Alternative titles; symbols
HGNC Approved Gene Symbol: TAP1
SNOMEDCT: 725136003;
Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38): 6:32,845,209-32,853,704 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.32 | Bare lymphocyte syndrome, type I | 604571 | Autosomal recessive | 3 |
The ATP-binding cassette transporter TAP translocates peptides from the cytosol to awaiting major histocompatibility complex (MHC) class I molecules in the endoplasmic reticulum. TAP is made up of the TAP1 and TAP2 (170261) polypeptides.
A gene in the MHC with a role in antigen presentation was isolated by Trowsdale et al. (1990) and by Spies et al. (1990). Spies et al. (1990) referred to the gene product as peptide supply factor (PSF). They identified the gene by deletion mapping in mutants and by chromosome walking. They pointed out that PSF is homologous to mammalian and bacterial ATP-dependent transport proteins, suggesting that it operates in the intracellular transport of peptides. Trowsdale et al. (1990) prepared probes from genomic clones from the MHC region and probed these onto cDNA libraries. Attention was focused on probes from regions of genomic DNA containing clusters of restriction sites with CpG dinucleotides in their recognition sequence, as these are often found near the 5-prime end of genes. One gene so isolated, called by them RING4, appeared to have a role in antigen presentation. It was found to have a sequence related to the ABC (ATP-binding cassette) superfamily of transporters. This superfamily includes the human multidrug-resistance proteins (171050, 171060), a series of transporters from bacteria, including the oligopeptide permease system, and the human cystic fibrosis gene product.
Monaco et al. (1990) demonstrated that in the mouse the Ham1 and Ham2 genes are located in the class II region of the MHC and are functionally and structurally homologous to TAP1 and TAP2, respectively.
Neefjes et al. (1993) defined the conditions by which the TAP1 and TAP2 heterodimer is involved in assembly of class I molecules and presentation of endogenous peptides derived from nuclear and cytosolic proteins to CD8(+) T cells.
TAP1 and TAP2 polypeptides possess a nucleotide-binding domain (NBD). Karttunen et al. (2001) presented biochemical and functional evidence that the NBDs of TAP1 and TAP2 are nonequivalent. Photolabeling experiments with 8-azido-ATP demonstrated a cooperative interaction between the 2 NBDs that can be stimulated by peptide. The substitution of key lysine residues in the Walker A motifs of TAP1 and TAP2 suggested that TAP1-mediated ATP hydrolysis is not essential for peptide translocation but that TAP2-mediated ATP hydrolysis is critical, not only for translocation, but for peptide binding.
By comparative sequence analysis, Ritz et al. (2003) predicted that glu263 or phe265 of TAP1 are critical for TAP transporter function. They found that deletion or mutation of phe265 of TAP1 had little effect on TAP function, whereas deletion or alteration of glu264 had a major effect.
The TAP1 gene maps to chromosome 6p21.3 within the MHC.
The MHC encodes the class I and class II families of glycoproteins that present peptides for immunorecognition by cytotoxic and helper T lymphocytes, respectively. Class I molecules bind peptides generated by degradation of proteins intracellularly, whereas class II molecules associate mainly with peptides derived from endocytosed extracellular proteins. Two genes encode components of the proteasome complex (see 176842), which degrades cytosolic proteins and may generate antigenic peptides. Two closely linked genes, PSF1 and PSF2, encode subunits of a transporter that presumably translocates peptides into an exocytic compartment where they associate with class I molecules. The location of these genes in the MHC in close linkage to the class I and class II gene families suggests that they coevolved to optimize functional interactions. If this is so, the question is raised whether the proteasome subunits and the transporter genes, like most class I and class II genes, are polymorphic. Both proteasome subunits display electrophoretic polymorphism in the mouse. Allelic variation in the peptide transporter might influence the selection of peptide epitopes presented by class I molecules. Colonna et al. (1992) investigated variability of PSF1 and PSF2 by SSCP analysis and DNA sequencing. They identified several variants and examined possible involvement of the PSF1 and PSF2 genes in susceptibility to MHC-associated diseases such as ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease. Two diallelic variants were identified in the PSF1 gene and 3 in the PSF2 gene.
Van Endert et al. (1992) noted that screening for novel genes within the class II region of the major histocompatibility complex led to discovery of 4 genes residing in a closely linked complex within a 50-kb region upstream of the HLA-DO gene (142920). The TAP1 (also known as RING4 or PSF1) and TAP2 (also known as RING11 or PSF2) genes belong to a family of membrane transporters that possess an ATP binding cassette and 6 to 8 transmembrane domains. The other 2 genes, LMP2 (also known as RING12; 177045) and LMP7 (also known as RING10; 177046), encode proteins that belong to a large multicatalytic cytosolic protease complex referred to as the proteasome, or large multifunctional protease (LMP). Studying DNA from 27 consanguineous human cell lines, van Endert et al. (1992) sought genomic polymorphism by restriction fragment length polymorphism (RFLP) analysis. Studies demonstrated strong linkage disequilibrium between TAP1 and LMP2 RFLPs. Moreover, RFLPs, as well as a polymorphic stop codon in the telomeric TAP2 gene, appeared to be in linkage disequilibrium with HLA-DR (see HLA-DRA, 142860) alleles and RFLPs in the HLA-DO gene. A high rate of recombination seemed to occur in the center of the complex, between the TAP1 and TAP2 genes.
Cerundolo et al. (1990) described a mutant cell line that had lost a function required for presentation of intracellular viral antigens with class I molecules of the MHC, but retained the capacity to present defined epitopes as extracellular peptides. Cerundolo et al. (1990) demonstrated that the genetic defect mapped within the MHC region on human chromosome 6. They showed that the presence of a normal human chromosome 6 in a hybrid cell was necessary for the correction of the defect. The cell line with the defective function carried a large homozygous deletion on 6p between the DP-alpha-2 locus (142880) and the complement gene cluster. Cerundolo et al. (1990) demonstrated further that the genetic defect resulted also in defective expression of class I molecules at the cell surface. They interpreted this to mean that class I assembly and transport are facilitated by association with peptides derived from intracellular antigens. DeMars et al. (1985) had isolated mutants with derangement in class I antigen expression, after mutagenic treatment of human B lymphoblastoid cell lines. The mutant cells had simultaneously reduced expression of HLA-B antigens even though their genes and the B2M gene were present and transcribed. Antigen expression was fully restored in hybrids of these mutants with other B lymphoblastoid cells.
Individuals with certain HLA-DR alleles have an increased relative risk of developing insulin-dependent diabetes mellitus (IDDM; 222100). The disease association is even stronger with certain HLA-DQ (see HLA-DQA, 146880) alleles, but there is little association with HLA-DP providing a boundary of disease association to the 430 kb between DQ and DP. The TAP genes map approximately midway between DP and DQ. Studying single-stranded conformational polymorphism at the TAP1 locus in diabetics and normal controls, Jackson and Capra (1993) determined relative risks. In a population group studied extensively previously, they found a higher association of a TAP1 allele with IDDM than with any single HLA-DP allele, but the risk was lower than with HLA-DQB1*0302 (see HLA-DQB1, 604305). The data provided new limits for IDDM susceptibility to the 190-kb interval between TAP1 and HLA-DQB1.
Chen et al. (1996) evaluated 79 human solid tumors and cell lines for genetic abnormalities in TAP1 that might have led to an acquired loss of antigen presenting ability. They discovered a mutation (R659Q; 170260.0003) in the TAP1 gene near the ATP-binding site in a human small cell lung cancer cell line. This cell line was heterozygous for this allele, but only the R659Q allele was transcribed into RNA. Even though the R659Q protein was expressed, the cells acted as if they were TAP-deficient by peptide binding and antigen presentation studies. Chen et al. (1996) showed that transfection of a functional TAP1 allele into the cells corrected the deficiency phenotype.
Cullen et al. (1997) noted that studies of linkage disequilibrium across the HLA class II region have been useful in predicting where recombination is most likely to occur. The strong associations between genes was in the 85-kb region from DQB1 to DRB1 (142857) are consistent with low frequency of recombination in this segment of DNA. Conversely, a lack of association between alleles of TAP1 and TAP2 (which are separated by approximately 15 kb) has been observed, suggesting that recombination occurs here with relatively high frequency. Cullen et al. (1997) confirmed the increased rate of recombination in this and other segments. They noted a (TGGA)12 tandem repeat within the TAP2 gene possibly associated with the increased rate of recombination.
In a Japanese woman with type I bare lymphocyte syndrome, Furukawa et al. (1999) identified homozygosity for a splice site mutation in intron 1 of the TAP1 gene (170260.0004).
Class I MHC molecules, known to be important for immune responses to antigen, are expressed also by neurons that undergo activity-dependent, long-term structural and synaptic modifications. Huh et al. (2000) showed that in mice genetically deficient for cell surface class I MHC, due to deletion of either TAP1 or beta-2-microglobulin (109700), or for a class I MHC receptor component, CD3-zeta (186780), refinement of connections between retina and central targets during development is incomplete. In the hippocampus of adult mutants, N-methyl-D-aspartate receptor-dependent long-term potentiation is enhanced, and long-term depression is absent. Specific class I MHC mRNAs are expressed by distinct mosaics of neurons, reflecting a potential for diverse neuronal functions. These results demonstrated an important role for these molecules in the activity-dependent remodeling and plasticity of connections in the developing and mature mammalian central nervous system.
By SSCP followed by DNA sequencing, Colonna et al. (1992) identified an A-to-G transition at nucleotide 1069 in the PSF1 gene, changing isoleucine-333 to valine.
By SSCP analysis followed by DNA sequencing, Colonna et al. (1992) identified an A-to-G transition at nucleotide 1982 in segment 8 of the PSF1 gene, replacing asp-637 with glycine. The allele designated PSF1A showed linkage of ile-333 and asp-637; val-333 together with gly-637 or asp-637 form the PSF1B and PSF1C alleles, respectively.
In a human small cell lung cancer cell line, Chen et al. (1996) identified heterozygosity for an R659Q allele at the TAP1 locus. Only the R659Q allele was transcribed into RNA. Even though the protein was expressed, the cells acted as if they were TAP-deficient and were restored to normal by transfection of a functional TAP1 allele. Thus the cells had a defect in the conveying of intracellular peptides into the endoplasmic reticulum for complex formation with class I MHC and subsequent recognition by cytotoxic T lymphocytes.
In a 46-year-old Japanese woman originally reported by Maeda et al. (1985) with type I bare lymphocyte syndrome (604571), Furukawa et al. (1999) identified homozygosity for a G-to-A transition at basepair 536 in intron 1 of the TAP1 gene. This resulted in an altered splice acceptor site and deletion of a G in codon 200 of mRNA, causing a frameshift and a premature stop codon at 228. The patient's first-cousin parents and other family members were heterozygous for the mutation.
Cerundolo, V., Alexander, J., Anderson, K., Lamb, C., Cresswell, P., McMichael, A., Gotch, F., Townsend, A. Presentation of viral antigen controlled by a gene in the major histocompatibility complex. Nature 345: 449-452, 1990. [PubMed: 2342577] [Full Text: https://doi.org/10.1038/345449a0]
Chen, H. L., Gabrilovich, D., Tampe, R., Girgis, K. R., Nadaf, S., Carbone, D. P. A functionally defective allele of TAP1 results in loss of MHC class I antigen presentation in a human lung cancer. Nature Genet. 13: 210-213, 1996. [PubMed: 8640228] [Full Text: https://doi.org/10.1038/ng0696-210]
Colonna, M., Bresnahan, M., Bahram, S., Strominger, J. L., Spies, T. Allelic variants of the human putative peptide transporter involved in antigen processing. Proc. Nat. Acad. Sci. 89: 3932-3936, 1992. [PubMed: 1570316] [Full Text: https://doi.org/10.1073/pnas.89.9.3932]
Cullen, M., Noble, J., Erlich, H., Thorpe, K., Beck, S., Klitz, W., Trowsdale, J., Carrington, M. Characterization of recombination in the HLA class II region. Am. J. Hum. Genet. 60: 397-407, 1997. [PubMed: 9012413]
DeMars, R., Rudersdorf, R., Chang, C., Petersen, J., Strandtmann, J., Korn, N., Sidwell, B., Orr, H. T. Mutations that impair a posttranscriptional step in expression of HLA-A and -B antigens. Proc. Nat. Acad. Sci. 82: 8183-8187, 1985. [PubMed: 3906658] [Full Text: https://doi.org/10.1073/pnas.82.23.8183]
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., Juji, T. Splice acceptor site mutation of the transporter associated with antigen processing-1 gene in human bare lymphocyte syndrome. J. Clin. Invest. 103: 755-758, 1999. [PubMed: 10074494] [Full Text: https://doi.org/10.1172/JCI5335]
Huh, G. S., Boulanger, L. M., Du, H., Riquelme, P. A., Brotz, T. M., Shatz, C. J. Functional requirement for class I MHC in CNS development and plasticity. Science 290: 2155-2159, 2000. [PubMed: 11118151] [Full Text: https://doi.org/10.1126/science.290.5499.2155]
Jackson, D. G., Capra, J. D. TAP1 alleles in insulin-dependent diabetes mellitus: a newly defined centromeric boundary of disease susceptibility. Proc. Nat. Acad. Sci. 90: 11079-11083, 1993. [PubMed: 8248212] [Full Text: https://doi.org/10.1073/pnas.90.23.11079]
Karttunen, J. T., Lehner, P. J., Gupta, S. S., Hewitt, E. W., Cresswell, P. Distinct functions and cooperative interaction of the subunits of the transporter associated with antigen processing (TAP). Proc. Nat. Acad. Sci. 98: 7431-7436, 2001. [PubMed: 11381133] [Full Text: https://doi.org/10.1073/pnas.121180198]
Maeda, H., Hirata, R., Chen, R. F., Suzaki, H., Kudoh, S., Tohyama, H. Defective expression of HLA class I antigens: a case of the bare lymphocyte without immunodeficiency. Immunogenetics 21: 549-558, 1985. [PubMed: 3891604] [Full Text: https://doi.org/10.1007/BF00395879]
Monaco, J. J., Cho, S., Attaya, M. Transport protein genes in the murine MHC: possible implications for antigen processing. Science 250: 1723-1726, 1990. [PubMed: 2270487] [Full Text: https://doi.org/10.1126/science.2270487]
Neefjes, J. J., Momburg, F., Hammerling, G. J. Selective and ATP-dependent translocation of peptides by the MHC-encoded transporter. Science 261: 769-771, 1993. Note: Erratum: Science 264: 16 only, 1994. [PubMed: 8342042] [Full Text: https://doi.org/10.1126/science.8342042]
Ritz, U., Drexler, I., Sutter, D., Abele, R., Huber, C., Seliger, B. Impaired transporter associated with antigen processing (TAP) function attributable to a single amino acid alteration in the peptide TAP subunit TAP1. J. Immun. 170: 941-946, 2003. [PubMed: 12517960] [Full Text: https://doi.org/10.4049/jimmunol.170.2.941]
Spies, T., Bresnahan, M., Bahram, S., Arnold, D., Blanck, G., Mellins, E., Pious, D., DeMars, R. A gene in the human major histocompatibility complex class II region controlling the class I antigen presentation pathway. Nature 348: 744-747, 1990. [PubMed: 2259384] [Full Text: https://doi.org/10.1038/348744a0]
Trowsdale, J., Hanson, I., Mockridge, I., Beck, S., Townsend, A., Kelly, A. Sequences encoded in the class II region of the MHC related to the 'ABC' superfamily of transporters. Nature 348: 741-744, 1990. [PubMed: 2259383] [Full Text: https://doi.org/10.1038/348741a0]
van Endert, P. M., Lopez, M. T., Patel, S. D., Monaco, J. J., McDevitt, H. O. Genomic polymorphism, recombination, and linkage disequilibrium in human major histocompatibility complex-encoded antigen-processing genes. Proc. Nat. Acad. Sci. 89: 11594-11597, 1992. [PubMed: 1360671] [Full Text: https://doi.org/10.1073/pnas.89.23.11594]