Abstract
The melanocortin-2-receptor (MC2R), also known as the ACTH receptor, is a critical component of the hypothalamic–pituitary–adrenal axis. The importance of MC2R in adrenal physiology is exemplified by the condition familial glucocorticoid deficiency (FGD), a potentially fatal disease characterised by isolated cortisol deficiency. MC2R mutations cause ~25% of cases. The discovery of a MC2R accessory protein MRAP, mutations of which account for ~20% of FGD, has provided insight into MC2R trafficking and signalling. MRAP is a single transmembrane domain accessory protein highly expressed in the adrenal gland and essential for MC2R expression and function. Mouse models helped elucidate the action of ACTH. The Mc2r-knockout (Mc2r−/−) mice was the first mouse model developed to have adrenal insufficiency with deficiencies in glucocorticoid, mineralocorticoid and catecholamines. We recently reported the generation of the Mrap−/− mice which better mimics the human FGD phenotype with isolated glucocorticoid deficiency alone. The adrenal glands of adult Mrap−/− mice were grossly dysmorphic with a thickened capsule, deranged zonation and deranged WNT4/beta-catenin and sonic hedgehog (SHH) pathway signalling. Collectively, these mouse models of FGD highlight the importance of ACTH and MRAP in adrenal progenitor cell regulation, cortex maintenance and zonation.
Highlights
H adrenal physiology is exemplified by the condition familial glucocorticoid deficiency (FGD), ff Melanocortin-2-receptor accessory protein (MRAP) a potentially fatal disease characterised by isolated cortisol deficiency
We recently reported the generation of the Mrap−/− mice which better mimics the human FGD phenotype with isolated glucocorticoid deficiency alone
The adrenal glands of adult Mrap−/− mice were grossly dysmorphic with a thickened capsule, deranged zonation and deranged WNT4/beta-catenin and sonic hedgehog (SHH) pathway signalling
Summary
Much of what we know about MC2R has been through the study of the ACTH resistance syndrome, FGD. Growth velocity falls after the introduction of glucocorticoid replacement, during which plasma ACTH levels often remain high Another clinical feature, absent adrenarche, has been described [27] and, in conjunction with findings that have linked polymorphisms in MC2R with age of onset of adrenarche, highlights the importance of ACTH in the regulation of adrenarche in children [28]. Genetic studies of FGD patients with a normal MC2R identified variants in the C21orf gene These variants would result in a truncation or complete absence of the protein product, which was found to be highly expressed in the adrenal gland and adipose tissue [17]. MRAP in vitro binds and modulates the function of other MCRs [30], it is unclear what physiological relevance this has at present
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