|Coordinate||43,411,386 bp (GRCm38)|
|Base Change||T ⇒ A (forward strand)|
|Gene Name||sialic acid binding Ig-like lectin G|
|Chromosomal Location||43,408,204-43,418,358 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] SIGLECs are members of the immunoglobulin superfamily that are expressed on the cell surface. Most SIGLECs have 1 or more cytoplasmic immune receptor tyrosine-based inhibitory motifs, or ITIMs. SIGLECs are typically expressed on cells of the innate immune system, with the exception of the B-cell expressed SIGLEC6 (MIM 604405).[supplied by OMIM, Jul 2002]
PHENOTYPE: Mice homozygous for a null allele exhibit increased B-1 cell numbers, increased IgM levels and IgM-producing plasma cells, and produce more IgM autoantibodies. [provided by MGI curators]
|Amino Acid Change|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000005592]|
|Predicted Effect||probably benign|
|Meta Mutation Damage Score||0.0898|
|Is this an essential gene?||Probably nonessential (E-score: 0.087)|
|Candidate Explorer Status||CE: excellent candidate; human score: 0; ML prob: 0.596|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Last Updated||2019-09-04 9:37 PM by Diantha La Vine|
|Record Created||2018-04-09 7:16 PM by Xue Zhong|
The Montblanc phenotype was identified among G3 mice of the pedigree R5017, some of which showed increased frequencies of B1 cells (Figure 1), B1a cells (Figure 2), and B1a cells in B1 cells (Figure 3) with concomitant reduced frequencies of B2 cells (Figure 4) in the peripheral blood. Some mice also showed reduced expression of IgM on peripheral blood B cells (Figure 5).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 45 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Siglecg: a T to A transversion at base pair 43,411,386 (v38) on chromosome 7, or base pair 3,194 in the GenBank genomic region NC_000073 within intron 6 (28-base pairs from exon 7). The strongest association was found with an additive model of inheritance to the increased B1a cell frequency phenotype, wherein eight variant homozygotes departed phenotypically from 20 homozygous reference mice and 34 heterozygous mice with a P value of 3.676 x 10-10 (Figure 6).
The effect of the mutation at the cDNA and protein levels has not been examined.
The acceptor splice site of intron 6 is indicated in blue lettering and the mutated nucleotide is indicated in red.
Siglec-G (Siglec-10 in humans) is a member of the CD33-related Siglec (sialic acid–binding immunoglobulin‐like lectin) family of adhesion molecules. Siglecs specifically recognize sialic acids attached to the terminal regions of cell-surface glycoconjugates; Siglec-G preferentially binds α2,3-linked or α2,6-linked sialic acid (α2,3Sia or α2,6Sia).
Siglec-C is a type 1 transmembrane protein with a signal peptide, a sialic-binding V-set Ig-like domain, three C2-set Ig-like domains, a transmembrane domain, and a cytoplasmic tail with two putative immune receptor tyrosine-based inhibitory motifs (ITIMs) and a Grb-2 binding motif (Figure 7) (1).
For more information about Siglecg, please see the record Shenandoah.
Siglec-G/-10 is one of two Siglecs expressed by B cells (the other being CD22; see the record for well), and was originally identified as a B cell-associated adhesion protein that functions in the regulation of B cell activation [reviewed by (2)]. Siglec-G/-10 is a B1 cell inhibitory receptor that inhibits B cell receptor-associated NF-κB and calcium signaling, subsequently controlling the expansion and survival of B1 cells (1;3-5). The mechanism by which Siglec-G/-10 functions as an inhibitory receptor is unknown.
Siglecg-/- mice have increased levels of serum IgM and produce more IgM autoantibodies than wild-type mice (1;3). Over time, the Siglecg-/- mice develop B-cell lymphoproliferative disorders, including diffuse large B-cell lymphoma, follicular lymphoma, medium-to-large B-cell monomorphic lymphoma and atypical lymphoproliferations (6). Older Siglecg-/- mice also exhibited an autoimmune phenotype with increased autoantibody levels and mild glomerulonephritis as well as increased numbers of plasma cells, germinal center B cells, and activated CD4 T cells (7;8).
The phenotype of the Montblanc mice indicate loss of Siglec-GMontblanc function.
1) 94°C 2:00
The following sequence of 401 nucleotides is amplified (chromosome 7, + strand):
1 ataccctgga cctctctgtg ctgtgtgagt atgatctacc aaaggttcct ggtcccaaga
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Hoffmann, A., Kerr, S., Jellusova, J., Zhang, J., Weisel, F., Wellmann, U., Winkler, T. H., Kneitz, B., Crocker, P. R., and Nitschke, L. (2007) Siglec-G is a B1 Cell-Inhibitory Receptor that Controls Expansion and Calcium Signaling of the B1 Cell Population. Nat Immunol. 8, 695-704.
2. Nitschke, L. (2009) CD22 and Siglec-G: B-Cell Inhibitory Receptors with Distinct Functions. Immunol Rev. 230, 128-143.
3. Ding, C., Liu, Y., Wang, Y., Park, B. K., Wang, C. Y., Zheng, P., and Liu, Y. (2007) Siglecg Limits the Size of B1a B Cell Lineage by Down-Regulating NFkappaB Activation. PLoS One. 2, e997.
4. Hutzler, S., Ozgor, L., Naito-Matsui, Y., Klasener, K., Winkler, T. H., Reth, M., and Nitschke, L. (2014) The Ligand-Binding Domain of Siglec-G is Crucial for its Selective Inhibitory Function on B1 Cells. J Immunol. 192, 5406-5414.
5. Jellusova, J., Duber, S., Guckel, E., Binder, C. J., Weiss, S., Voll, R., and Nitschke, L. (2010) Siglec-G Regulates B1 Cell Survival and Selection. J Immunol. 185, 3277-3284.
6. Simonetti, G., Bertilaccio, M. T., Rodriguez, T. V., Apollonio, B., Dagklis, A., Rocchi, M., Innocenzi, A., Casola, S., Winkler, T. H., Nitschke, L., Ponzoni, M., Caligaris-Cappio, F., and Ghia, P. (2014) SIGLEC-G Deficiency Increases Susceptibility to Develop B-Cell Lymphoproliferative Disorders. Haematologica. 99, 1356-1364.
7. Muller, J., Lunz, B., Schwab, I., Acs, A., Nimmerjahn, F., Daniel, C., and Nitschke, L. (2015) Siglec-G Deficiency Leads to Autoimmunity in Aging C57BL/6 Mice. J Immunol. 195, 51-60.
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Jin Huk Choi, Xue Zhong, and Bruce Beutler|