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|Coordinate||3,789,908 bp (GRCm38)|
|Base Change||T ⇒ A (forward strand)|
|Gene Name||Yamaguchi sarcoma viral (v-yes-1) oncogene homolog|
|Chromosomal Location||3,678,115-3,813,122 bp (+)|
|MGI Phenotype||Homozygotes for targeted null mutations exhibit splenomegaly, reduced numbers of peripheral B cells, impaired immune responses, IgM hyperglobulinemia, autoimmunity with glomerulonephritis, and monocyte/macrophage tumors.|
|Amino Acid Change||Tyrosine changed to Stop codon|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000038838] [ENSMUSP00000100075]|
AA Change: Y501*
|Predicted Effect||probably null|
AA Change: Y480*
|Predicted Effect||probably null|
|Phenotypic Category||Autosomal Semidominant|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Semidominant|
|Last Updated||2016-09-16 3:55 PM by Katherine Timer|
|Record Created||2014-12-18 12:06 AM by Jin Huk Choi|
The Cress phenotype was identified among N-Nitroso-N-ethylurea (ENU)-mutagenized G3 mice of the pedigree R1460, some of which showed a reduced B to T cell ratio (Figure 1) due to a reduced frequency of total B cells (Figure 2), an increased frequency of B1a cells (Figure 3), an increased frequency of B1a cells in B1 cells (Figure 4), a reduced frequency of IgM+ B cells (Figure 5), and a reduced percentage of IgD+ B cells (Figure 6) with a concomitant increased frequency of T cells (Figure 7) including both CD4+ T cells (Figure 8) and CD8+ T cells (Figure 9), all in the peripheral blood. Some mice also exhibited a reduced B220 mean fluorescence intensity on B cells in the peripheral blood (Figure 10). Some mice showed a diminished T-dependent antibody response to ovalbumin administered with aluminum hydroxide (OVA/Alum) (Figure 11), a diminished T-dependent response to recombinant Semliki Forest virus (rSFV)-encoded β-galactosidase (rSFV-β-gal) (Figure 12), and a diminished T-independent antibody response to 4-hydroxy-3-nitrophenylacetyl-Ficoll (NP-Ficoll) (Figure 13).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 96 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Lyn: a T to A transversion at base pair 3,789,908 (v38) on chromosome 4, or base pair 111,788 in the GenBank genomic region NC_000070. The strongest association was found with an additive model of linkage to the normalized peripheral IgD+ B cell percentage, wherein three variant homozygotes and eight heterozygotes departed phenotypically from five homozygous reference mice with a P value of 1.583 x 10-8 (Figure 14). A dominant effect was observed for the T-independent B cell response to NP-Ficoll as well as the frequency of B1a cells in B1 cells; a recessive effect was observed for the T-dependent antibody response to OVA/Alum. The mutation corresponds to residue 1,752 in the mRNA sequence NM_001111096 within exon 13 of 13 total exons and residue 1,689 in the mRNA sequence NM_010747 within exon 13 of 13 total exons.
Genomic numbering corresponds to NC_000070. The mutated nucleotide is indicated in red. Alternative splicing of exon 2 of Lyn produces two Lyn isoforms, Lynp56 and Lynp53, that differ at the N-terminus (1;2); Lynp56 contains an additional 21 amino acids compared to Lynp53 (1). The mutation results in substitution of tyrosine 501 (Tyr501) for a premature stop codon (Tyr501*) in the Lynp56 protein and a Tyr480* in the Lynp53 protein.
Lyn is a member of the Src family of tyrosine kinases (SFKs). The members of the SFKs share highly conserved domains including a Src-homology 3 (SH3) domain (amino acids 66-122 in Lyn), an SH2 domain (amino acids 127-217), a tyrosine kinase domain (amino acids 247-497), and a C-terminal regulatory region [Figure 15; reviewed in (3)]. A ‘unique’ domain of 50-70 amino acids between the N-terminus and the SH3 domain varies among the members of the SFKs (3). The Cress mutation (Tyr501*) occurs in the undefined region following the kinase domain in both Lyn isoforms. No functions have been attributed to this region.
Please see the record Lemon for information about Lyn.
Lyn can act as both a positive and negative signaling molecule in several cell types including hematopoietic progenitors, mature myeloid cells (neutrophils, macrophages, monocytes, eosinophils, and dendritic cells), platelets, erythrocytes, and osteoclasts. As a result, Lyn regulates several cellular functions including proliferation, degranulation, cytokine production, adhesion, activation, migration, and survival. Following BCR ligation, Lyn phosphorylates the ITAMs of the Igα/Igβ BCR subunits (4-6). These signals allow the activation of multiple transcription factors, including nuclear factor of activated T cells (NF-AT), NF-κB (see the records for Finlay and xander) and AP-1, which subsequently regulate biological responses including cell proliferation, differentiation, and apoptosis as well as the secretion of antigen-specific antibodies [reviewed in (7)]. Lyn has a non-redundant role in negative regulation of BCR signaling (4). Lyn phosphorylates the ITIMs of the BCR associated co-receptors CD22 (see the record for well), Fc receptor gamma IIb (FcγRIIb), and paired immunoglobulin-like receptor-B (PIR-B) (8-13).
Lyn-/- mice exhibit progressive splenomegaly and enlargement of lymph nodes, reduced numbers of mature follicular B cells, absence of marginal zone B cells, produce large quantities of anti-nuclear antibodies, and develop glomerulonephritis as early as 5 months of age (8;14-16). B cells from Lyn-/- mice are both hyperresponsive to BCR ligation and resistant to the inhibitory signals from FcγRIIb and CD22 (8;10;11;14). Peritoneal IgM+ B220+ B cell numbers were significantly lower in Lyn-/- mice at 2 months of age compared to wild-type mice and the size of the Peyer’s patches were reduced (14;16). As a result, CD5− B220high conventional B cells and B1 cells were also reduced (16). The Cress mice also exhibited a significant reduction in the frequency of peripheral B cell numbers. In addition, the function of the Cress B cells in mounting an antigen-specific immune response is deficient indicating that LynCress exhibits loss of function.
Cress(F):5'- TGCCACTGAGCAGGGCTTCTAAAC -3'
Cress(R):5'- GCAACAGTCTCTGAACCTGAGTCAC -3'
Cress_seq(F):5'- TGAGCAGGGCTTCTAAACTCTAC -3'
Cress_seq(R):5'- ACTGTGGTCCCATTGAGC -3'
1. Stanley, E., Ralph, S., McEwen, S., Boulet, I., Holtzman, D. A., Lock, P., and Dunn, A. R. (1991) Alternatively Spliced Murine Lyn mRNAs Encode Distinct Proteins. Mol Cell Biol. 11, 3399-3406.
2. Yi, T. L., Bolen, J. B., and Ihle, J. N. (1991) Hematopoietic Cells Express Two Forms of Lyn Kinase Differing by 21 Amino Acids in the Amino Terminus. Mol Cell Biol. 11, 2391-2398.
3. Boggon, T. J., and Eck, M. J. (2004) Structure and Regulation of Src Family Kinases. Oncogene. 23, 7918-7927.
4. Avila, M., Martinez-Juarez, A., Ibarra-Sanchez, A., and Gonzalez-Espinosa, C. (2012) Lyn Kinase Controls TLR4-Dependent IKK and MAPK Activation Modulating the Activity of TRAF-6/TAK-1 Protein Complex in Mast Cells. Innate Immun. 18, 648-660.
5. Verhagen, A. M., Wallace, M. E., Goradia, A., Jones, S. A., Croom, H. A., Metcalf, D., Collinge, J. E., Maxwell, M. J., Hibbs, M. L., Alexander, W. S., Hilton, D. J., Kile, B. T., and Starr, R. (2009) A Kinase-Dead Allele of Lyn Attenuates Autoimmune Disease Normally Associated with Lyn Deficiency. J Immunol. 182, 2020-2029.
6. Yamamoto, T., Yamanashi, Y., and Toyoshima, K. (1993) Association of Src-Family Kinase Lyn with B-Cell Antigen Receptor. Immunol Rev. 132, 187-206.
7. Guo, B., Su, T. T., and Rawlings, D. J. (2004) Protein Kinase C Family Functions in B-Cell Activation. Curr Opin Immunol. 16, 367-373.
8. Chan, V. W., Meng, F., Soriano, P., DeFranco, A. L., and Lowell, C. A. (1997) Characterization of the B Lymphocyte Populations in Lyn-Deficient Mice and the Role of Lyn in Signal Initiation and Down-Regulation. Immunity. 7, 69-81.
9. Nishizumi, H., Horikawa, K., Mlinaric-Rascan, I., and Yamamoto, T. (1998) A Double-Edged Kinase Lyn: A Positive and Negative Regulator for Antigen Receptor-Mediated Signals. J Exp Med. 187, 1343-1348.
10. Chan, V. W., Lowell, C. A., and DeFranco, A. L. (1998) Defective Negative Regulation of Antigen Receptor Signaling in Lyn-Deficient B Lymphocytes. Curr Biol. 8, 545-553.
11. 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.
12. Maeda, A., Kurosaki, M., Ono, M., Takai, T., and Kurosaki, T. (1998) Requirement of SH2-Containing Protein Tyrosine Phosphatases SHP-1 and SHP-2 for Paired Immunoglobulin-Like Receptor B (PIR-B)-Mediated Inhibitory Signal. J Exp Med. 187, 1355-1360.
13. Ho, L. H., Uehara, T., Chen, C. C., Kubagawa, H., and Cooper, M. D. (1999) Constitutive Tyrosine Phosphorylation of the Inhibitory Paired Ig-Like Receptor PIR-B. Proc Natl Acad Sci U S A. 96, 15086-15090.
14. Nishizumi, H., Taniuchi, I., Yamanashi, Y., Kitamura, D., Ilic, D., Mori, S., Watanabe, T., and Yamamoto, T. (1995) Impaired Proliferation of Peripheral B Cells and Indication of Autoimmune Disease in Lyn-Deficient Mice. Immunity. 3, 549-560.
15. Hibbs, M. L., Tarlinton, D. M., Armes, J., Grail, D., Hodgson, G., Maglitto, R., Stacker, S. A., and Dunn, A. R. (1995) Multiple Defects in the Immune System of Lyn-Deficient Mice, Culminating in Autoimmune Disease. Cell. 83, 301-311.
|Science Writers||Anne Murray|
|Authors||Kuan-Wen Wang, Jin Huk Choi, Ming Zeng, Apiruck Watthanasurorot, Bruce Beutler|
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