|Coordinate||43,412,017 bp (GRCm38)|
|Base Change||C ⇒ 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||Asparagine changed to Lysine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000005592]|
AA Change: N481K
|Predicted Effect||possibly damaging
PolyPhen 2 Score 0.819 (Sensitivity: 0.84; Specificity: 0.93)
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Last Updated||2019-02-11 5:44 PM by Diantha La Vine|
|Record Created||2018-04-05 9:48 AM by Bruce Beutler|
The shenandoah2 phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R6153, some of which showed increased frequencies of B1 cells in the peripheral blood (Figure 1) as well as increased CD4+ to CD8+ T cell ratios (Figure 2) due to increased frequencies of CD4+ T cells in CD3+ T cells (Figure 3) with concomitant reduced frequencies of CD8+ T cells in CD3+ T cells (Figure 4) in the peripheral blood.
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 65 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Siglecg: a C to A transversion at base pair 43,412,017 (v38) on chromosome 7, or base pair 3,825 in the GenBank genomic region NC_000073. The strongest association was found with a recessive model of inheritance to the increased B1 cell frequency phenotype, wherein six variant homozygotes departed phenotypically from nine homozygous reference mice and 20 heterozygous mice with a P value of 2.939 x 10-13 (Figure 5).
The mutation corresponds to residue 1,588 in the mRNA sequence NM_172900 within exon 9 of 12 total exons.
The mutated nucleotide is indicated in red. The mutation results in an asparagine to lysine substitution at position 481 (N481K) in the Siglec-G protein, and is strongly predicted by PolyPhen-2 to be damaging (score = 0.819).
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 6) (1).
The shenandoah2 mutation results in an asparagine to lysine substitution at position 481 (N481K) in the Siglec-G protein; amino acid 481 is within an undefined region in the extracellular N-terminal tail.
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 shenandoah2 mice indicate loss of Siglec-Gshenandoah2 function.
shenandoah2(F):5'- CTCTCTGTGCACTGTGAGTAGG -3'
shenandoah2(R):5'- TAGCGAATCTTAGTCCCAAAAGGG -3'
shenandoah2_seq(F):5'- CTGTGCACTGTGAGTAGGCAAAG -3'
shenandoah2_seq(R):5'- TCCTTTACCAGGTAGCAG -3'
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||Xue Zhong, Jin Huk Choi, Evan Nair-Gill, and Bruce Beutler|