Endocrine Abstracts (2009) 20 S3.2

ACTH insensitivity syndromes

Adrian Clark, Claire Hughes & Louise Metherell

Barts and the London School of Medicine, London, UK.

ACTH insensitivity or familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder first described in 1959. We demonstrated in 1993 that about 25% of affected patients have nonsense or (more commonly) missense mutations in the ACTH receptor (melanocoprtin 2 receptor, MC2R). Functional analysis of these mutations had been especially difficult until our discovery in 2005 that the receptor requires an essential accessory factor – the melanocortin 2 receptor accessory protein (MRAP) for membrane trafficking and signal generation. Furthermore, mutations in MRAP account for about 20% of FGD patients. Availability of MRAP enables the development of efficient MC2R functional assays and it emerges that the majority of naturally occurring MC2R missense mutations result in failure of receptor trafficking and cell surface expression. A further group of patients have a form of FGD that was linked to a gene on chromosome 8 following a whole genome mapping strategy in 2002. Recently we have shown that this gene is that encoding StAR. The StAR protein is responsible for the transport of cholesterol across the mitochondrial membrane and is the first step in steroidogenesis. Typically mutations in StAR result in congenital lipoid adrenal hyperplasia. However certain mutations result in a StAR protein that retains some function, and consequently gonadal steroidogenesis is unaffected while adrenal glucocorticoid production is compromised, resulting in an FGD phenotype. In about 50% of FGD patients there is no defect in any of these genes, and further genetic loci remain to be identified.

Article tools

My recent searches

No recent searches.

My recently viewed abstracts