|Coordinate||106,312,713 bp (GRCm38)|
|Base Change||C ⇒ T (forward strand)|
|Gene Name||CD79B antigen|
|Synonym(s)||Igbeta, Ig-beta, Igb, B29|
|Chromosomal Location||106,311,341-106,314,762 bp (-)|
FUNCTION: The B lymphocyte antigen receptor is a multimeric complex that includes the antigen-specific component, surface immunoglobulin (Ig). Surface Ig non-covalently associates with two other proteins, Ig-alpha and Ig-beta, which are necessary for expression and function of the B-cell antigen receptor. This gene encodes the Ig-beta protein of the B-cell antigen component. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Sep 2015]
PHENOTYPE: Homozygotes for targeted null mutations exhibit arrested development of B cells at the pro-B cell stage due to diminished signaling of the B cell receptor. [provided by MGI curators]
|Amino Acid Change||Glycine changed to Aspartic acid|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000048239] [ENSMUSP00000129029]|
AA Change: G176D
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
AA Change: G116D
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|Meta Mutation Damage Score||0.9440|
|Is this an essential gene?||Probably nonessential (E-score: 0.162)|
|Candidate Explorer Status||CE: excellent candidate; human score: 2.5; ML prob: 0.806|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Last Updated||2019-09-04 9:28 PM by Anne Murray|
|Record Created||2019-02-22 4:47 PM by Bruce Beutler|
The Jeju phenotype was identified among G3 mice of the pedigree R6605, some of which showed reduced B to T cell ratios (Figure 1) due to reduced frequencies of B cells (Figure 2) and B1 cells (Figure 3) in the peripheral blood.
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 40 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Cd79b: a G to A transition at base pair 106,312,713 (v38) on chromosome 11, or base pair 1,850 in the GenBank genomic region NC_000077. The strongest association was found with an additive model of inheritance to the normalized B1 cell frequency, wherein six variant homozygotes and 21 heterozygous mice departed phenotypically from 19 homozygous reference mice with a P value of 2.064 x 10-17 (Figure 4).
The mutation corresponds to residue 425 in the mRNA sequence NM_008339 within exon 3 of 6 total exons.
The mutated nucleotide is indicated in red. The mutation results in a glycine to aspartic acid substitution at position 116 (G116D) in the CD79B protein, and is strongly predicted by Polyphen-2 to cause loss of function (score = 1.000).
B cell antigen receptors (BCR) consist of two functional components [reviewed in (1)]. The antigen binding component is a membrane bound form of immunoglobulin (mIg), which consists of two transmembrane spanning heavy (H) chains and two associated light (L) chains. A heterodimer of Igα (see the record for crab) and Igβ constitutes the signaling component of the BCR (2-4). The Igα/Igβ heterodimer associates noncovalently with all mIg isotypes (IgM, IgD, IgG, IgA, and IgE) (5), and is found in each BCR complex in a 1:1 stoichiometry with mIg (6).
Igβ is a type I transmembrane glycoprotein of approximately 40 kD in mice (Figure 5). Igβ consists of 228 and 229 amino acids in mice and humans, respectively, and are 68% identical. The cytoplasmic tail of Igβ is 48 amino acids in length and contains a single immunoreceptor tyrosine-based activation motif (ITAM) (7), a conserved domain containing two tyrosines that upon phosphorylation act as a binding site for SH2 domain-containing effectors (D/ExxxxxxxD/ExxYxxL/IxxxxxxxYxxL/I). BCR activation results in the phosphorylation of ITAM tyrosines in both Igα and Igβ by membrane-localized Src family kinases, which are subsequently recruited to the receptor through binding of the phosphorylated ITAMs to Src SH2 domains, thereby amplifying signaling (8).
The extracellular N-terminus of Igβ forms a V-type Ig fold (9). The extracellular domains of Igα and Igβ each contain features that are highly conserved in Ig superfamily proteins, including two cysteine residues that form an intrachain disulfide bond (Cys50 and Cys101 in Igα; Cys65 and Cys120 in Igβ), as well as several other conserved residues (10;11). The predicted Ig fold of Igβ was confirmed by X-ray crystallographic analysis, which demonstrated an I-type rather than a V-type fold (Figure 3; PDB ID 3KHQ) (12). Igα and Igβ each contain an additional extracellular cysteine residue (Cys113 and Cys135, respectively); these form an interchain disulfide bond that mediates heterodimerization of the proteins (12;13). The function of the extracellular domains of Igα/Igβ in BCR signaling is not well understood. They contribute to interactions with mIg (3;12;14), and may be required for transport of mIgM to the cell surface (15).
The Jeju mutation results in a glycine to aspartic acid substitution at position 116 (G116D) in the CD79B protein; Gly116 is within the Ig-like V-type domain.
Please see the record hallasan for more information about Cd79b.
Once phosphorylated on both tyrosines, the Igα/Igβ ITAMs serve as docking sites for the adapter protein BLNK (16) and the two SH2 domains of Syk (see the record for poppy), which is then activated by SFK-dependent trans-phosphorylation (17-20). Syk-deficient B cells are deficient in downstream BCR signaling responses, but display normal SFK activation and Igα/Igβ phosphorylation, indicating that Syk is essential for transmitting signals from the BCR to distal signaling molecules (21). Syk phosphorylates a number of targets including BLNK (see the record for busy), PLC-γ2 (see the record for queen), and PKCβ (see the record for untied). BLNK serves as a scaffold to bring together several important signaling molecules (22;23). In particular, phosphorylated BLNK provides docking sites for the tyrosine kinase Btk as well as PLC-γ2, resulting in phosphorylation and activation of PLC-γ2 by Btk (24;25).
Igα and Igβ were proposed to promote V(D)J recombination (see maladaptive). However, pro-B cells from Igα- and Igβ-deficient mice initiated and completed V(D)J recombination as well wild type cells (26). Despite normal V(D)J recombination, these cells failed to express the pre-BCR (a complex composed of the recombined mIgM heavy chain, the surrogate light chains λ5 and VpreB, and the Igα/Igβ heterodimer) on the cell surface, and B cell development was blocked at the pro-B cell stage (26;27). In mature B cells, signaling through Igα/Igβ is required for cell survival.
In mice expressing Igβ truncated after the third amino acid of the cytoplasmic domain, B cell development proceeds up through the immature B stage (28). In contrast, B cell progression is impaired before the pre-B stage (50% reduction of pre-B cells) and severely impaired beyond it (80% reduction of immature B cells) in mice with a deletion of 40 of the 61 amino acids of the Igα cytoplasmic domain (29). Furthermore, a negative regulatory role of the Igα cytoplasmic domain was suggested by the observation of increased tyrosine phosphorylation and calcium flux in B cells with cytoplasmically truncated Igα (30;31). Phosphorylation of serine and threonine residues in the Igα tail has been implicated in such negative signaling (32).
The phenotype of the Jeju mice is consistent with a loss of function of Igβ.
1) 94°C 2:00
The following sequence of 400 nucleotides is amplified (chromosome 11, - strand):
1 gaagcccttg ttcccagatc tggcagcacc cgaggtttgc agccaaaaag cggagctcca
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
2. Campbell, K. S., Hager, E. J., Friedrich, R. J., and Cambier, J. C. (1991) IgM Antigen Receptor Complex Contains Phosphoprotein Products of B29 and Mb-1 Genes. Proc. Natl. Acad. Sci. U. S. A.. 88, 3982-3986.
3. Hombach, J., Tsubata, T., Leclercq, L., Stappert, H., and Reth, M. (1990) Molecular Components of the B-Cell Antigen Receptor Complex of the IgM Class. Nature. 343, 760-762.
4. Campbell, K. S., and Cambier, J. C. (1990) B Lymphocyte Antigen Receptors (mIg) are Non-Covalently Associated with a Disulfide Linked, Inducibly Phosphorylated Glycoprotein Complex. EMBO J.. 9, 441-448.
5. Venkitaraman, A. R., Williams, G. T., Dariavach, P., and Neuberger, M. S. (1991) The B-Cell Antigen Receptor of the Five Immunoglobulin Classes. Nature. 352, 777-781.
6. Schamel, W. W., and Reth, M. (2000) Monomeric and Oligomeric Complexes of the B Cell Antigen Receptor. Immunity. 13, 5-14.
7. Flaswinkel, H., and Reth, M. (1994) Dual Role of the Tyrosine Activation Motif of the Ig-Alpha Protein during Signal Transduction Via the B Cell Antigen Receptor. EMBO J.. 13, 83-89.
8. Kurosaki, T. (1999) Genetic Analysis of B Cell Antigen Receptor Signaling. Annu. Rev. Immunol.. 17, 555-592.
9. Hermanson, G. G., Eisenberg, D., Kincade, P. W., and Wall, R. (1988) B29: A Member of the Immunoglobulin Gene Superfamily Exclusively Expressed on Beta-Lineage Cells. Proc. Natl. Acad. Sci. U. S. A.. 85, 6890-6894.
10. Sakaguchi, N., Kashiwamura, S., Kimoto, M., Thalmann, P., and Melchers, F. (1988) B Lymphocyte Lineage-Restricted Expression of Mb-1, a Gene with CD3-Like Structural Properties. EMBO J.. 7, 3457-3464.
11. Williams, A. F., and Barclay, A. N. (1988) The Immunoglobulin Superfamily--Domains for Cell Surface Recognition. Annu. Rev. Immunol.. 6, 381-405.
12. Radaev, S., Zou, Z., Tolar, P., Nguyen, K., Nguyen, A., Krueger, P. D., Stutzman, N., Pierce, S., and Sun, P. D. (2010) Structural and Functional Studies of Igalphabeta and its Assembly with the B Cell Antigen Receptor. Structure. 18, 934-943.
13. Siegers, G. M., Yang, J., Duerr, C. U., Nielsen, P. J., Reth, M., and Schamel, W. W. (2006) Identification of Disulfide Bonds in the Ig-alpha/Ig-Beta Component of the B Cell Antigen Receptor using the Drosophila S2 Cell Reconstitution System. Int. Immunol.. 18, 1385-1396.
14. Dylke, J., Lopes, J., Dang-Lawson, M., Machtaler, S., and Matsuuchi, L. (2007) Role of the Extracellular and Transmembrane Domain of Ig-alpha/beta in Assembly of the B Cell Antigen Receptor (BCR). Immunol. Lett.. 112, 47-57.
15. Indraccolo, S., Minuzzo, S., Zamarchi, R., Calderazzo, F., Piovan, E., and Amadori, A. (2002) Alternatively Spliced Forms of Igalpha and Igbeta Prevent B Cell Receptor Expression on the Cell Surface. Eur. J. Immunol.. 32, 1530-1540.
16. Kabak, S., Skaggs, B. J., Gold, M. R., Affolter, M., West, K. L., Foster, M. S., Siemasko, K., Chan, A. C., Aebersold, R., and Clark, M. R. (2002) The Direct Recruitment of BLNK to Immunoglobulin Alpha Couples the B-Cell Antigen Receptor to Distal Signaling Pathways. Mol. Cell. Biol.. 22, 2524-2535.
17. Chen, T., Repetto, B., Chizzonite, R., Pullar, C., Burghardt, C., Dharm, E., Zhao, Z., Carroll, R., Nunes, P., Basu, M., Danho, W., Visnick, M., Kochan, J., Waugh, D., and Gilfillan, A. M. (1996) Interaction of Phosphorylated FcepsilonRIgamma Immunoglobulin Receptor Tyrosine Activation Motif-Based Peptides with Dual and Single SH2 Domains of p72syk. Assessment of Binding Parameters and Real Time Binding Kinetics. J. Biol. Chem.. 271, 25308-25315.
18. Kurosaki, T., Johnson, S. A., Pao, L., Sada, K., Yamamura, H., and Cambier, J. C. (1995) Role of the Syk Autophosphorylation Site and SH2 Domains in B Cell Antigen Receptor Signaling. J. Exp. Med.. 182, 1815-1823.
19. Johnson, S. A., Pleiman, C. M., Pao, L., Schneringer, J., Hippen, K., and Cambier, J. C. (1995) Phosphorylated Immunoreceptor Signaling Motifs (ITAMs) Exhibit Unique Abilities to Bind and Activate Lyn and Syk Tyrosine Kinases. J. Immunol.. 155, 4596-4603.
20. Rowley, R. B., Burkhardt, A. L., Chao, H. G., Matsueda, G. R., and Bolen, J. B. (1995) Syk Protein-Tyrosine Kinase is Regulated by Tyrosine-Phosphorylated Ig alpha/Ig Beta Immunoreceptor Tyrosine Activation Motif Binding and Autophosphorylation. J. Biol. Chem.. 270, 11590-11594.
21. Takata, M., Sabe, H., Hata, A., Inazu, T., Homma, Y., Nukada, T., Yamamura, H., and Kurosaki, T. (1994) Tyrosine Kinases Lyn and Syk Regulate B Cell Receptor-Coupled Ca2+ Mobilization through Distinct Pathways. EMBO J.. 13, 1341-1349.
22. Chiu, C. W., Dalton, M., Ishiai, M., Kurosaki, T., and Chan, A. C. (2002) BLNK: Molecular Scaffolding through 'Cis'-Mediated Organization of Signaling Proteins. EMBO J.. 21, 6461-6472.
23. Wienands, J., Schweikert, J., Wollscheid, B., Jumaa, H., Nielsen, P. J., and Reth, M. (1998) SLP-65: A New Signaling Component in B Lymphocytes which Requires Expression of the Antigen Receptor for Phosphorylation. J. Exp. Med.. 188, 791-795.
24. Baba, Y., Hashimoto, S., Matsushita, M., Watanabe, D., Kishimoto, T., Kurosaki, T., and Tsukada, S. (2001) BLNK Mediates Syk-Dependent Btk Activation. Proc. Natl. Acad. Sci. U. S. A.. 98, 2582-2586.
25. Ishiai, M., Kurosaki, M., Pappu, R., Okawa, K., Ronko, I., Fu, C., Shibata, M., Iwamatsu, A., Chan, A. C., and Kurosaki, T. (1999) BLNK Required for Coupling Syk to PLC Gamma 2 and Rac1-JNK in B Cells. Immunity. 10, 117-125.
26. Pelanda, R., Braun, U., Hobeika, E., Nussenzweig, M. C., and Reth, M. (2002) B Cell Progenitors are Arrested in Maturation but have Intact VDJ Recombination in the Absence of Ig-Alpha and Ig-Beta. J. Immunol.. 169, 865-872.
27. Gong, S., and Nussenzweig, M. C. (1996) Regulation of an Early Developmental Checkpoint in the B Cell Pathway by Ig Beta. Science. 272, 411-414.
28. Reichlin, A., Hu, Y., Meffre, E., Nagaoka, H., Gong, S., Kraus, M., Rajewsky, K., and Nussenzweig, M. C. (2001) B Cell Development is Arrested at the Immature B Cell Stage in Mice Carrying a Mutation in the Cytoplasmic Domain of Immunoglobulin Beta. J. Exp. Med.. 193, 13-23.
29. Torres, R. M., Flaswinkel, H., Reth, M., and Rajewsky, K. (1996) Aberrant B Cell Development and Immune Response in Mice with a Compromised BCR Complex. Science. 272, 1804-1808.
30. Kraus, M., Saijo, K., Torres, R. M., and Rajewsky, K. (1999) Ig-Alpha Cytoplasmic Truncation Renders Immature B Cells More Sensitive to Antigen Contact. Immunity. 11, 537-545.
31. Torres, R. M., and Hafen, K. (1999) A Negative Regulatory Role for Ig-Alpha during B Cell Development. Immunity. 11, 527-536.
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Xue Zhong, Jin Huk Choi, and Bruce Beutler|