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|Coordinate||34,214,032 bp (GRCm38)|
|Base Change||C ⇒ A (forward strand)|
|Gene Name||transporter 2, ATP-binding cassette, sub-family B (MDR/TAP)|
|Synonym(s)||Abcb3, Ham-2, HAM2, Ham2, MTP2, PSF2, Tap-2|
|Chromosomal Location||34,203,527-34,216,321 bp (+)|
FUNCTION: The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is involved in antigen presentation. This protein forms a heterodimer with Tap1 in order to transport peptides from the cytoplasm to the endoplasmic reticulum. Mutations in the human gene may be associated with ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease. [provided by RefSeq, Jul 2008]
PHENOTYPE: Homozygous mutant mice have no CD8+ T cells, although their numbers of CD4+ T cells and B cells are normal. [provided by MGI curators]
|Limits of the Critical Region||34203527 - 34216321 bp|
|Amino Acid Change||Tyrosine changed to Stop codon|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000025197] [ENSMUSP00000112395]|
AA Change: Y429*
|Predicted Effect||probably null|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2018-01-31 9:59 AM by Anne Murray|
|Record Created||2016-09-20 9:03 PM by Jin Huk Choi|
The date2 phenotype was identified among G3 mice of the pedigree R4682, some of which showed an increase in in the CD4+ to CD8+ T cell ratio (Figure 1) caused by an increased frequency of CD4+ T cells (Figure 2), an increased frequency of CD4+ T cells in CD3+ T cells (Figure 3), a reduced frequency of effector memory CD4+ T cells in CD4 T cells (Figure 4), and an increased frequency of naive CD4+ T cells in CD4+ T cells (Figure 5) coupled with a reduced frequency of CD8+ T cells (Figure 6), a reduced frequency of CD8+ T cells in CD3+ T cells (Figure 7), a reduced frequency of naive CD8+ T cells in CD8+ T cells (Figure 8), and an increased frequency in central memory CD8+ T cells in CD8+ T cells (Figure 9), all in the peripheral blood. Some mice also showed a reduced frequency of CD44+ CD8+ T cells (Figure 10), a reduction in the CD44 mean fluorescence intensity (MFI) on peripheral blood CD4+ T cells (Figure 11) and CD8+ T cells (Figure 12) as well as increased frequencies of natural killer cells in the peripheral blood (Figure 13).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 40 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Tap2: a C to A transversion at base pair 34,214,032 (v38) on chromosome 17, or base pair 9,554 in the GenBank genomic region NC_000083 encoding Tap2. The strongest association was found with a recessive model of linkage to the normalized frequency of CD8+ T cells in CD3+ T cells, wherein 15 variant homozygotes departed phenotypically from 8 homozygous reference mice and 20 heterozygous mice with a P value of 8.881 x 10-23 (Figure 14). A substantial semidominant effect was observed in most of the assays but the mutation is preponderantly recessive, and in no assay was a purely dominant effect observed.
The mutation corresponds to residue 1,440 in the mRNA sequence NM_011530 within exon 8 of 12 total exons.
The mutated nucleotide is indicated in red. The mutation results in substitution of tyrosine 429 for a premature stop codon (Y429*) in the TAP2 protein.
The transporter associated with antigen processing (TAP) pumps cytosolic peptides into the endoplasmic reticulum (ER) lumen for loading onto class I major histocompatibility (MHC) molecules and presentation to T lymphocytes. TAP is a member of the ATP-binding cassette (ABC) transporter family, ubiquitous proteins that shuttle a variety of substrates, including ions, sugars, amino acids, peptides, vitamins, lipids, antibiotics, and drugs, across cellular membranes (1;2). TAP is a heterodimer of the homologous TAP1 (724 amino acids in mice) and TAP2 proteins (702 amino acids in mice), each of which contains a six-helix TMD, a C-terminal NBD, and three transmembrane N-terminal accessory domains (Figure 15). The date2 mutation results in substitution of tyrosine 429 for a premature stop codon. Tyr429 is located within the cytoplasmic C-terminal tail immediately following the last transmembrane domain.
Please see the record for ganymede for information about Tap2.
TAP is essential for the transport of peptides into the ER for loading onto MHC class I molecules and display at the cell surface. Peptide binding is required to stabilize MHC class I molecules, so mice with disrupted TAP1 or TAP2 genes assemble drastically reduced amounts of MHC class I molecules, and have nearly absent surface expression of MHC class I. The cells of Tap1-/- mice (3) and mice with an ENU-induced point mutation in TAP2 (Tap2jasmine) (4) are deficient in cytosolic antigen presentation, and consequently CD8+ T cells fail to develop in these animals. Similarly, human mutations in TAP1 (5;6), TAP2 (7;8), or tapasin (9) cause the rarely occurring bare lymphocyte syndrome type I (type I BLS, OMIM #604571), characterized a reduction in MHC class I surface expression to 1-3% of normal levels. The lack of CD8+ T cells in date2 is due to death after failure to interact with peptide-MHC class I in the thymus, which is known to promote the development and maintenance of these T cells.
date2(F):5'- TCCAAGGTTCCCTCTCTGAG -3'
date2(R):5'- GAAAATGATGTTCAGGCTGCG -3'
date2_seq(F):5'- AAGGTTCCCTCTCTGAGTTTATCCG -3'
date2_seq(R):5'- GAGAAAGGTTCCGATCCCACG -3'
1. Borst, P., and Elferink, R. O. (2002) Mammalian ABC Transporters in Health and Disease. Annu Rev Biochem. 71, 537-592.
2. Higgins, C. F. (1992) ABC Transporters: From Microorganisms to Man. Annu Rev Cell Biol. 8, 67-113.
3. Van Kaer, L., Ashton-Rickardt, P. G., Ploegh, H. L., and Tonegawa, S. (1992) TAP1 Mutant Mice are Deficient in Antigen Presentation, Surface Class I Molecules, and CD4-8+ T Cells. Cell. 71, 1205-1214.
4. Theodoratos, A., Whittle, B., Enders, A., Tscharke, D. C., Roots, C. M., Goodnow, C. C., and Fahrer, A. M. (2010) Mouse Strains with Point Mutations in TAP1 and TAP2. Immunol Cell Biol. 88, 72-78.
5. de la Salle, H., Zimmer, J., Fricker, D., Angenieux, C., Cazenave, J. P., Okubo, M., Maeda, H., Plebani, A., Tongio, M. M., Dormoy, A., and Hanau, D. (1999) HLA Class I Deficiencies due to Mutations in Subunit 1 of the Peptide Transporter TAP1. J Clin Invest. 103, R9-R13.
6. Furukawa, H., Murata, S., Yabe, T., Shimbara, N., Keicho, N., Kashiwase, K., Watanabe, K., Ishikawa, Y., Akaza, T., Tadokoro, K., Tohma, S., Inoue, T., Tokunaga, K., Yamamoto, K., Tanaka, K., and Juji, T. (1999) Splice Acceptor Site Mutation of the Transporter Associated with Antigen Processing-1 Gene in Human Bare Lymphocyte Syndrome. J Clin Invest. 103, 755-758.
7. de la Salle, H., Hanau, D., Fricker, D., Urlacher, A., Kelly, A., Salamero, J., Powis, S. H., Donato, L., Bausinger, H., and Laforet, M. (1994) Homozygous Human TAP Peptide Transporter Mutation in HLA Class I Deficiency. Science. 265, 237-241.
8. Moins-Teisserenc, H. T., Gadola, S. D., Cella, M., Dunbar, P. R., Exley, A., Blake, N., Baykal, C., Lambert, J., Bigliardi, P., Willemsen, M., Jones, M., Buechner, S., Colonna, M., Gross, W. L., and Cerundolo, V. (1999) Association of a Syndrome Resembling Wegener's Granulomatosis with Low Surface Expression of HLA Class-I Molecules. Lancet. 354, 1598-1603.
9. Yabe, T., Kawamura, S., Sato, M., Kashiwase, K., Tanaka, H., Ishikawa, Y., Asao, Y., Oyama, J., Tsuruta, K., Tokunaga, K., Tadokoro, K., and Juji, T. (2002) A Subject with a Novel Type I Bare Lymphocyte Syndrome has Tapasin Deficiency due to Deletion of 4 Exons by Alu-Mediated Recombination. Blood. 100, 1496-1498.
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine, Katherine Timer|
|Authors||Ming Zeng, Xue Zhong, Bruce Beutler|
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