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|Coordinate||10,031,534 bp (GRCm38)|
|Base Change||T ⇒ C (forward strand)|
|Gene Name||tumor necrosis factor (ligand) superfamily, member 13b|
|Synonym(s)||D8Ertd387e, BAFF, BLyS, TALL-1, zTNF4|
|Chromosomal Location||10,006,843-10,035,441 bp (+)|
|MGI Phenotype||Homozygous null mice have reduced number of B cells and reduced levels of immunoglobulins.|
|Amino Acid Change||Methionine changed to Threonine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000033892]|
AA Change: M232T
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|Phenotypic Category||decrease in B:T cells, T-dependent humoral response defect- decreased antibody response to rSFV|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Semidominant|
|Last Updated||12/08/2016 10:16 AM by Katherine Timer|
|Record Created||01/18/2015 8:59 AM by Kuan-Wen Wang|
The Applecrisp phenotype was identified among N-Nitroso-N-ethylurea (ENU)-mutagenized G3 mice of the pedigree R1648, some of which showed a reduced B:T cell ratio in the peripheral blood (Figure 1) as well as a diminished T-dependent antibody response to recombinant Semliki Forest virus (rSFV)-encoded β-galactosidase (rSFV-β-gal) (Figure 2).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 76 mutations. Both of the above anomalies were linked by continuous variable mapping to a mutation in Tnfsf13b: a T to C transition at base pair 10,031,534 (v38) on chromosome 8, or base pair 25,342 in the GenBank genomic region NC_000074 encoding Tnfsf13b. The strongest association was found with a recessive model of linkage to the normalized T-dependent antibody response to rSFV-β-gal, wherein one variant homozygote departed phenotypically from 4 homozygous reference mice and 9 heterozygous mice with a P value of 1.487 x 10-6 (Figure 3). A substantial semidominant effect was observed in the B:T cell ratio assay. The mutation corresponds to residue 911 in the mRNA sequence NM_033622 within exon 6 of 7 total exons.
The mutated nucleotide is indicated in red. The mutation results in a methionine (M) to threonine (T) substitution at position 232 (M232T) in the BAFF protein, and is strongly predicted by Polyphen-2 to cause loss of function (score = 1.00).
Tnfsf13b encodes B cell activating factor (BAFF; alternatively, BLyS, TALL-1, zTNF-4, THANK, or TNFSF13), a member of the tumor necrosis factor (TNF) family (Figure 4). BAFF is a type II transmembrane protein that undergoes cleavage between Arg126 and Ala127 by furin-like proteases to generate a soluble form of BAFF (1-3). BAFF contains a single transmembrane domain at amino acids 48-68 and a TNF homology domain (THD) at amino acids 169-308. The applecrisp mutation (M232T) is within the THD. Alteration of the THD may result in aberrant association of BAFFApplecrisp with its receptors BCMA, TACI (transmembrane activator and calcium modulator ligand (CAML) interactor), and BAFFR.
Please see the Frozen entry for more information about Tnfsf13b.
BAFF/BAFFR activates the alternative NF-κB (NF-κB2) signaling pathway (see the record for xander) to mediate the survival and maturation of splenic B cells (4;5). BAFF/BAFFR-induced NF-κB2 signaling promotes B cell survival by upregulating integrins that retains autoreactive B cells in the splenic marginal zone (6). In addition, ERK activation is sustained and there is an increased turnover of Bim, a proapoptotic protein (4;5;7). BAFF activates the classical NF-κB (NF-κB1) signaling pathway (see the record for Finlay) to regulate immunoglobulin class switching through an induction of activation induced deaminase (AID) and to generate antibodies (6). BAFF also induces the protein kinase Cδ (PKCδ)-mediated nuclear signaling pathway and the Akt/mTOR signaling pathway to regulate B-cell survival (7-10). BAFF is required for the maintenance, but not initiation, of the germinal center (GC) reaction (11). In Tnfsf13b -deficient (Tnfsf13b-/-) mice, total numbers of cells in the thymus, bone marrow, and PEC were comparable to wild-type mice (12;13); however, the number of B cells in the spleen and lymph nodes were reduced in Tnfsf13b-/- mice compared to wild-type mice (12;14). The percentage of peripheral B1 B cells in the Tnfsf13b-/- mice was comparable to that in wild-type mice; however, the B2 (B220+, CD23hi) B cell percentage in the periphery was reduced compared to wild-type mice (12;13). T-dependent and T-independent humoral responses were diminished in BAFF-deficient (Tnfsf13b-/-) mice (12-17). Similar to the Tnfsf13b-/- mice, the T-dependent antibody response was diminished in the Applecrisp mice; however the Applecrisp mice do not exhibit a significant reduction in the frequency of peripheral B cells. Taken together, this indicates that in BAFFApplecrisp may retain some function, but it exhibits loss of function in the T-dependent antibody response.
Applecrisp(F):5'- TGTTTGGCAGATAGCCCAATGGAG -3'
Applecrisp(R):5'- CAGCACAGTCTATGGCAGAAGGTC -3'
Applecrisp_seq(F):5'- ccttctcctcctcctcctc -3'
Applecrisp_seq(R):5'- CCAAAGCAGCACTTTTGGG -3'
1. Schneider, P., MacKay, F., Steiner, V., Hofmann, K., Bodmer, J. L., Holler, N., Ambrose, C., Lawton, P., Bixler, S., Acha-Orbea, H., Valmori, D., Romero, P., Werner-Favre, C., Zubler, R. H., Browning, J. L., and Tschopp, J. (1999) BAFF, a Novel Ligand of the Tumor Necrosis Factor Family, Stimulates B Cell Growth. J Exp Med. 189, 1747-1756.
2. Moore, P. A., Belvedere, O., Orr, A., Pieri, K., LaFleur, D. W., Feng, P., Soppet, D., Charters, M., Gentz, R., Parmelee, D., Li, Y., Galperina, O., Giri, J., Roschke, V., Nardelli, B., Carrell, J., Sosnovtseva, S., Greenfield, W., Ruben, S. M., Olsen, H. S., Fikes, J., and Hilbert, D. M. (1999) BLyS: Member of the Tumor Necrosis Factor Family and B Lymphocyte Stimulator. Science. 285, 260-263.
3. Tribouley, C., Wallroth, M., Chan, V., Paliard, X., Fang, E., Lamson, G., Pot, D., Escobedo, J., and Williams, L. T. (1999) Characterization of a New Member of the TNF Family Expressed on Antigen Presenting Cells. Biol Chem. 380, 1443-1447.
4. Claudio, E., Brown, K., Park, S., Wang, H., and Siebenlist, U. (2002) BAFF-Induced NEMO-Independent Processing of NF-Kappa B2 in Maturing B Cells. Nat Immunol. 3, 958-965.
5. Kayagaki, N., Yan, M., Seshasayee, D., Wang, H., Lee, W., French, D. M., Grewal, I. S., Cochran, A. G., Gordon, N. C., Yin, J., Starovasnik, M. A., and Dixit, V. M. (2002) BAFF/BLyS Receptor 3 Binds the B Cell Survival Factor BAFF Ligand through a Discrete Surface Loop and Promotes Processing of NF-kappaB2. Immunity. 17, 515-524.
6. Enzler, T., Bonizzi, G., Silverman, G. J., Otero, D. C., Widhopf, G. F., Anzelon-Mills, A., Rickert, R. C., and Karin, M. (2006) Alternative and Classical NF-Kappa B Signaling Retain Autoreactive B Cells in the Splenic Marginal Zone and Result in Lupus-Like Disease. Immunity. 25, 403-415.
7. Otipoby, K. L., Sasaki, Y., Schmidt-Supprian, M., Patke, A., Gareus, R., Pasparakis, M., Tarakhovsky, A., and Rajewsky, K. (2008) BAFF Activates Akt and Erk through BAFF-R in an IKK1-Dependent Manner in Primary Mouse B Cells. Proc Natl Acad Sci U S A. 105, 12435-12438.
8. Mecklenbrauker, I., Kalled, S. L., Leitges, M., Mackay, F., and Tarakhovsky, A. (2004) Regulation of B-Cell Survival by BAFF-Dependent PKCdelta-Mediated Nuclear Signalling. Nature. 431, 456-461.
9. Woodland, R. T., Fox, C. J., Schmidt, M. R., Hammerman, P. S., Opferman, J. T., Korsmeyer, S. J., Hilbert, D. M., and Thompson, C. B. (2008) Multiple Signaling Pathways Promote B Lymphocyte Stimulator Dependent B-Cell Growth and Survival. Blood. 111, 750-760.
10. Xu, L. G., Wu, M., Hu, J., Zhai, Z., and Shu, H. B. (2002) Identification of Downstream Genes Up-Regulated by the Tumor Necrosis Factor Family Member TALL-1. J Leukoc Biol. 72, 410-416.
11. Rahman, Z. S., Rao, S. P., Kalled, S. L., and Manser, T. (2003) Normal Induction but Attenuated Progression of Germinal Center Responses in BAFF and BAFF-R Signaling-Deficient Mice. J Exp Med. 198, 1157-1169.
12. Gross, J. A., Dillon, S. R., Mudri, S., Johnston, J., Littau, A., Roque, R., Rixon, M., Schou, O., Foley, K. P., Haugen, H., McMillen, S., Waggie, K., Schreckhise, R. W., Shoemaker, K., Vu, T., Moore, M., Grossman, A., and Clegg, C. H. (2001) TACI-Ig Neutralizes Molecules Critical for B Cell Development and Autoimmune Disease. Impaired B Cell Maturation in Mice Lacking BLyS. Immunity. 15, 289-302.
13. Schiemann, B., Gommerman, J. L., Vora, K., Cachero, T. G., Shulga-Morskaya, S., Dobles, M., Frew, E., and Scott, M. L. (2001) An Essential Role for BAFF in the Normal Development of B Cells through a BCMA-Independent Pathway. Science. 293, 2111-2114.
14. Do, R. K., and Chen-Kiang, S. (2002) Mechanism of BLyS Action in B Cell Immunity. Cytokine Growth Factor Rev. 13, 19-25.
15. Vora, K. A., Wang, L. C., Rao, S. P., Liu, Z. Y., Majeau, G. R., Cutler, A. H., Hochman, P. S., Scott, M. L., and Kalled, S. L. (2003) Cutting Edge: Germinal Centers Formed in the Absence of B Cell-Activating Factor Belonging to the TNF Family Exhibit Impaired Maturation and Function. J Immunol. 171, 547-551.
16. Jones, D. D., Jones, M., DeIulio, G. A., Racine, R., MacNamara, K. C., and Winslow, G. M. (2013) B Cell Activating Factor Inhibition Impairs Bacterial Immunity by Reducing T Cell-Independent IgM Secretion. Infect Immun. 81, 4490-4497.
|Science Writers||Anne Murray|
|Authors||Kuan-Wen Wang, Jin Huk Choi, Apiruck Watthanasurorot, Bruce Beutler|
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