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|Mutation Type||critical splice donor site|
|Coordinate||11,226,986 bp (GRCm38)|
|Base Change||G ⇒ A (forward strand)|
|Gene Name||protein kinase C, theta|
|Synonym(s)||PKC theta, PKC-0, PKCtheta, PKC-theta, A130035A12Rik, Pkcq|
|Chromosomal Location||11,172,108-11,301,222 bp (+)|
|MGI Phenotype||Homozygotes for targeted null mutations exhibit reduced T cell proliferative responses and interleukin 2 production and a lack of T cell receptor-initiated NF-kappaB activation in mature T lymphocytes.|
|Limits of the Critical Region||11172108 - 11301222 bp|
|Amino Acid Change|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000028118] [ENSMUSP00000100035]|
|Predicted Effect||probably null|
|Predicted Effect||probably null|
|Phenotypic Category||T-dependent humoral response defect- decreased antibody response to OVA+ alum immunization|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||11/08/2016 10:08 AM by Anne Murray|
|Record Created||10/10/2016 8:59 PM by Jin Huk Choi|
The celina2 phenotype was identified among G3 mice of the pedigree R4820, some of which showed diminished T-dependent antibody responses to OVA/alum (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 36 mutations. The diminished T-dependent antibody response to OVA/alum was linked by continuous variable mapping to a mutation in Prkcq. The Prkcq mutation is an A to G transition at base pair 11,226,986 (v38) on chromosome 2, or base pair 55,083 in the GenBank genomic region NC_000068 within the donor splice site of intron 2 (Transcript_ID = ENSMUST00000028118.8). Linkage was found with a recessive model of inheritance, wherein two variant homozygotes departed phenotypically from five homozygous reference mice and seven heterozygous mice with a P value of 2.54 x 10-4 (Figure 2). The effect of the mutation at the cDNA and protein level have not examined, but the mutation is predicted to result in the use of a cryptic site in exon 1 (out of 16 total exons; Transcript_ID = ENSMUST00000102970.4). Use of the cryptic site in exon 1 would result in a 14-base pair deletion in exon 1 and a frame-shifted protein product beginning after amino acid 34 and terminating after the inclusion of 20 aberrant amino acids.
Genomic numbering corresponds to NC_000068. The donor splice site of intron 1, which is destroyed by the celina2 mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
Prkcq encodes protein kinase C theta (PKCθ), a member of the PKC family of serine threonine kinases. PKC kinases share certain structural features including a highly conserved catalytic domain consisting of motifs required for ATP-substrate binding and catalysis, and a regulatory domain that maintains the enzyme in an inactive conformation. The regulatory and catalytic domains are attached to each other by a hinge region (Figure 3). PKCθ has a N-terminal C2-like pTyr-binding domain (amino acids 8-123), a C2-like domain, a proline-rich motif in the V3 (hinge) domain that mediates CD28 interaction and immunological synapse translocation, and two tandem cysteine-rich zinc finger C1 domains (amino acids 159-209 and 231-281) that bind diacylglycerol (1).
The celina2 mutation is predicted to destroy the splice donor site of intron 1, leading to a frame-shifted protein product and coding of a premature stop codon at amino acid 54 after the inclusion of 20 aberrant amino acids.
For more information about Prkcq, please see the record for celina.
PKCs are involved in receptor desensitization, modulating membrane structure events, regulating transcription, mediating immune responses, regulating cell growth, and in learning and memory. PKCθ has roles in the regulation of migration, lymphoid cell motility, insulin signaling in skeletal muscle cells, insulin secretion and resistance, T cell activation, survival responses in adult T cells and T cell FasL-mediated apoptosis (see the record for riogrande), mast cell activation, neuronal differentiation and function, development of the peripheral and central nervous system (2-13). PKCθ also has putative functions in mitosis and the cell cycle (14-18).
B cell responses are classified as T-dependent (T-D) or T-independent (T-I) based on their requirement for T cell help in antibody production. T cell-dependent antigens are processed and presented to helper T cells via the MHC class II molecules, whereas T cell-independent antigens are typically polysaccharides that cannot be processed and presented by MHC molecules. These antigens are often expressed on the surface of pathogens in an organized, highly repetitive form that can activate specific B cells by cross-linking of antigen receptors. The formation of antigen receptor clusters can recruit and activate multiple Btk molecules, resulting in long-term mobilization of intracellular ionized Ca2+, gene transcription and B cell activation and proliferation. Toll-like receptor (TLR) engagement provides a second signal that allows the secretion of antibody in response to these antigens. The T-D B cell response is mediated by conventional (follicular B-2) B cells, while T-I B cell responses are mediated by peritoneal B-1 and marginal zone (MZ) B cells [reviewed by (19;20)]. The reduction of B cell antibody responses to OVA-alum in the celina2 mice suggests that the function of antigen processing may be impaired.
celina2(F):5'- CTGTCTGAGATAAAACACTAAGTGG -3'
celina2(R):5'- AGAGGCCATCACTAAGCCTG -3'
celina2_seq(F):5'- CTGAGATAAAACACTAAGTGGAGGTG -3'
celina2_seq(R):5'- TTGTCTAGTCTAGCCACC -3'
1. Kong, K. F., Yokosuka, T., Canonigo-Balancio, A. J., Isakov, N., Saito, T., and Altman, A. (2011) A Motif in the V3 Domain of the Kinase PKC-Theta Determines its Localization in the Immunological Synapse and Functions in T Cells Via Association with CD28. Nat Immunol. 12, 1105-1112.
2. Tang, S., Gao, Y., and Ware, J. A. (1999) Enhancement of Endothelial Cell Migration and in Vitro Tube Formation by TAP20, a Novel Beta 5 Integrin-Modulating, PKC Theta-Dependent Protein. J Cell Biol. 147, 1073-1084.
3. Shahabi, N. A., McAllen, K., and Sharp, B. M. (2008) Stromal Cell-Derived Factor 1-Alpha (SDF)-Induced Human T Cell Chemotaxis Becomes Phosphoinositide 3-Kinase (PI3K)-Independent: Role of PKC-Theta. J Leukoc Biol. 83, 663-671.
4. Schmitz-Peiffer, C., Browne, C. L., Oakes, N. D., Watkinson, A., Chisholm, D. J., Kraegen, E. W., and Biden, T. J. (1997) Alterations in the Expression and Cellular Localization of Protein Kinase C Isozymes Epsilon and Theta are Associated with Insulin Resistance in Skeletal Muscle of the High-Fat-Fed Rat. Diabetes. 46, 169-178.
5. Serra, C., Federici, M., Buongiorno, A., Senni, M. I., Morelli, S., Segratella, E., Pascuccio, M., Tiveron, C., Mattei, E., Tatangelo, L., Lauro, R., Molinaro, M., Giaccari, A., and Bouche, M. (2003) Transgenic Mice with Dominant Negative PKC-Theta in Skeletal Muscle: A New Model of Insulin Resistance and Obesity. J Cell Physiol. 196, 89-97.
6. Kim, J. K., Fillmore, J. J., Sunshine, M. J., Albrecht, B., Higashimori, T., Kim, D. W., Liu, Z. X., Soos, T. J., Cline, G. W., O'Brien, W. R., Littman, D. R., and Shulman, G. I. (2004) PKC-Theta Knockout Mice are Protected from Fat-Induced Insulin Resistance. J Clin Invest. 114, 823-827.
7. Monks, C. R., Kupfer, H., Tamir, I., Barlow, A., and Kupfer, A. (1997) Selective Modulation of Protein Kinase C-Theta during T-Cell Activation. Nature. 385, 83-86.
8. Coudronniere, N., Villalba, M., Englund, N., and Altman, A. (2000) NF-Kappa B Activation Induced by T Cell receptor/CD28 Costimulation is Mediated by Protein Kinase C-Theta. Proc Natl Acad Sci U S A. 97, 3394-3399.
9. Villalba, M., Bushway, P., and Altman, A. (2001) Protein Kinase C-Theta Mediates a Selective T Cell Survival Signal Via Phosphorylation of BAD. J Immunol. 166, 5955-5963.
10. Bertolotto, C., Maulon, L., Filippa, N., Baier, G., and Auberger, P. (2000) Protein Kinase C Theta and Epsilon Promote T-Cell Survival by a Rsk-Dependent Phosphorylation and Inactivation of BAD. J Biol Chem. 275, 37246-37250.
11. Manicassamy, S., Gupta, S., Huang, Z., and Sun, Z. (2006) Protein Kinase C-Theta-Mediated Signals Enhance CD4+ T Cell Survival by Up-Regulating Bcl-xL. J Immunol. 176, 6709-6716.
12. Manicassamy, S., and Sun, Z. (2007) The Critical Role of Protein Kinase C-Theta in Fas/Fas Ligand-Mediated Apoptosis. J Immunol. 178, 312-319.
13. Besalduch, N., Santafe, M. M., Garcia, N., Gonzalez, C., Tomas, M., Tomas, J., and Lanuza, M. A. (2011) Transmitter Release in the Neuromuscular Synapse of the Protein Kinase C Theta-Deficient Adult Mouse. J Comp Neurol. 519, 849-855.
14. Deeds, L., Teodorescu, S., Chu, M., Yu, Q., and Chen, C. Y. (2003) A p53-Independent G1 Cell Cycle Checkpoint Induced by the Suppression of Protein Kinase C Alpha and Theta Isoforms. J Biol Chem. 278, 39782-39793.
15. Passalacqua, M., Patrone, M., Sparatore, B., Melloni, E., and Pontremoli, S. (1999) Protein Kinase C-Theta is Specifically Localized on Centrosomes and Kinetochores in Mitotic Cells. Biochem J. 337 ( Pt 1), 113-118.
16. Wilda, M., Ghaffari-Tabrizi, N., Reisert, I., Utermann, G., Baier, G., and Hameister, H. (2001) Protein Kinase C Isoenzyme: Selective Expression Pattern of Protein Kinase C-θ during Mouse Development. Mech Dev. 103, 197-200.
17. Hilgenberg, L., and Miles, K. (1995) Developmental Regulation of a Protein Kinase C Isoform Localized in the Neuromuscular Junction. J Cell Sci. 108 ( Pt 1), 51-61.
18. Michalczyk, I., Sikorski, A. F., Kotula, L., Junghans, R. P., and Dubielecka, P. M. (2013) The Emerging Role of Protein Kinase Ctheta in Cytoskeletal Signaling. J Leukoc Biol. 93, 319-327.
19. Alugupalli, K. R. (2008) A Distinct Role for B1b Lymphocytes in T Cell-Independent Immunity. Curr Top Microbiol Immunol. 319, 105-130.
|Science Writers||Anne Murray|
|Authors||Jin Huk Choi, James Butler, Bruce Beutler|
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