Adrenocorticotropin resistance syndromes.

Familial glucocorticoid deficiency (FGD) and triple A syndrome belong to a rare group of autosomal recessive disorders characterized by adrenocorticotropin (ACTH) insensitivity. Unlike triple A syndrome which presents a range of clinical features, FGD is solely characterized by glucocorticoid deficiency. ACTH regulates steroid biosynthesis in the adrenal cortex by exerting its effects via the ACTH receptor (melanocortin- 2 receptor, MC2R). In FGD, mutations in the MC2R account for only approximately 25% of cases (FGD type 1). The inability to express a functional MC2R in non-adrenal cell lines had implied the presence of an adrenal specific accessory factor(s), essential for MC2R expression. More recently, this factor was identified as melanocortin receptor accessory protein (MRAP). Mutations in MRAP account for 20% of cases (FGD type 2). Like the receptor activity-modifying proteins (RAMPs) and receptor transporter proteins (RTPs), which are well-characterized accessory proteins for G-protein-coupled receptors (GPCRs), MRAP is a small single transmembrane domain protein. MRAP is essential for the functional expression of the MC2R. About 55% of FGD cases have no identifiable gene defect, implying the involvement of additional genes. This chapter briefly describes the clinical and biochemical features of ACTH resistance syndromes. However, we will focus on the recent progress made towards understanding the molecular defect underlying these conditions, in particular the interaction of MC2R and MRAP.