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|Coordinate||30,877,787 bp (GRCm38)|
|Base Change||G ⇒ A (forward strand)|
|Gene Name||CD22 antigen|
|Chromosomal Location||30,865,402-30,880,342 bp (-)|
|MGI Phenotype||PHENOTYPE: Homozygous null mice have reduced mature B cell numbers with altered proliferation kinetics and reduced antibody production to T cell independent antigens. [provided by MGI curators]|
|Amino Acid Change||Glutamine changed to Stop codon|
|Institutional Source||Beutler Lab|
Q32* in Ensembl: ENSMUSP00000019248 (fasta)
Q31* in Ensembl: ENSMUSP00000019248 (fasta)
Q32* in Ensembl: ENSMUSP00000140521 (fasta)
|Gene Model||not available|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Sperm, gDNA|
|Last Updated||2018-07-27 4:22 PM by Diantha La Vine|
|Record Created||2010-07-07 12:49 PM by Carrie N. Arnold|
The well mutation was discovered while screening N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice for aberrant T-dependent and T-independent B cell responses. The index mouse mounted no detectable T-independent immunoglobin M (IgM) response to haptenated ficoll, but had a normal T-dependent IgG response to model antigens encoded by a recombinant suicide vector based on the Semliki Forest Virus (rSFV; Figure 1). Flow cytometry analysis of blood from this mouse revealed a reduction in peripheral B cells, which have a slight maturation defect.
|Nature of Mutation|
The well mutation was mapped on the basis of anemia by bulk segregation analysis (BSA) of F2 intercross offspring using C57BL/10J as the mapping strain. The mutation showed strongest linkage with Chromosome 7, and causes a C to T transition at nucleotide 457 of the Cd22 transcript using Genbank record NM_001043317.2 in exon 6 of 17 total exons (Figure 2). Three transcripts of the Cd22 gene are displayed on Ensembl.
The murine Cd22 gene encodes an 868 amino acid protein, with 62% homology to the human protein, that belongs to the Siglec (sialic acid-binding) family of adhesion molecules (1;2) (Figure 3). Siglecs are members of the immunoglobulin (Ig) superfamily, which specifically recognize sialic acids attached to the terminal regions of cell-surface glycoconjugates. They are type 1 transmembrane proteins with a sialic acid-binding N-terminal Ig-like V-type domain, variable numbers of Ig-like C2-type domains, a transmembrane region, and a cytoplasmic tail. CD22 contains seven immunoglobulin domains in its extracellular region at amino acids 31-147, 156-254, 269-337, 365-424,448-523, 541-599, and 628-687 (2). X-ray and NMR studies have shown that Ig-like domains form Greek-key β-sandwich structures with the varying types differing in the number of strands in the β-sheets as well as in their sequence patterns. By convention, the strands are labelled a to g in sequence with the two strands present between the c and d strands in V domains being labelled c' and c″. One β-sheet consists of strands a, b, e and possibly d while the other contains strands c, f, g and possibly c' and c″. In addition, the C-terminal ends of strands a and g may form a small stretch of parallel β-sheet, disrupting the original strands and giving rise to strands a' and/or g' (3). Ig-like domains are classified into V-type having all strands, C-type (for the C1-set) lacking the c' and c″ strands, S-type (for the C2-set) having the c' strand but not the c″ or d strands and the H-type, which lacks the c″ strand. Ig-like domains usually contain a structural motif composed of cysteine residues generally located in the b and f strands that form a disulfide bridge, and a tryptophan residue located in the c strand (4).
Human CD22 is expressed in the cytoplasm of B cell receptor (BCR)-negative pro- and pre-B cells and on the cell surface of mature B cells after acquisition of IgM. Once expressed as a membrane protein, CD22 persists on human B cells until they differentiate into plasma cells (40).
CD22 is one of two Siglecs expressed by B cells (the other being Siglec-G), and was originally identified as a B cell-associated adhesion protein that functions in the regulation of B cell activation [reviewed by (45;46)]. Siglecs can be divided into two groups. The first group includes Siglecs that are well conserved in mammals and consist of sialoadhesin (Siglec-1), CD22 (Siglec-2), myelin-associated glycoprotein (MAG; Siglec-4) and Siglec-15. CD33-related Siglecs are a rapidly evolving subset consisting of 10 members in humans, among them Siglec-10/Siglec-G, but just five members in the mouse. With the exception of MAG, which is found on glia cells of the nervous system, all Siglecs are expressed on cells of the immune system. Most of these molecules are negative immunoregulators carrying ITIMs that are phosphorylated on tyrosines by Src family kinases, creating binding sites for several SH2 domain-containing signaling molecules. The most important of these are SHP1 and SHP2, which are known to be recruited to many ITIM-containing receptors leading to dephosphorylation of intracellular substrates and inhibition of several signaling pathways. ITIM-carrying Siglecs are typically coreceptors that inhibit associated activating receptors that contain immunoreceptor tyrosine-based activation motifs (ITAMs). Some CD33-related Siglecs lack ITIMs but have charged amino acid residues in their transmembrane domain and can associate with DAP12 (12 kDa DNAX-activating protein), an ITAM-containing adapter that triggers both activating and inhibitory signaling [reviewed by (47)]. Siglecs without ITIMs can also play a role as positive regulators of the immune system (48).
As mentioned above (Protein Prediction), CD22 associates with a number of BCR signaling molecules including the BCR complex itself. Upon cross-linking of the BCR by antigen, associated CD22 is rapidly phosphorylated by Lyn (17;21;22;64) (Figure 4). The subsequent association of SHP1 with CD22 leads to the dephosphorylation of a number of BCR signaling components that dampens the BCR signal and Ca2+ mobilization such as Vav-1, CD19 and BLNK (65-67). Another target of SHP1 is PMCA4, which is activated by CD22 and promotes Ca2+ efflux further attenuating the BCR signal (29). The roles of other CD22-recruited molecules are less clear. SHIP-1 is also a negative regulator of Ca2+ signaling, but the inhibition of Ca2+ signaling by CD22 appears to be mediated by SHP1 and not by SHIP-1 (29). The other molecules, including Syk, PLC-γ2, and PI3K, are positive effectors B cell activation and loss of recruitment of these factors may contribute to the reduced anti-IgM triggered proliferation observed in CD22-deficient B cells (68-71). In the absence of BCR ligation, CD22 cross-linking results in JNK signaling and proliferation of human tonsillar B cells (32;72). Finally, CD22 can serve as a B-cell stimulatory molecule when aggregated by anti-CD22 antibodies that sequester it from the BCR thus relieving BCR inhibition (23).
Due to the premature stop codon introduced by the well mutation near the beginning of the Cd22 transcript, the well allele is likely to be null. Accordingly, mice carrying this allele are a phenocopy of CD22 knockout mice, displaying defects in peripheral B cell maturation and an absence of T-independent antibody responses that are likely caused by reduced MZB cell numbers. Like CD22 knockout mice, well animals display relatively normal T-dependent antibody responses (68-71).
|Primers||Primers cannot be located by automatic search.|
Well genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide change.
Well (F): 5’- CAACCCCAGATTCCCACTGTCATTG -3’
Well (R): 5’- AGAGATTCTGTGCTCCTGCTCCAC -3’
1) 95°C 2:00
2) 95°C 0:30
3) 56°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 29X
6) 72°C 7:00
7) 4°C 8
Primers for sequencing
Well _seq(F): 5'- CCTTGCTTAGAAAGGTACAGCTC -3'
Well _seq(R): 5’- ACCGTGTGTCTCCCCAG -3’
The following sequence of 463 nucleotides (NCBI Mouse Genome Build 37.1, Chromosome 7, bases 31,662,513 to 31,662,975) is amplified:
agagattctg tgctcctgct ccaccgtgtg tctccccagt gtctccctct cctacttcca gtggaagttc tcacccctca gtaacaactt ctgaccagag ttgtggcctt taggacacgt ggcttcggct cggtacagct cagcaaatga ttggaccgtt gaccatcccc aaaccctctt tgcctgggag ggagcctgca tcaggattcc ttgcaagtac aaaactccac tacccaaggc acgtctggac aacatcctcc tttttcagaa ctatgagttt gacaaggcca ccaagaaatt cacaggaact gtcctgtaca acgccacaaa gactgagaag gacccagagt ctgagctgta cctttctaag caagggagag taacatttct ggggaacaga atagacaatt gtaccctgaa aatccacccg atacgtgcca atgacagtgg gaatctgggg ttg
Primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated C is indicated in red.
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|Science Writers||Nora G. Smart|
|Illustrators||Diantha La Vine|
|Authors||Carrie N. Arnold, Elaine Pirie, and Bruce Beuter|
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