Trends in Endocrinology & Metabolism
Inherited ACTH insensitivity illuminates the mechanisms of ACTH action
Introduction
Defects in the pituitary–adrenal axis are potentially fatal if untreated. This is particularly true for syndromes of adrenal failure, including Addison's disease and inherited forms of adrenocorticotrophin (ACTH) insensitivity, such as the familial glucocorticoid deficiencies and triple A syndrome. The triple A syndrome is a complex disorder that includes several non-endocrine components and will not be reviewed in detail here, although key aspects are indicated in Box 1. Work over the past decade has shown that although familial glucocorticoid deficiency (FGD) is genetically heterogeneous, it might result from defective functioning of the ACTH receptor, or defective trafficking of this receptor to the cell surface.
In general, understanding of the mechanisms of G-protein-coupled receptor (GPCR) trafficking and folding is poor, and important aspects of this phenomenon will probably be revealed by investigation of genetic disorders of receptor expression, such as the ACTH insensitivity syndromes. This review will focus on some unresolved clinical aspects of these syndromes and recent advances in understanding of the genetic defects underlying them.
Section snippets
Familial glucocorticoid deficiency
First described over 40 years ago, FGD (also known as isolated glucocorticoid deficiency or hereditary unresponsiveness to ACTH; OMIM# 202200) is an autosomal recessive syndrome characterized by cortisol deficiency despite a high plasma ACTH and a preserved renin–aldosterone axis 1, 2 (reviewed in [3]). There is considerable phenotypic variation within this definition. Although many cases present in the neonatal period and can have undetectable circulating cortisol, others pass unrecognized
Tall stature
An unusual feature of FGD is that some patients are unusually tall and have advanced or dissociated bone age 16, 17. A typical growth chart is shown in Figure 2. There might be a higher frequency of this phenomenon in those patients with MC2R mutations [3], but there are clearly some patients without demonstrable mutations in this receptor who also exhibit this feature.
There is no obvious explanation for this phenomenon. In one small study there was no disturbance of growth hormone or
High ACTH
Another common observation in FGD patients on replacement with glucocorticoids is that plasma ACTH often remains markedly raised despite normal or even supranormal glucocorticoid treatment. This often results in patients remaining pigmented and the suspicion that they are not complying with therapy, so that the physician might be tempted to increase the glucocorticoid dose or change the treatment regimen to suppress ACTH. This tactic will lead to iatrogenic Cushing's syndrome and, in children,
MC2R promoter variants
An aspect of MC2R function that might be of clinical significance is the finding that a single nucleotide polymorphism close to the transcription initiation site of the MC2R gene appears to impair expression of this gene [29]. These authors demonstrated that the rare −2C allele (present in 10%) was associated with reduced basal and forskolin-stimulated luciferase activity in MC2R–luciferase transfected cells compared with the wild-type −2T allele. A reduced cortisol response to ACTH stimulation
Genetic heterogeneity in FGD
MC2R coding region mutations have been detected in only ∼25% of families with one or more members affected by FGD, and in many cases the disease does not map genetically to the MC2R locus on chromosome 18p11.2, indicating that this is a genetically heterogeneous disease 30, 31. The name FGD type 2 has been proposed for these alternative genetic forms [32]. In an attempt to identify alternative genetic loci we performed a microsatellite-based whole genome search on several of these families with
FGD type 2 and MRAP
Recent work has identified the gene encoding a small single transmembrane domain protein now known as melanocortin 2 receptor accessory protein (MRAP) as one of the other genes underlying FGD type 2. MRAP had formerly been identified as a protein spot on two dimensional gel electrophoresis, which was induced when NIH3T3-L1 cells differentiated into adipocytes [34]. It was named fat-associated low molecular weight protein at that time, although its functional role was not clear. Interestingly,
Receptor accessory proteins: a growing family
An inevitable question that arises is whether MRAP functions with MC2R in a similar manner to that with which the receptor activity modifying proteins (RAMPs) facilitate and modify the calcitonin-like receptor (CLR). RAMPs are a group of three related single transmembrane domain proteins that are required for CLR, a class 2 GPCR, to act as a calcitonin gene-related peptide (CGRP) receptor (RAMP1), or adrenomedullin receptor (RAMP2 and 3) 38, 39. It appears that these proteins assist in
Summary
The study of FGD, a rare autosomal recessive disease, has revealed various inactivating mutations of the MC2R and the difficulties in expressing this receptor. Recently, it has led to the discovery of a novel gene whose product appears to work by enabling cell surface expression of the receptor to occur. Parallels between this protein, MRAP, and other small receptor accessory proteins (RAMPs, RTPs and REEPs) suggest a common theme with certain GPCRs. There are clearly other as yet unidentified
Acknowledgements
Our work on ACTH insensitivity syndromes would not have been possible without the continuing support and assistance of many adult and paediatric endocrinologists and their patients, and for this we are greatly indebted. Our research has been supported by the BBSRC and the Wellcome Trust.
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