Alternative titles; symbols
HGNC Approved Gene Symbol: FKBP5
Cytogenetic location: 6p21.31 Genomic coordinates (GRCh38): 6:35,573,590-35,728,583 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.31 | {Major depressive disorder and accelerated response to antidepressant drug treatment} | 608516 | 3 |
For background information on FK506-binding proteins (FKBPs), see FKBP1A (186945).
Nair et al. (1997) cloned a cDNA for human FKBP51 from a HeLa cell cDNA library. The FKBP51 cDNA encodes a predicted 457-amino acid polypeptide with 90% identity to mouse fkbp51 and 55% identity to FKBP52 (600611). Baughman et al. (1997) cloned a cDNA encoding human FKBP51 by screening a human thymus cDNA library with a fragment of the murine Fkbp51 cDNA. The human FKBP51 cDNA encodes a deduced 457-amino acid protein that shows 87% sequence identity to the mouse protein. Northern blot analysis revealed that treatment of leukemic T cells with glucocorticoids results in a marked increase in expression of a 3.7-kb transcript. Western blot analysis showed that unlike the predominant T-cell expression of the mouse protein, FKBP51 is expressed as a 51-kD protein in a variety of tissues but not in brain, colon, or lung. The expression is frequently in molar excess of that of FKBP12 (FKBP1A; 186945), but its capacity to inhibit calcineurin is significantly lower than that of FKBP1A.
Baughman et al. (1995) and Yeh et al. (1995) cloned and characterized the mouse Fkbp51 gene. Baughman et al. (1995) isolated the gene based on its induction during glucocorticoid-induced apoptosis in murine thymoma cells. Murine Fkbp51 encodes a 456-amino acid polypeptide with a predicted mass of 51 kD. Yeh et al. (1995) isolated the mouse gene based on the selective accumulation of its transcript during adipocyte differentiation. By Northern blot analysis, the gene is expressed in a variety of tissues, with highest levels in liver, skeletal muscle, and kidney.
International Radiation Hybrid Mapping Consortium mapped the FKBP51 gene to chromosome 6 (RH47153).
By Western blot analysis, Baughman et al. (1995) showed that the murine Fkbp51 gene is expressed in all tissues, most abundantly in T lymphocytes and in the thymus. Baughman et al. (1995) showed that FKBP5 has PPIase activity and is inhibited by rapamycin and FK520, a structural analog that is virtually identical to FK506. Yeh et al. (1995) showed that the PPIase activity of murine Fkbp51 is inhibited by FK506 but not by cyclosporin A.
Nair et al. (1997) showed that FKBP51 is inhibited by FK506 but not by cyclosporine. The authors demonstrated that FKBP51 and FKBP52 bind to Hsp90 (140571) in a competitive manner. Nair et al. (1997) also showed that Hsp90, Hsp70 (140550), and p23 (607061), a component of the progesterone receptor complex, bind directly or indirectly to FKBP51.
Vermeer et al. (2003) studied whether the glucocorticoid-induced increase of the mRNA encoding FKBP5 could be used for the development of a novel assay, ultimately to be used in native human peripheral blood mononuclear cells (PBMCs). Glucocorticoid addition to human lymphoblastoid cells resulted in a dose-dependent increase of FKBP5 mRNA levels within 2 hours, followed by a further increase until 24 hours. Northern blot analysis and real-time PCR yielded similar results. Coincubation of glucocorticoids with the glucocorticoid receptor (138040) antagonist ORG34116 or the protein synthesis inhibitor cycloheximide suggested a direct, glucocorticoid receptor-mediated upregulation of FKBP5 gene transcription. They concluded that the induction of FKBP5 mRNA by glucocorticoids may be a suitable marker to assess individual glucocorticoid sensitivity, the in vitro measurement of glucocorticoid potency, and the in vivo determination of glucocorticoid bioavailability.
Using gene expression microarrays, Woodruff et al. (2007) found that CLCA1 (603906), periostin (POSTN; 608777), and SERPINB2 (PAI2; 173390) were upregulated in airway epithelial cells of individuals with asthma (see 600807), but not smokers. Corticosteroid treatment downregulated expression of these 3 genes and upregulated expression of FKBP51. High baseline expression of CLCA1, POSTN, and SERPINB2 was associated with a good clinical response to corticosteroids, whereas high expression of FKBP51 was associated with a poor response.
Tissing et al. (2007) found that 8 hours of prednisolone treatment altered expression of 51 genes in leukemic cells from children with precursor-B- or T-acute lymphoblastic leukemia compared with nonexposed cells. The 3 most highly upregulated genes were FKBP5, ZBTB16 (176797), and TXNIP (606599), which were upregulated 35.4-, 8.8-, and 3.7-fold, respectively.
Attwood et al. (2011) demonstrated in mice that the serine protease neuropsin (605644) is critical for stress-related plasticity in the amygdala by regulating the dynamics of the EphB2 (600997)-NMDA receptor interaction, the expression of Fkbp5, and anxiety-like behavior. Stress results in neuropsin-dependent cleavage of EphB2 in the amygdala, causing dissociation of EphB2 from the NR1 (138249) subunit of the NMDA receptor and promoting membrane turnover of EphB2 receptors. Dynamic EphB2-NR1 interaction enhances NMDA receptor current, induces Fkpb5 gene expression, and enhances behavioral signatures of anxiety. On stress, neuropsin-deficient mice do not show EphB2 cleavage and its dissociation from NR1, resulting in a static EphB2-NR1 interaction, attenuated induction of the Fkbp5 gene, and low anxiety. The behavioral response to stress can be restored by intraamygdala injection of neuropsin into neuropsin-deficient mice and disrupted by the injection of either anti-EphB2 antibodies or silencing the Fkbp5 gene in the amygdala of wildtype mice. Attwood et al. (2011) concluded that their findings established a novel neuronal pathway linking stress-induced proteolysis of EphB2 in the amygdala to anxiety.
The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression (608516). To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, Binder et al. (2004) genotyped single-nucleotide polymorphisms (SNPs) in 8 of these genes in depressed individuals and matched controls. They found significant associations of response to antidepressants and the recurrence of depressive episodes with SNPs in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp90 (see 140571), in 2 independent samples. These SNPs were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. Binder et al. (2004) proposed that the FKBP5 variant-dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this group of depressed individuals. These findings supported a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.
In 294 individuals with major depressive disorder (608516) and 339 matched controls, Binder et al. (2004) found that individuals homozygous for the T allele of a C/T polymorphism in the FKBP5 gene, rs1360780, had an accelerated response to antidepressants over 5 weeks of treatment. The responses of CT heterozygotes and CC homozygotes were significantly slower than those of TT homozygotes and were almost identical to each other. The authors also found that individuals with the TT genotype had experienced more than twice as many depressive episodes before the index episode, suggesting that these individuals have more lifetime depressive episodes in addition to their faster response to antidepressant drugs.
Attwood, B. K., Bourgognon, J.-M., Patel, S., Mucha, M., Schiavon, E., Skrzypiec, A. E., Young, K. W., Shiosaka, S., Korostynski, M., Piechota, M., Przewlocki, R., Pawlak, R. Neuropsin cleaves EphB2 in the amygdala to control anxiety. Nature 473: 372-375, 2011. [PubMed: 21508957] [Full Text: https://doi.org/10.1038/nature09938]
Baughman, G., Wiederrecht, G. J., Campbell, N. F., Martin, M. M., Bourgeois, S. FKBP51, a novel T-cell-specific immunophilin capable of calcineurin inhibition. Molec. Cell. Biol. 15: 4395-4402, 1995. [PubMed: 7542743] [Full Text: https://doi.org/10.1128/MCB.15.8.4395]
Baughman, G., Wiederrecht, G. J., Chang, F., Martin, M. M., Bourgeois, S. Tissue distribution and abundance of human FKBP51, an FK506-binding protein that can mediate calcineurin inhibition. Biochem. Biophys. Res. Commun. 232: 437-443, 1997. [PubMed: 9125197] [Full Text: https://doi.org/10.1006/bbrc.1997.6307]
Binder, E. B., Salyakina, D., Lichtner, P., Wochnik, G. M., Ising, M., Putz, B., Papiol, S., Seaman, S., Lucae, S., Kohli, M. A., Nickel, T., Kunzel, H. E., and 27 others. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nature Genet. 36: 1319-1325, 2004. [PubMed: 15565110] [Full Text: https://doi.org/10.1038/ng1479]
Nair, S. C., Rimerman, R. A., Toran, E. J., Chen, S., Prapapanich, V., Butts, R. N., Smith, D. F. Molecular cloning of human FKBP51 and comparisons of immunophilin interactions with Hsp90 and progesterone receptor. Molec. Cell. Biol. 17: 594-603, 1997. [PubMed: 9001212] [Full Text: https://doi.org/10.1128/MCB.17.2.594]
Tissing, W. J. E., den Boer, M. L., Meijerink, J. P. P., Menezes, R. X., Swagemakers, S., van der Spek, P. J., Sallan, S. E., Armstrong, S. A., Pieters, R. Genomewide identification of prednisolone-responsive genes in acute lymphoblastic leukemia cells. Blood 109: 3929-3935, 2007. [PubMed: 17218380] [Full Text: https://doi.org/10.1182/blood-2006-11-056366]
Vermeer, H., Hendriks-Stegeman, B. I., van der Burg, B., van Buul-Offers, S. C., Jansen, M. Glucocorticoid-induced increase in lymphocytic FKBP51 messenger ribonucleic acid expression: a potential marker for glucocorticoid sensitivity, potency, and bioavailability. J. Clin. Endocr. Metab. 88: 277-284, 2003. [PubMed: 12519866] [Full Text: https://doi.org/10.1210/jc.2002-020354]
Woodruff, P. G., Boushey, H. A., Dolganov, G. M., Barker, C. S., Yang, Y. H., Donnelly, S., Ellwanger, A., Sidhu, S. S., Dao-Pick, T. P., Pantoja, C., Erle, D. J., Yamamoto, K. R., Fahy, J. V. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc. Nat. Acad. Sci. 104: 15858-15863, 2007. [PubMed: 17898169] [Full Text: https://doi.org/10.1073/pnas.0707413104]
Yeh, W.-C., Li, T.-K, Bierer, B. E., McKnight, S. L. Identification and characterization of an immunophilin expressed during the clonal expansion phase of adipocyte differentiation. Proc. Nat. Acad. Sci. 92: 11081-11085, 1995. [PubMed: 7479941] [Full Text: https://doi.org/10.1073/pnas.92.24.11081]