbol: CD79B
Cytogenetic location: 17q23.3 Genomic coordinates (GRCh38): 17:63,928,740-63,932,331 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q23.3 | Agammaglobulinemia 6 | 612692 | Autosomal recessive | 3 |
The signal transduction molecule CD79B plays a critical role in B-cell receptor (BCR) expression. CD79B forms a disulfide-linked heterodimeric complex with CD79A (112205) that escorts the immunoglobulin mu (IgM) heavy chain (IGHM; 147020) to the cell surface (Dobbs et al., 2007).
By screening a human B-cell leukemia cDNA library using mouse B29 cDNA as probe, Wood et al. (1993) isolated a full-length cDNA encoding human CD79B, which they called B29. The deduced 229-amino acid protein has a hydrophobic leader sequence, an Ig-like domain, a positively charged extracellular domain, a transmembrane domain, and an intracytoplasmic tail containing a motif present in molecules involved in lymphocyte activation. Human and mouse B29 share 75% amino acid identity.
Hashimoto et al. (1993) presented the cDNA sequence of CD79B, and Hashimoto et al. (1994) determined its complete genomic sequence.
Dobbs et al. (2007) noted that both CD79A and CD79B consist of an extracellular Ig domain, a membrane proximal spacer region containing a cysteine required for disulfide linkage, a transmembrane domain, and a cytoplasmic domain containing a single immunoreceptor tyrosine-based activation motif (ITAM).
The human CD79B/GH locus contains 6 tightly linked genes with 3 mutually exclusive tissue specificities and interdigitated control elements. Consequently, pituitary cell-specific transcriptional events that activate GHN (GH1; 139250) ectopically activate CD79B, whereas B lymphocyte-specific events that activate CD79B do not activate GHN. Using DNase I hypersensitive site mapping, chromatin immunoprecipitation assays of human and mouse cell lines, and transgenic mouse models, Yoo et al. (2006) found tissue-specific patterns of chromatin structure and transcriptional controls at the CD79B/GH locus in B cells that were distinct from those in pituitary gland and placenta. Yoo et al. (2006) proposed that such gene expression pathways and transcriptional interactions are likely to be juxtaposed at multiple sites within eukaryote genomes.
Roughly 10% of activated B cell-like diffuse large B-cell lymphomas (ABC DLBCL; see 605027) have mutant CARD11 (607210) isoforms that activate NF-kappa-B (see 164011). Davis et al. (2010) used an RNA interference genetic screen to elucidate the mechanism that engages wildtype CARD11 in other ABC DLBCLs and found that the BCR signaling component Bruton tyrosine kinase (BTK; 300300) is essential for the survival of ABC DLBCLs with wildtype CARD11. In addition, knockdown of proximal BCR subunits IgM (see 147020), Ig-kappa (see 147200), CD79A (112205), and CD79B killed ABC DLBCLs with wildtype CARD11 but not other lymphomas. The B cell receptors in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells. Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signaling modules of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt lymphoma or mucosa-associated lymphoid tissue lymphoma. In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine at position 196, was mutated. These mutations increased surface BCR expression and attenuated Lyn kinase (165120), a feedback inhibitor of BCR signaling. Davis et al. (2010) concluded that their findings establish chronic active BCR signaling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies.
By fluorescence in situ hybridization, Wood et al. (1993) localized the IGB gene to chromosome 17q23. They pointed out that a subset of human B-cell chronic lymphocytic leukemias has translocations in this band. Genomic Southern blot analysis gave patterns consistent with the presence of a single-copy gene.
Shulzhenko et al. (2009) reported that the mouse Cd79b gene maps to chromosome 11.
Somatic Hypermutation in B Cells
Gordon et al. (2000) demonstrated that B29 mutations previously identified in chronic lymphatic leukemia (CLL) patients can affect surface BCR-dependent signaling and may contribute to the unresponsive B-cell phenotype in CLL. The features of the B29 mutations in CLL predicted that they may be generated by somatic hypermutation.
Somatic hypermutation, coupled to selection by antigen, generates high-affinity antibodies during the maturation of B cells in germinal centers. Somatic hypermutation affects BCL6 (109565) and 4 additional oncogenes in diffuse large B-cell lymphomas: PAX5 (167414), PIM1 (164960), RHOH/TTF (602037), and MYC (190080), as well as the CD95/FAS gene (134637); it is also regarded as a major mechanism of B-cell tumorigenesis. Gordon et al. (2003) found that mutations in the CD79B and CD79A genes occur in a broad spectrum of germinal center and postgerminal center-derived malignant B-cell lines, as well as in normal peripheral B cells. These CD79A and CD79B mutations are typical somatic hypermutations consisting largely of single-nucleotide substitutions targeted to hotspots.
Germline Mutation in Agammaglobulinemia 6
In a 15-year-old female patient with onset of infections under age 5 years, hypogammaglobulinemia, and less than 2% circulating CD19 (107265)-positive B cells, consistent with a diagnosis of autosomal recessive agammaglobulinemia-6 (AGM6; 612692), Dobbs et al. (2007) identified a homozygous mutation in the CD79B gene (G137S; 147245.0001). The amino acid substitution occurred adjacent to the cysteine required for the disulfide bond between IGA and IGB. Flow cytometric analysis demonstrated that the patient had a profound deficit in IgM-expressing B cells. Expression of the mutant protein in 293T cells or Jurkat T cells showed that it formed disulfide-linked complexes and brought IGHM to the cell surface inefficiently. Dobbs et al. (2007) concluded that minor changes in the ability of the IGA/IGB complex to bring BCR to the cell surface have profound effects on B-cell development.
Ferrari et al. (2007) identified a homozygous mutation in the CD79B gene in an Italian patient with AGM6. Functional expression studies in Drosophila cells showed that the mutation prevented reconstitution of the IgM BCR on the cell surface. Phenotyping of patient bone marrow cells indicated a block of B-cell development at the transition from the pro-B to pre-B stage, a phenotype resembling that observed in other known forms of agammaglobulinemia.
Shulzhenko et al. (2009) reported a subset of inbred mice that lacked Peyer patches and B lymphocytes but had no alterations in Ig loci. In these mice, they identified a spontaneous, recessive c.224G-A mutation in exon 3 of the Cd79b gene, resulting in a trp75-to-ter (W75X) substitution in the Ig-like domain. Flow cytometric analysis confirmed the absence of Cd79b in mutant mice.
In a 15-year-old female patient of Georgian (South Caucasus) descent living in Austria who exhibited onset of infections under age 5 years, hypogammaglobulinemia, and less than 2% circulating CD19 (107265)-positive B cells (612692), Dobbs et al. (2007) identified a homozygous G-to-A transition in codon 137 in exon 3 of the CD79B gene. The mutation resulted in a gly137-to-ser (G137S) substitution adjacent to the cysteine required for the disulfide bond between CD79A (112205) and CD79B. The wildtype glycine at this site is conserved not only in CD79B from humans, mice, dogs, and cattle, but also in CD79A from these species. The patient's parents were heterozygous for the mutation, which was not present in 100 normal controls. Flow cytometric analysis demonstrated that the patient had a profound deficit in IgM-expressing B cells. Expression of the mutant protein in 293T cells or Jurkat T cells showed that it formed disulfide-linked complexes and brought IGHM to the cell surface inefficiently.
In an Italian patient with agammaglobulinemia-6 (612692), Ferrari et al. (2007) identified a homozygous 238C-T transition in exon 3 of the CD79B gene, resulting in a gln80-to-ter (Q80X) substitution within the extracellular immunoglobulin domain, thus preventing the expression of the functional transmembrane protein. Both unaffected parents were heterozygous for the mutation, which was not found in 90 healthy controls. The patient had onset of pneumonia and enteritis at age 8 months and had recurrent infections throughout his life. Functional expression studies in Drosophila cells showed that the Q80X mutation prevented reconstitution of the IgM BCR on the cell surface. Phenotyping of patient bone marrow cells indicated a block of B-cell development at the transition from the pro-B to pre-B stage, a phenotype resembling that observed in other known forms of agammaglobulinemia.
Davis, R. E., Ngo, V. N., Lenz, G., Tolar, P., Young, R. M., Romesser, P. B., Kohlhammer, H., Lamy, L., Zhao, H., Yang, Y., Xu, W., Shaffer, A. L., and 25 others. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463: 88-92, 2010. [PubMed: 20054396] [Full Text: https://doi.org/10.1038/nature08638]
Dobbs, A. K., Yang, T., Farmer, D., Kager, L., Parolini, O., Conley, M. E. Cutting edge: a hypomorphic mutation in Ig-beta (CD79b) in a patient with immunodeficiency and a leaky defect in B cell development. J. Immun. 179: 2055-2059, 2007. [PubMed: 17675462] [Full Text: https://doi.org/10.4049/jimmunol.179.4.2055]
Ferrari, S., Lougaris, V., Caraffi, S., Zuntini, R., Yang, J., Soresina, A., Meini, A., Cazzola, G., Rossi, C., Reth, M., Plebani, A. Mutations of the Ig-beta gene cause agammaglobulinemia in man. J. Exp. Med. 204: 2047-2051, 2007. [PubMed: 17709424] [Full Text: https://doi.org/10.1084/jem.20070264]
Gordon, M. S., Kanegai, C. M., Doerr, J. R., Wall, R. Somatic hypermutation of the B cell receptor genes B29 (Ig-beta, CD79b) and mb1 (Ig-alpha, CD79a). Proc. Nat. Acad. Sci. 100: 4126-4131, 2003. [PubMed: 12651942] [Full Text: https://doi.org/10.1073/pnas.0735266100]
Gordon, M. S., Kato, R. M., Lansigan, F., Thompson, A. A., Wall, R., Rawlings, D. J. Aberrant B cell receptor signaling from B29 (Ig-beta, CD79b) gene mutations of chronic lymphocytic leukemia B cells. Proc. Nat. Acad. Sci. 97: 5504-5509, 2000. [PubMed: 10792036] [Full Text: https://doi.org/10.1073/pnas.090087097]
Hashimoto, S., Chiorazzi, N., Gregersen, P. K. The complete sequence of the human CD79b (Ig-beta/B29) gene: identification of a conserved exon/intron organization, immunoglobulin-like regulatory regions, and allelic polymorphism. Immunogenetics 40: 145-149, 1994. [PubMed: 7913081] [Full Text: https://doi.org/10.1007/BF00188178]
Hashimoto, S., Gregersen, P. K., Chiorazzi, N. The human Ig-beta cDNA sequence, a homologue of murine B29, is identical in B cell and plasma cell lines producing all the human Ig isotypes. J. Immun. 150: 491-498, 1993. [PubMed: 8419481]
Shulzhenko, N., Morgun, A., Matzinger, P. Spontaneous mutation in the Cd79b gene leads to a block in B-lymphocyte development at the C-prime (early pre-B) stage. Genes Immunity 10: 722-726, 2009. [PubMed: 19727123] [Full Text: https://doi.org/10.1038/gene.2009.70]
Wood, W. J., Jr., Thompson, A. A., Korenberg, J., Chen, X., May, W., Wall, R., Denny, C. T. Isolation and chromosomal mapping of the human immunoglobulin-associated B29 gene (IGB). Genomics 16: 187-192, 1993. [PubMed: 8486355] [Full Text: https://doi.org/10.1006/geno.1993.1157]
Yoo, E. J., Cajiao, I., Kim, J.-S., Kimura, A. P., Zhang, A., Cooke, N. E., Liebhaber, S. A. Tissue-specific chromatin modifications at a multigene locus generate asymmetric transcriptional interactions. Molec. Cell. Biol. 26: 5569-5579, 2006. [PubMed: 16847312] [Full Text: https://doi.org/10.1128/MCB.00405-06]