Mutations of the Human Mineralocorticoid Receptor and Targeted Deletion in Model Organisms

Abstract The mineralocorticoid receptor (MR) mediates the action of two adrenal steroid hormones, aldosterone, and cortisol, in many tissues in response to normal physiological change and in response to stress, adaption, or disease states. Aldosterone is a key regulator of cardiovascular homeostasis, and cortisol mediates adaptive responses to stress, both centrally and in the periphery. The MR is a large multidomain intracellular receptor that once activated triggers multiple cytoplasmic signaling pathways and in the nucleus directly regulates target gene expression to change cellular responses. Human MR gene mutations cause forms of pseudohypoaldosteronism-type-1 with prominent renal dysfunction, abnormalities in HPA axis activity, and cognitive behavior and have recently been associated with autism. MR mutations modeled in the mouse and fish are defining tissue-specific functions and molecular mechanisms related to normal function and disease. Future research will define new roles for the MR in the body and provide further detail of MR-activated cellular responses.