Phenotypic Mutation 'Yosemite' (pdf version)
Allele | Yosemite |
Mutation Type |
critical splice donor site
(1 bp from exon)
|
Chromosome | 7 |
Coordinate | 30,568,934 bp (GRCm39) |
Base Change | C ⇒ A (forward strand) |
Gene |
Cd22
|
Gene Name | CD22 antigen |
Synonym(s) | Lyb8, Lyb-8 |
Chromosomal Location |
30,564,829-30,579,767 bp (-) (GRCm39)
|
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]
|
Accession Number | NCBI RefSeq: NM_001043317.2, NM_009845.3; MGI: 88322
|
Mapped | Yes |
Amino Acid Change |
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000019248 †]
[ENSMUSP00000103760 †]
[ENSMUSP00000139685 †]
[ENSMUSP00000141178 †]
[ENSMUSP00000140521 †]
[ENSMUSP00000140528 †]
[ENSMUSP00000139871 †]
[ENSMUSP00000150025 †]
† probably from a misspliced transcript
|
AlphaFold |
no structure available at present |
SMART Domains |
Protein: ENSMUSP00000019248 Gene: ENSMUSG00000030577
Domain | Start | End | E-Value | Type |
signal peptide
|
1 |
18 |
N/A |
INTRINSIC |
IG
|
31 |
147 |
2.75e-1 |
SMART |
IG_like
|
156 |
254 |
4.07e1 |
SMART |
IGc2
|
269 |
337 |
2.68e-4 |
SMART |
IGc2
|
365 |
424 |
4.52e-11 |
SMART |
IG
|
448 |
523 |
1.21e-2 |
SMART |
IGc2
|
541 |
599 |
6.75e-10 |
SMART |
IGc2
|
628 |
687 |
2.68e-4 |
SMART |
transmembrane domain
|
709 |
726 |
N/A |
INTRINSIC |
|
Predicted Effect |
probably null
|
SMART Domains |
Protein: ENSMUSP00000103760 Gene: ENSMUSG00000030577
Domain | Start | End | E-Value | Type |
signal peptide
|
1 |
18 |
N/A |
INTRINSIC |
IG
|
31 |
147 |
2.75e-1 |
SMART |
IG_like
|
156 |
254 |
4.07e1 |
SMART |
IGc2
|
269 |
337 |
2.68e-4 |
SMART |
IGc2
|
365 |
424 |
4.52e-11 |
SMART |
IG
|
448 |
523 |
1.21e-2 |
SMART |
IGc2
|
541 |
599 |
6.75e-10 |
SMART |
IGc2
|
628 |
687 |
2.68e-4 |
SMART |
transmembrane domain
|
709 |
726 |
N/A |
INTRINSIC |
|
Predicted Effect |
probably null
|
SMART Domains |
Protein: ENSMUSP00000139685 Gene: ENSMUSG00000030577
Domain | Start | End | E-Value | Type |
signal peptide
|
1 |
18 |
N/A |
INTRINSIC |
IG
|
31 |
147 |
2.75e-1 |
SMART |
IG_like
|
156 |
254 |
4.07e1 |
SMART |
IGc2
|
269 |
337 |
2.68e-4 |
SMART |
IGc2
|
365 |
424 |
4.52e-11 |
SMART |
IG
|
448 |
523 |
1.21e-2 |
SMART |
IGc2
|
541 |
599 |
6.75e-10 |
SMART |
IGc2
|
628 |
687 |
2.68e-4 |
SMART |
transmembrane domain
|
709 |
726 |
N/A |
INTRINSIC |
|
Predicted Effect |
probably null
|
Predicted Effect |
probably benign
|
SMART Domains |
Protein: ENSMUSP00000140521 Gene: ENSMUSG00000030577
Domain | Start | End | E-Value | Type |
signal peptide
|
1 |
18 |
N/A |
INTRINSIC |
IG
|
31 |
147 |
2.75e-1 |
SMART |
IG_like
|
156 |
254 |
4.07e1 |
SMART |
IGc2
|
269 |
337 |
2.68e-4 |
SMART |
IGc2
|
365 |
424 |
4.52e-11 |
SMART |
IG
|
448 |
523 |
1.21e-2 |
SMART |
IGc2
|
541 |
599 |
6.75e-10 |
SMART |
IGc2
|
628 |
687 |
2.68e-4 |
SMART |
transmembrane domain
|
709 |
726 |
N/A |
INTRINSIC |
|
Predicted Effect |
probably null
|
Predicted Effect |
probably benign
|
SMART Domains |
Protein: ENSMUSP00000140528 Gene: ENSMUSG00000030577
Domain | Start | End | E-Value | Type |
signal peptide
|
1 |
18 |
N/A |
INTRINSIC |
IG
|
31 |
147 |
1.1e-3 |
SMART |
IG_like
|
166 |
245 |
1.6e-2 |
SMART |
IGc2
|
269 |
337 |
1.1e-6 |
SMART |
|
Predicted Effect |
probably benign
|
SMART Domains |
Protein: ENSMUSP00000139871 Gene: ENSMUSG00000030577
Domain | Start | End | E-Value | Type |
signal peptide
|
1 |
18 |
N/A |
INTRINSIC |
IG
|
31 |
147 |
2.75e-1 |
SMART |
IG_like
|
156 |
254 |
4.07e1 |
SMART |
IGc2
|
269 |
337 |
2.68e-4 |
SMART |
IGc2
|
365 |
424 |
4.52e-11 |
SMART |
IG
|
448 |
523 |
1.21e-2 |
SMART |
IGc2
|
541 |
599 |
6.75e-10 |
SMART |
IGc2
|
628 |
687 |
2.68e-4 |
SMART |
transmembrane domain
|
709 |
726 |
N/A |
INTRINSIC |
|
Predicted Effect |
probably null
|
Predicted Effect |
probably null
|
Meta Mutation Damage Score |
0.9587 |
Is this an essential gene? |
Non Essential (E-score: 0.000) |
Phenotypic Category |
Autosomal Recessive |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | |
Alleles Listed at MGI | All mutations/alleles(16) : Chemically induced (ENU)(3) Targeted(13)
|
Lab Alleles |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
IGL00714:Cd22
|
APN |
7 |
30575572 |
missense |
probably benign |
0.01 |
IGL02236:Cd22
|
APN |
7 |
30566893 |
missense |
possibly damaging |
0.54 |
IGL02321:Cd22
|
APN |
7 |
30569308 |
missense |
probably damaging |
1.00 |
IGL02335:Cd22
|
APN |
7 |
30575559 |
missense |
probably damaging |
1.00 |
IGL02397:Cd22
|
APN |
7 |
30577050 |
missense |
probably benign |
|
IGL02402:Cd22
|
APN |
7 |
30576955 |
missense |
possibly damaging |
0.86 |
IGL02538:Cd22
|
APN |
7 |
30576985 |
missense |
probably benign |
0.40 |
IGL02736:Cd22
|
APN |
7 |
30577470 |
splice site |
probably null |
|
blitz
|
UTSW |
7 |
30569329 |
missense |
probably damaging |
1.00 |
crullers
|
UTSW |
7 |
30569308 |
missense |
probably damaging |
1.00 |
gansu
|
UTSW |
7 |
30569530 |
missense |
probably damaging |
1.00 |
lacrima
|
UTSW |
7 |
30575578 |
missense |
probably damaging |
1.00 |
Lluvia
|
UTSW |
7 |
30569912 |
missense |
possibly damaging |
0.48 |
Mist
|
UTSW |
7 |
30566083 |
missense |
probably damaging |
1.00 |
rain
|
UTSW |
7 |
30576959 |
missense |
probably damaging |
1.00 |
well
|
UTSW |
7 |
30577212 |
nonsense |
probably null |
|
FR4304:Cd22
|
UTSW |
7 |
30577507 |
missense |
possibly damaging |
0.95 |
FR4340:Cd22
|
UTSW |
7 |
30577507 |
missense |
possibly damaging |
0.95 |
FR4342:Cd22
|
UTSW |
7 |
30577507 |
missense |
possibly damaging |
0.95 |
FR4589:Cd22
|
UTSW |
7 |
30577507 |
missense |
possibly damaging |
0.95 |
LCD18:Cd22
|
UTSW |
7 |
30577507 |
missense |
possibly damaging |
0.95 |
PIT4142001:Cd22
|
UTSW |
7 |
30577224 |
missense |
possibly damaging |
0.92 |
R0123:Cd22
|
UTSW |
7 |
30566533 |
splice site |
probably benign |
|
R0130:Cd22
|
UTSW |
7 |
30569389 |
missense |
possibly damaging |
0.92 |
R0926:Cd22
|
UTSW |
7 |
30568934 |
critical splice donor site |
probably null |
|
R1245:Cd22
|
UTSW |
7 |
30569308 |
missense |
probably damaging |
1.00 |
R1332:Cd22
|
UTSW |
7 |
30569912 |
missense |
possibly damaging |
0.48 |
R1457:Cd22
|
UTSW |
7 |
30572595 |
missense |
probably benign |
0.07 |
R1716:Cd22
|
UTSW |
7 |
30577103 |
missense |
probably damaging |
1.00 |
R1980:Cd22
|
UTSW |
7 |
30572658 |
missense |
probably damaging |
1.00 |
R2017:Cd22
|
UTSW |
7 |
30572205 |
missense |
probably damaging |
0.99 |
R2061:Cd22
|
UTSW |
7 |
30575581 |
missense |
probably benign |
0.03 |
R2061:Cd22
|
UTSW |
7 |
30569530 |
missense |
probably damaging |
1.00 |
R2075:Cd22
|
UTSW |
7 |
30569123 |
missense |
probably damaging |
1.00 |
R2216:Cd22
|
UTSW |
7 |
30566471 |
missense |
probably damaging |
1.00 |
R3886:Cd22
|
UTSW |
7 |
30569532 |
missense |
possibly damaging |
0.57 |
R4599:Cd22
|
UTSW |
7 |
30575325 |
missense |
probably damaging |
0.98 |
R4701:Cd22
|
UTSW |
7 |
30575578 |
missense |
probably damaging |
1.00 |
R4796:Cd22
|
UTSW |
7 |
30572381 |
splice site |
probably null |
|
R5179:Cd22
|
UTSW |
7 |
30575299 |
missense |
possibly damaging |
0.81 |
R5233:Cd22
|
UTSW |
7 |
30576959 |
missense |
probably damaging |
1.00 |
R5456:Cd22
|
UTSW |
7 |
30575464 |
missense |
probably benign |
0.02 |
R5511:Cd22
|
UTSW |
7 |
30569496 |
missense |
probably damaging |
1.00 |
R5513:Cd22
|
UTSW |
7 |
30566450 |
missense |
probably damaging |
0.99 |
R5611:Cd22
|
UTSW |
7 |
30577575 |
unclassified |
probably benign |
|
R5656:Cd22
|
UTSW |
7 |
30569198 |
missense |
probably damaging |
1.00 |
R5966:Cd22
|
UTSW |
7 |
30566083 |
missense |
probably damaging |
1.00 |
R6329:Cd22
|
UTSW |
7 |
30577193 |
missense |
probably damaging |
0.99 |
R6356:Cd22
|
UTSW |
7 |
30577127 |
missense |
probably damaging |
1.00 |
R6455:Cd22
|
UTSW |
7 |
30575578 |
missense |
probably damaging |
1.00 |
R6550:Cd22
|
UTSW |
7 |
30576977 |
missense |
probably benign |
0.00 |
R6656:Cd22
|
UTSW |
7 |
30577182 |
missense |
probably benign |
0.11 |
R6688:Cd22
|
UTSW |
7 |
30572389 |
missense |
possibly damaging |
0.91 |
R6844:Cd22
|
UTSW |
7 |
30572856 |
splice site |
probably null |
|
R6957:Cd22
|
UTSW |
7 |
30566999 |
missense |
possibly damaging |
0.88 |
R7068:Cd22
|
UTSW |
7 |
30577504 |
missense |
probably benign |
0.03 |
R7083:Cd22
|
UTSW |
7 |
30567473 |
missense |
probably damaging |
0.99 |
R7225:Cd22
|
UTSW |
7 |
30577059 |
missense |
not run |
|
R7732:Cd22
|
UTSW |
7 |
30569482 |
missense |
probably damaging |
1.00 |
R8686:Cd22
|
UTSW |
7 |
30569494 |
missense |
probably benign |
0.03 |
R8851:Cd22
|
UTSW |
7 |
30577084 |
missense |
probably benign |
0.01 |
R8987:Cd22
|
UTSW |
7 |
30577172 |
missense |
probably damaging |
1.00 |
R9051:Cd22
|
UTSW |
7 |
30575449 |
missense |
probably benign |
|
R9098:Cd22
|
UTSW |
7 |
30567391 |
missense |
probably benign |
0.00 |
R9124:Cd22
|
UTSW |
7 |
30572662 |
missense |
probably benign |
0.01 |
R9167:Cd22
|
UTSW |
7 |
30575430 |
missense |
probably benign |
0.07 |
R9319:Cd22
|
UTSW |
7 |
30569329 |
missense |
probably damaging |
1.00 |
R9369:Cd22
|
UTSW |
7 |
30576999 |
missense |
probably benign |
0.09 |
X0025:Cd22
|
UTSW |
7 |
30572844 |
splice site |
probably null |
|
Z1176:Cd22
|
UTSW |
7 |
30568955 |
missense |
probably damaging |
1.00 |
Z1176:Cd22
|
UTSW |
7 |
30567388 |
missense |
probably benign |
0.03 |
Z1186:Cd22
|
UTSW |
7 |
30566891 |
missense |
probably benign |
|
Z1186:Cd22
|
UTSW |
7 |
30566478 |
missense |
probably benign |
0.01 |
Z1186:Cd22
|
UTSW |
7 |
30575292 |
missense |
probably damaging |
0.97 |
|
Mode of Inheritance |
Autosomal Recessive |
Local Stock | |
MMRRC Submission |
038179-MU
|
Last Updated |
2019-09-04 9:46 PM
by Diantha La Vine
|
Record Created |
2015-03-04 10:50 AM
by Anne Murray
|
Record Posted |
2015-03-31 |
Phenotypic Description |
The yosemite phenotype was identified among N-nitroso-N-ethylurea (ENU)-mutagenized G3 mice of the pedigree R0926, some of which showed a decrease in the frequency of B cells (Figure 1), an increased frequency of B1a cells in B1 cells (Figure 2), a reduced frequency of IgM+ B cells (Figure 3), a decrease in the percentage of IgD+ B cells (Figure 4), all in the peripheral blood.
|
Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 61 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Cd22: a G to T transversion at base pair 30,869,509 (v38) on chromosome 7, or base pair 10,834 in the GenBank genomic region NC_000073 within the donor splice site of intron 9. The strongest association was found with an additive model of linkage to the normalized frequency of peripheral B1a cells in B1 cells, wherein 1 variant homozygote and 14 heterozygotes departed phenotypically from 10 homozygous reference mice with a P value of 3.57 x 10-4 (Figure 5). A substantial semidominant effect was observed in the B1a assay, but the mutation is preponderantly recessive; in no assay was a purely dominant effect observed. The mutation is predicted to result in an in-frame skipping of the 264-nucleotide exon 9 (out of 14 total exons), which encodes amino acids 612-699. The effect of the mutation at the cDNA and protein level has not been tested.
<--exon 8 <--exon 9 intron 9--> exon 10--> <--exon 14
10473 ……CTCCAAGTGCTGT……CTCACTGTCTACT gtaagttcccctt……ACAGTCCAGAGACC……ACCCTCAAGCACTGA
607 ……-L--Q--V--L--……-L--T--V--Y-- Y--S--P--E--T-……-T--L--K--H--*-
correct deleted correct
|
Genomic numbering corresponds to NC_000073. The donor splice site of intron 9, which is destroyed by the yosemite mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
|
Illustration of Mutations in
Gene & Protein |
|
---|
Protein Prediction |
CD22 belongs to the Siglec (sialic acid-binding) family of adhesion molecules (1;2) (Figure 6). Siglecs are members of the immunoglobulin (Ig) superfamily, which specifically recognize sialic acids attached to the terminal regions of cell-surface glycoconjugates. Siglec proteins 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 (1). The yosemite mutation is predicted to result in the deletion of amino acids 612-699 the seventh immunoglobulin domain. See the record well for more information about Cd22.
|
Putative Mechanism | 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 in (3;4)]. 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 (5-7). 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 (8-10). In response to BCR stimulation, CD22-deficient B cells predominantly undergo apoptosis (11). Although CD22 appears to be dispensable for the differentiation of B cells to mature follicular cells, CD22-deficient B cells express less surface IgM, which may be a consequence of a faster and more complete maturation process. In addition, CD22-deficient mice have severely reduced numbers of marginal zone B (MZB) cells, and increased numbers of B-1 peritoneal cells was observed in two of the four knockout strains (12-15). The loss of MZB cells and increased B-1 cell numbers in these mice may be due to altered BCR signaling during development as maturation into the three mature B cell subsets is driven in part by differences in BCR signal strength, and a strong BCR signal disrupts MZB development and promotes B-1 differentiation [reviewed by (16;17)]. Due to the lack of MZB cells, these animals display impaired immune responses to T-independent antigens (12;15;18), while T-dependent immune responses remain intact and subsequent germinal center formation occurs normally (11). Mice carrying the yosemite allele share several phenotypes with the Cd22 knockout mice including defects in peripheral B cell maturation that are likely caused by reduced MZB cell numbers. A defect in immune responses to T-dependent or T-independent antigens was not observed in the yosemite mice indicating that some residual CD22 function may occur in the yosemite mice.
|
Primers |
PCR Primer
Yosemite_pcr_F: ATCCATCAAGGGCGAGATTGGC
Yosemite_pcr_R: AACCTCCAAGTGCTGTGTGAGTG
Sequencing Primer
Yosemite_seq_F: GGGCGAGATTGGCATGTAG
Yosemite_seq_R: CTGTGAGAGTGATGCCAATCC
|
Genotyping | PCR program 1) 94°C 2:00 2) 94°C 0:30 3) 55°C 0:30 4) 72°C 1:00 5) repeat steps (2-4) 40x 6) 72°C 10:00 7) 4°C hold
The following sequence of 540 nucleotides is amplified (chromosome 7, - strand):
1 aacctccaag tgctgtgtga gtggctggag ctggggccta aatgagaaga tgatgaggtg 61 acccgctgcc ccggcctgac tcggggtctc ctttacagat gctcctcgga ggctgcgtgt 121 gtccatcagc cctggggacc atgtgatgga ggggaagaag gccaccttgt cctgtgagag 181 tgatgccaat ccgcccatct cacagtacac ctggtttgac tccagtggcc aagacctcca 241 ctcctcaggc cagaaactga gactggaacc cctggaggtc caacacacgg gttcctaccg 301 ctgcaaaggg accaatggga taggcacagg agagtcacca cccagcaccc tcactgtcta 361 ctgtaagttc cccttgctgt cttcccttgg tccctgtcct gtcctgggag ctgcagtccc 421 ttccctcttc cttctcctgt gtctagctca gacataccct gtgacctgag tggaaagtcc 481 cctgctcttc cggcctgcct tcctcctttc ttctacatgc caatctcgcc cttgatggat
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red. |
References | 1. Torres, R. M., Law, C. L., Santos-Argumedo, L., Kirkham, P. A., Grabstein, K., Parkhouse, R. M., and Clark, E. A. (1992) Identification and Characterization of the Murine Homologue of CD22, a B Lymphocyte-Restricted Adhesion Molecule. J Immunol. 149, 2641-2649.
5. Leprince, C., Draves, K. E., Geahlen, R. L., Ledbetter, J. A., and Clark, E. A. (1993) CD22 Associates with the Human Surface IgM-B-Cell Antigen Receptor Complex. Proc Natl Acad Sci U S A. 90, 3236-3240.
6. Smith, K. G., Tarlinton, D. M., Doody, G. M., Hibbs, M. L., and Fearon, D. T. (1998) Inhibition of the B Cell by CD22: A Requirement for Lyn. J Exp Med. 187, 807-811.
8. Gerlach, J., Ghosh, S., Jumaa, H., Reth, M., Wienands, J., Chan, A. C., and Nitschke, L. (2003) B Cell Defects in SLP65/BLNK-Deficient Mice can be Partially Corrected by the Absence of CD22, an Inhibitory Coreceptor for BCR Signaling. Eur J Immunol. 33, 3418-3426.
10. Fujimoto, M., Bradney, A. P., Poe, J. C., Steeber, D. A., and Tedder, T. F. (1999) Modulation of B Lymphocyte Antigen Receptor Signal Transduction by a CD19/CD22 Regulatory Loop. Immunity. 11, 191-200.
11. Poe, J. C., Fujimoto, Y., Hasegawa, M., Haas, K. M., Miller, A. S., Sanford, I. G., Bock, C. B., Fujimoto, M., and Tedder, T. F. (2004) CD22 Regulates B Lymphocyte Function in Vivo through both Ligand-Dependent and Ligand-Independent Mechanisms. Nat Immunol. 5, 1078-1087.
12. Otipoby, K. L., Andersson, K. B., Draves, K. E., Klaus, S. J., Farr, A. G., Kerner, J. D., Perlmutter, R. M., Law, C. L., and Clark, E. A. (1996) CD22 Regulates Thymus-Independent Responses and the Lifespan of B Cells. Nature. 384, 634-637.
13. Sato, S., Miller, A. S., Inaoki, M., Bock, C. B., Jansen, P. J., Tang, M. L., and Tedder, T. F. (1996) CD22 is both a Positive and Negative Regulator of B Lymphocyte Antigen Receptor Signal Transduction: Altered Signaling in CD22-Deficient Mice. Immunity. 5, 551-562.
15. Nitschke, L., Carsetti, R., Ocker, B., Kohler, G., and Lamers, M. C. (1997) CD22 is a Negative Regulator of B-Cell Receptor Signalling. Curr Biol. 7, 133-143.
18. Samardzic, T., Marinkovic, D., Danzer, C. P., Gerlach, J., Nitschke, L., and Wirth, T. (2002) Reduction of Marginal Zone B Cells in CD22-Deficient Mice. Eur J Immunol. 32, 561-567.
|
Science Writers | Anne Murray |
Illustrators | Peter Jurek |