Endocrine Abstracts

An intact pituitary-adrenal axis is essential for life, yet is entirely dependent on a system with no inbuilt redundancy. Central to its activity a single peptide hormone, ACTH, acts on a single G protein-coupled receptor (GPCR) at the adrenal cortex. This ACTH receptor, otherwise known as the Melanocortin 2 receptor (MC2R) is the smallest of all GPCRs, consequently being highly hydrophobic and lacking a signal sequence – hence its resemblance to a “blob”. Multi...

It is a widely held view that genetic mutations cause diseases by interfering with the normal function of the protein encoded by the gene in question, and there are many examples of this phenomenon. However it is increasingly apparent that in some cases mutant proteins have altered function because they have failed to assemble correctly, or because they fail to reach the correct compartment of the cell correctly. Recent work investigating certain inherited disorders of the adr...

Adrian Clark, Barts & the London, QMUL, London, United Kingdom. AbstractAdrian Clark graduated in Medicine from St Bartholomew’s Hospital Medical College in 1976. After several junior medical training posts at Barts, Nottingham, Hammersmith and Guys, he spent two years at the NCI in Bethesda working on the cloning of the EGF receptor with Ira Pastan, then later moved to work for three years with Kevin Catt, al...

The melanocortin 2 receptor accessory protein (MRAP) is essential for the functional expression of the ACTH receptor/melanocortin 2 receptor (MC2R). The pituitary hormone ACTH acts via this complex to stimulate glucocorticoid production in the adrenal cortex. Using the bioluminescence resonance energy transfer (BRET) system we investigated the formation of MC2R–MRAP homo/heterodimers in living cells and the influence of ACTH on these interactions. ACTH was found to have a...

Background: The ACTH receptor (melanocortin 2 receptor – MC2R) is unique in that it is highly selective for ACTH and excludes all other MSH peptides. This contrasts with all other members of the melanocortin receptor family, which show broader specificity. The specificity of recognition of ACTH by the MC2R appears to depend on the presence of four basic residues, lysine, lysine, arginine, arginine at positions 15–18. Of α-, β- and γ-MSH are either iden...

Background: Triple A syndrome is a rare, autosomal recessive cause of adrenal insufficiency. Additional features include alacrima, achalasia of the oesophageal cardia, and neurodegenerative disease in 60%. The AAAS gene product is the nuclear pore complex protein ALADIN of unknown function. AAAS patient dermal fibroblasts have been described as hypersensitive to oxidative stress1,2,3.Objective: To establish a better disease model by kno...

Background: Triple A Syndrome is a rare, autosomal recessive cause of adrenal failure that usually manifests in the first decade. Most cases have isolated glucocorticoid deficiency, but this is accompanied by mineralocorticoid deficiency in approximately 10% of cases. Additional features include alacrima (~90%), achalasia of the oesophageal cardia (~75%), and a progressive neurodegenerative process (~60%). The AAAS gene product is the nuclear pore complex protein ALADIN...

Introduction: Triple A syndrome is a rare, autosomal recessive cause of adrenal failure that usually manifests in the first decade. Most cases have isolated glucocorticoid deficiency, but this is accompanied by mineralocorticoid deficiency in ~10%. Additional features include alacrima (~90%), achalasia of the oesophageal cardia (~75%), and a progressive neurodegenerative process (~60%). The AAAS gene product is the nuclear pore complex protein ALADIN of unknown function...

Melanocortin receptor accessory protein (MRAP) is a single transmembrane domain protein, which has been identified as essential for the cell surface trafficking and signalling of the ACTH receptor (melanocortin 2 receptor (MC2R)). MRAP is essential for the function of MC2R, but regulation of its expression remains unclear. This study aims to identify factors regulating MRAP gene expression and whether these factors would affect the signalling of MC2R.The...

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 recepto...