FKBP5 Epialleles

Abstract

Neuroendocrine regulation of the hypothalamic-pituitary-adrenal (HPA) axis relies on the fine-tuned interplay of a multitude of molecular players. The glucocorticoid receptor (GR) takes the central stage in balancing the activity of the HPA axis through its negative feedback on the peptides corticotrophin-releasing hormone and adrenocorticotropic hormone. The activity of GR, in turn, is also controlled by several cofactors including FK506-binding protein 51 (FKBP51) that emerged as potent inhibitory protein of GR. Polymorphisms of its gene FKBP5 have been consistently linked to stress-related diseases such as major depression post-traumatic stress disorder and other neuropsychiatric phenotypes. In addition, recent studies showed that polymorphisms of FKBP5 could also be linked to epigenetic changes evoked in response to stress exposure, giving rise to “epialleles.” Here we present and discuss FKBP5 as stress reactivity gene describing the molecular genetics and epigenetics of FKBP5 and illustrate FKBP5 as a model at the interface of genetics, epigenetics, and neuroendocrinology.